Prodrug of norepinephrine reuptake inhibitor and preparation method therefor

Abstract

The present invention relates to a novel prodrug of the active metabolite of atomoxetine. The present invention also relates to a pharmaceutically acceptable salt of the atomoxetine prodrug, a pharmaceutical composition containing same, a combination, or a use thereof. The novel prodrug of the active metabolite of atomoxetine has an effect of treating or preventing attention-deficient / hyperactivity disorder (ADHD), cognitive decline, ischemic stroke of a subject.

Description

Prodrugs of norepinephrine reuptake inhibitors and methods for preparing the same

[0001] The present invention relates to a prodrug of 4-hydroxy atomoxetine (4-OH ATX), a novel active metabolite of atomoxetine.

[0002] The present invention also relates to a pharmaceutically acceptable salt of a prodrug of 4-hydroxy atomoxetine, a pharmaceutical composition, combination or use comprising the same.

[0003] The novel 4-hydroxy atomoxetine prodrug has a therapeutic effect on attention-deficit / hyperactivity disorder (ADHD), cognitive decline, or ischemic stroke in subjects.

[0004] Atomoxetine is a selective norepinephrine reuptake inhibitor (NSRI) and is a representative drug used to treat attention deficit hyperactivity disorder (ADHD) in adults and adolescents.

[0005] Patent Publication No. 2017-0125271 discloses that atomoxetine can effectively prevent neural damage in the CA1 region of the hippocampus, which is known to be sensitive to cerebral ischemia, based on the fact that it has excellent neuroprotective and neuronal apoptosis inhibition abilities and excellent glial cell activation inhibition abilities, and thus can be usefully used to treat, prevent, and improve ischemic stroke.

[0006] Atomoxetine is primarily metabolized in the liver by the CYP2D6 enzyme. CYP2D6 is an enzyme with varying genetic variation, which can lead to individual differences in metabolism. Furthermore, individuals with active CYP2D6 may metabolize atomoxetine rapidly, resulting in lower blood concentrations. Conversely, individuals with inactive or low-functioning CYP2D6 may metabolize atomoxetine more slowly, resulting in higher blood concentrations. This may increase the risk of side effects and, in some cases, may require dosage adjustments.

[0007] Furthermore, when atomoxetine is taken with CYP2D6 inhibitors such as bupropion, paroxetine, fluoxetine, and quinidine, its metabolism is slowed, raising the risk of unexpected effects or side effects. Therefore, when prescribing atomoxetine, it is difficult to consider the patient's CYP2D6 genotype and the potential for interaction with CYP2D6 inhibitors.

[0008] Accordingly, the present inventors have invented a prodrug of a selective norepinephrine reuptake inhibitor with improved storage stability, processability, bioavailability, etc., as a prodrug of 4-hydroxy atomoxetine (4-OH ATX), an active metabolite that is converted by CYP2D6 and exhibits efficacy similar to that of atomoxetine, so that the effect of atomoxetine can be exhibited and related diseases can be treated regardless of CYP metabolism.

[0009] The purpose of the present invention is to provide a prodrug of an active metabolite of atomoxetine with improved storage stability, processability, bioavailability, etc. by providing a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof and a method for preparing the same.

[0010] To achieve the above objectives:

[0011] One aspect of the present invention provides a compound represented by Chemical Formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof.

[0012] Another aspect of the present invention provides a method for preparing a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising a step of deprotecting a compound represented by chemical formula 2.

[0013] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising a compound represented by chemical formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present invention provides a method for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising administering to a subject a compound represented by chemical formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof.

[0015] Another aspect of the present invention provides a use of a compound represented by Chemical Formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

[0016] Another aspect of the present invention provides the use of a compound represented by Chemical Formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof for preparing a medicament for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

[0017] The compound of the present invention provides a 4-hydroxy atomoxetine prodrug, which is an active metabolite of atomoxetine, with improved storage stability, processability, bioavailability, etc., so that it can treat various neurological diseases including attention deficit hyperactivity disorder (ADHD) regardless of CYP metabolism.

[0018] However, the effects of the present invention are not limited to the above-described effects, and should be understood to include all effects that can be inferred from the composition of the invention described in the detailed description or claims of the present invention.

[0019] Figure 1 shows the metabolic pathway of atomoxetine in the body by CYP enzymes.

[0020] Figure 2 shows a method for preparing a compound represented by chemical formula 1 by deprotecting a compound represented by chemical formula 2.

[0021] Figure 3 shows the in vivo pharmacokinetics of the prodrug of the present invention. The P in "-OP" shown in the compound of Figure 3 represents a protecting group.

[0022] Figure 4 is a graph showing the pharmacokinetic results of atomoxetine, 4-hydroxy atomoxetine, and compounds of Examples 1, 2, and 3 of the present invention.

[0023] Figure 5 is a graph showing the results of norepinephrine reuptake inhibition rates of atomoxetine, 4-hydroxy atomoxetine, and compounds of Examples 1, 2, and 3 of the present invention.

[0024] 1. A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical composition, treatment method and use containing the same.

[0025] One aspect of the present invention provides a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0026] [Chemical Formula 1]

[0027]

[0028] In chemical formula 1,

[0029] Z is any one amino acid selected from the group consisting of glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine, or W;

[0030] W is and;

[0031] R is H, halogen, C 1-20 Alkyl, C 1-20 Alkoxy, -OC 1-20 Alkyl, -SC 1-20 Alkyl, C 1-20 Alkenyl, C 1-20 alkynyl, C 3-12 Cycloalkyl, heterocycloalkyl having 3 to 12 ring atoms, C 5-10 Aryl, heteroaryl having 5 to 10 ring atoms, hydroxy (OH), thiol, amine, ester, carboxyl (COOH), or cyano (CN);

[0032] At this time, the amino acid, alkyl, alkenyl, alkynyl and amine are unsubstituted or each independently C 1-20 C substituted with one or more alkyl or halogens 1-20 Alkyl, -OC 1-20 Alkyl, -SC1-20 C substituted with alkyl, ester, or cyano 1-20 Alkyl, C 1-20 Alkyl-substituted amines, carboxyl (COOH), halogen, cyano (CN), and C 1-20 which may be substituted with one or more substituents selected from the group consisting of alkylcarbonyl;

[0033] The above n is an integer from 0 to 20.

[0034] In another aspect of the present invention, Z is C 1-10 An amino acid substituted with an alkylcarbonyl; or wherein Z is W and R is C 1-10 Alkyl, C 3-7 Cycloalkyl, or C 1-10 An amine substituted with an alkyl group, wherein n is 0.

[0035] In the present invention, the alkylcarbonyl group includes an acetyl group. For example, the amino acid may be substituted with an alkylcarbonyl group, and may be alanine, valine, or leucine substituted with an acetyl group.

[0036] Another aspect of the present invention provides a compound represented by chemical formula 1A or a pharmaceutically acceptable salt thereof.

[0037] [Chemical Formula 1A]

[0038]

[0039] In chemical formula 1A,

[0040] The above amino acid is any one amino acid selected from the group consisting of substituted or unsubstituted glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine.

[0041] Another aspect of the present invention provides a compound represented by chemical formula 1B or a pharmaceutically acceptable salt thereof.

[0042] [Chemical Formula 1B]

[0043]

[0044] In chemical formula 1B,

[0045] The above R is H, halogen, C 1-20 C substituted with one or more alkyl or halogens 1-20 Alkyl, -OC 1-20 Alkyl, -SC 1-20 C substituted with alkyl, cyano (CN) 1-20 Alkyl, hydroxy (OH), thiol, C 1-20 Alkyl substituted or unsubstituted amine, ester, carboxyl (COOH), cyano (CN), substituted or unsubstituted C 3-12Cycloalkyl, substituted or unsubstituted heterocycloalkyl having 3 to 12 ring atoms, substituted or unsubstituted C 5-10 Aryl, or substituted or unsubstituted heteroaryl having 5 to 10 ring atoms; wherein n is an integer from 0 to 20.

[0046] Another aspect of the present invention provides a compound represented by chemical formula 1C or a pharmaceutically acceptable salt thereof.

[0047] [Chemical Formula 1C]

[0048]

[0049] In chemical formula 1C,

[0050] A is , or And,

[0051] R2 is hydrogen, C 1-20 C substituted with one or more alkyl or halogens 1-20 Alkyl, -OC 1-20 Alkyl, -SC 1-20 C substituted with alkyl, ester, or cyano 1-20 Alkyl, C 1-20 Amine substituted with alkyl, carboxyl (COOH), halogen or cyano (CN).

[0052] In the present invention, the term "alkyl" means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, or 1 to 4 carbon atoms (if the number of carbon atoms is not particularly limited). Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, and saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-deethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.

[0053] In this specification “ 1-6 ” or “1 to C6” means that the number of carbon atoms is 1 to 6. For example, C 1-6 Alkyl refers to alkyl having 1 to 6 carbon atoms.

[0054] As used herein, the terms “halogen” and “halo” mean fluorine, chlorine, bromine or iodine.

[0055] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. In the present invention, the cycloalkyl may contain 3 to 20 ring atoms, preferably 3 to 15 ring atoms, and more preferably 3 to 12 or 3 to 7 ring atoms.

[0056] An example of a cycloalkyl group is C3-C 20 Cycloalkyl, C3-C 15 Cycloalkyl, C3-C 12 Cycloalkyl or C3-C7 cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl group may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic or bicyclic ring.

[0057] The term "substitution" as used herein may occur one or more times in each case, and is used as a concept including substitution with a side chain.

[0058] As used herein, "heterocycle" means a monocyclic or bicyclic ring having 3 to 20 ring atoms, saturated or unsaturated, containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a monocyclic or bicyclic ring having 3 to 15 ring atoms, or a monocyclic or bicyclic ring having 3 to 12 ring atoms. Alternatively, it means a monocyclic, saturated or unsaturated, or bicyclic, heterocyclic ring having 5 to 7 ring atoms, saturated or unsaturated, or 7 to 10 ring atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized, including a bicyclic ring in which some of the heterocycles are fused to a benzene ring. The heterocycles may be connected via heteroatoms or carbon atoms. Representative heterocycles include heterocycloalkyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiphenyl, tetrahydrothypyranyl, tetrahydrothiopyrimidinyl.

[0059] The term "aryl" as used herein refers to a carbon-cyclic aromatic group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, xylyl, naphtyl, tetrahydronaphtyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The carbon-cyclic aromatic group may be optionally substituted.

[0060] As used herein, "heteroaryl" is an aromatic heterocycle having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and having 3 to 20 ring atoms, preferably 3 to 15 ring atoms, more preferably 5 to 10 ring atoms, including mono- and bicyclic ring systems, and including at least one carbon atom. Representative heteroaryls include triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, These are pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanil, thietanyl, and oxazolyl.

[0061] In another aspect of the present invention, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be any one selected from the group below, but is not limited thereto.

[0062] Example 1 (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate 2(R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate 3(R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate 4(R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate 5(R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate 63-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaninate 73-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate 83-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate

[0063] The term "purified" as used herein means that the isolate is at least 90% pure when isolated, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and in yet another embodiment at least 99.9% pure.

[0064] In the present invention, the compound of the present invention can provide 4-OH ATX (4-hydroxy atomoxetine), which is an active metabolite of atomoxetine, by an enzyme.

[0065] In the present specification, chemical formula 2 represents 4-hydroxy atomoxetine in which the nitrogen is protected by a Boc (tert-butoxycarbonyl) group.

[0066] In the present invention, the CYP2D6 enzyme is a type of CYP enzyme (Cytochrome P450), which is mainly involved in drug metabolism, has a great influence on the drug's body kinetics, and plays an important role in indicating the drug's efficacy and toxicity. The main enzymes involved in drug metabolism include CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and the abundance ratio of each CYP enzyme varies depending on race, etc. Among them, CYP2D6 is a highly polymorphic gene, and more than 80 variant alleles are known to date.

[0067] CYP2D6*3, *4, *5, *6, *7, and *14 alleles are expressed as PM (Poor Metabolizer) genotypes with no enzyme activity or inability to produce the enzyme. CYP2D6*10 and *17 alleles have reduced enzyme activity and are expressed as IM (Intermediate Metabolizer), *1 and *2 are expressed as EM (Extensive Metabolizer), and CYP2D6*2×N and *4×N are expressed as UM (Extensive Metabolizer) with enhanced metabolism.

[0068] About 7 to 10% of Westerners and about 1% of Asians have the PM trait. Among PM, about 12 to 21% of Westerners have the CYP2D6*4 allele, and about 4 to 6% have the CYP2D6*5 allele. In Asians, the CYP2D6*5 genotype appears at about 6.2%, and the CYP2D6*4 genotype appears at a low rate of less than 1%. In particular, the CYP2D6*10 allele appears at a frequency of about 33 to 50% in Asians, and in African Americans, PM appears at a rate of 1.9%, and about 9 to 35% have the CYP2D6*17 allele. Additionally, several overlapping alleles expressed as UM have been reported, and 2D6*2×2 or *4×2 are known as representative UM alleles, which appear at a rate of about 1 to 10% in Westerners and a relatively high rate of about 30% in Africans.

[0069] Atomoxetine has different pharmacokinetic profiles and adverse drug reactions depending on the CYP2D6 genotype. In the case of the PM trait of CYP2D6 or when co-administered with CYP2D6 inhibitors such as bupropion, paroxetine, fluoxetine, and quinidine, dosage adjustment is required. Atomoxetine, which has these characteristics, is mainly metabolized by CYP2D6 (Figure 1).

[0070] In the case of PM type of CYP2D6, the metabolism of atomoxetine is inhibited, Cmax (Maximum concentration) increases 5-fold, AUC (Area Under the Curve) increases 10-fold, and the drug half-life, which is usually 5 hours, is prolonged to 24 hours. In the case of EM of CYP2D6, when taken together with a CYP2D6 inhibitor, the steady-state blood concentration was similar to that of CYP2D6 PM, AUC increased 6 to 8-fold, and Css (Steady-State Concentration) and Cmax increased about 3 to 4-fold.

[0071] Concomitant treatment with CYP2D6 inhibitors, such as bupropion, paroxetine, fluoxetine, or quinidine, increases plasma atomoxetine levels by more than 100%. It also increases the levels of N-dimethyl atomoxetine (N-DM-ATX), which has little pharmacological activity and is primarily responsible for adverse effects, and decreases the plasma levels of 4-hydroxy atomoxetine (4-OH ATX), which has a similar degree of activity to atomoxetine, to a similar degree.

[0072] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction, or ischemic stroke, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0073] In the present invention, the “cognitive dysfunction” may be any one selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, agnosia, aphasia, apraxia, and mild cognitive impairment.

[0074] In the present invention, the pharmaceutical composition can be administered in the form of a suitable pharmaceutical composition through any suitable route, and in an effective dosage for the intended treatment.

[0075] An effective dosage is generally about 0.001 to about 100 mg / kg body weight / day, preferably about 0.5 to about 30 mg / kg / day, in single or divided doses.

[0076] Depending on age, species, and the disease or condition being treated, dosage levels below the lower end of this range may be appropriate. Alternatively, higher dosages may be used without harmful side effects. Larger dosages may be divided into several smaller doses for administration throughout the day. Methods for determining appropriate dosages are well known in the art.

[0077] In the present invention, the pharmaceutical composition can be administered orally or topically.

[0078] (1) Oral administration

[0079] The compounds of the present invention may be administered orally, including by swallowing. Oral administration may cause the compounds of the present invention to enter the gastrointestinal tract, or, for example, may be absorbed directly into the bloodstream through the mouth, as in buccal or sublingual administration.

[0080] Suitable compositions for oral administration may be in the form of solids, liquids, gels, or powders, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0081] Compositions for oral administration may optionally be enteric coated, and may exhibit delayed or sustained release through the enteric coating. That is, the compositions for oral administration according to the present invention may be formulations having an immediate or modified release pattern.

[0082] In a tablet formulation, the amount of the active ingredient drug may be present in an amount of from about 0.05% to about 95% by weight of the total weight of the tablet, or from about 2% to about 50% by weight of the formulation. Additionally, the tablet may contain a disintegrant, which comprises from about 0.5% to about 35% by weight of the formulation, or from about 2% to about 25% by weight of the formulation.

[0083] Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. can be used as a binder for manufacturing into tablets, and mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. can be used as a suitable diluent for manufacturing into tablets, but the present invention is not limited to the types of these additives.

[0084] (2) Local administration

[0085] The compounds of the present invention can be administered topically, either skin-wise or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be accomplished by electroporation, iontophoresis, phonophoresis, and the like.

[0086] Compositions for topical administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or sustained release pattern.

[0087] Another aspect of the present invention provides a method for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction, or ischemic stroke, comprising administering to a subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0088] Another aspect of the present invention provides a use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

[0089] Another aspect of the present invention provides a use of the compound of the present invention or a pharmaceutically acceptable salt thereof for preparing a medicament for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

[0090] The contents of the pharmaceutical composition of the present invention can be equally applied to the above preventive or therapeutic methods, uses and uses for manufacturing medicines.

[0091] For example, with respect to the above treatment methods, uses and uses for manufacturing the medicament, “cognitive impairment” may be any one selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, agnosia, aphasia, apraxia and mild cognitive impairment.

[0092] 2. Method for producing a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof

[0093] One aspect of the present invention provides a method for preparing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising a step of deprotecting a compound represented by the following chemical formula 2 (tert-butyl(R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate).

[0094] [Chemical Formula 1]

[0095]

[0096] [Chemical Formula 2]

[0097]

[0098] Deprotection of the Boc protecting group of the nitrogen in the above chemical formula 2 represents a reaction that can be easily performed by a person skilled in the art using known techniques.

[0099] The N-Boc 4-OH ATX of the above chemical formula 2 used in the examples for preparing the compound of the present invention was prepared with reference to the reference document WO 2011 / 027359.

[0100] In the present invention, when manufactured using the manufacturing method according to the present invention, it has excellent advantages. More specifically, the present invention can provide 4-hydroxy atomoxetine, which is decomposed by the enzyme esterase in the body and exhibits a norepinephrine reuptake inhibitory effect, and has the advantage of being able to be metabolized regardless of CYP genotype while exhibiting a norepinephrine reuptake inhibitory effect.

[0101] 4-Hydroxyatomoxetine has a pharmacological activity similar to that of the parent drug, atomoxetine, but it is a highly viscous liquid and has poor processing and stability when formulated as an active drug.

[0102] In contrast, the materials of the examples manufactured according to the present invention are all solids, exhibiting excellent stability and processability. Furthermore, the compounds of the present invention exhibit improved photostability by introducing a protecting group to the OH group at the phenyl terminal, which is the primary cause of poor photostability. Furthermore, the compounds exhibit improved bioavailability by allowing the drug to act through enzymes in the body after administration, improving patient convenience in taking the drug by exhibiting sustained-release pharmacokinetics. Furthermore, the compounds are better distributed to brain tissue, the site of drug action, resulting in superior efficacy.

[0103] Another aspect of the present invention provides a manufacturing method comprising using any one compound selected from the group consisting of: deprotection;

[0104] a b c d e f g h

[0105] Hereinafter, the present invention will be described in more detail through examples and experimental examples. The following examples and experimental examples are described for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0106]

[0107] Manufacturing Example 1: Manufacturing of an intermediate for manufacturing a compound of chemical formula 1

[0108] A compound represented by chemical formula 2 was prepared as follows, and based on this, a compound represented by chemical formula 1 was prepared as described in the examples below.

[0109]

[0110] Step 1: Synthesis of tert-butyl (R)-(3-(4-acetyl-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate

[0111]

[0112] Tert-Butyl (R)-(3-hydroxy-3-phenylpropyl)(methyl) (20 g, 75.37 mmol, obtained from EOS) was dissolved in dimethylacetamide (300 ml, purchased from Aldrich), 5N sodium hydroxide solution (53.78 ml, 1.2 eq) was added, and the mixture was stirred at 5–20°C. 4-Fluoro-3-methyl acetophenone (20.37 g, 1.2 eq, 90.45 mmol, obtained from Sigma Aldrich) was added, and the mixture was stirred at 25–35°C for 12 hours. The pH was adjusted to pH 3–5 using acetic acid (obtained from Sigma Aldrich), and ethyl acetate (300 ml*3 times, obtained from Sigma Aldrich) was added, stirred for more than 1 hour, and extracted. Ammonium hydroxide solution was added to the extract and stirred at room temperature for more than 1 hour to perform extraction. The extract was concentrated under reduced pressure to obtain 23.41 g (yield: 78%) of tert-butyl (R)-(3-(4-acetyl-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate as a pale yellow solid compound.

[0113]

[0114] Step 2: Synthesis of tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (Formula 2)

[0115]

[0116] Tert-butyl (R)-(3-(4-acetyl-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (20 g, 50.31 mmol) prepared in Step 1 above was added to toluene (200 ml, obtained from Sigma Aldrich) and stirred at 50-55°C for more than 1 hour. After confirming dissolution, triethylamine (6.11 g, 60.37 mmol, obtained from Sigma Aldrich) was added, and the temperature was increased to 60-65°C and stirred for more than 2 hours. Thereafter, the temperature was increased to 80-85°C and stirred for an additional 10 minutes.

[0117] The reaction solution was concentrated under reduced pressure to obtain a residue. Methanol (100 ml, obtained from Sigma Aldrich) was added to the residue, and the mixture was stirred at 40-60°C for more than 10 minutes. Then, an ammonium hydroxide solution (obtained from Sigma Aldrich) was added and the mixture was stirred at 40-60°C for more than 17 hours. An aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 2-2.4, and ethyl acetate (200 ml x 3, obtained from Sigma Aldrich) was added and stirred for more than 1 hour to perform extraction. An ammonium hydroxide solution was added to the extract to adjust the pH to 10-11, and the mixture was extracted by stirring at room temperature for more than 1 hour. An aqueous hydrochloric acid solution was added to the extract to adjust the pH to 1-1.2, and the mixture was extracted by stirring at room temperature for more than 1 hour. The extract was concentrated under reduced pressure to obtain 14.98 g (yield: 80.6%) of a pale yellow solid compound.

[0118] 1H NMR δ: 8.91(s, 1H), 7.32-7.25(m, 5H), 7.01(d, 1H), 6.74-6.70(m, 2H), 4.88(t, 1H), 3.26(s, 3H), 2.53(t, 2H), 2.24(q, 2H), 2.12(s, 3H)

[0119]

[0120] Example: Preparation of a compound of chemical formula 1

[0121] From the compound of chemical formula 2 prepared in Manufacturing Example 1, a compound represented by chemical formula 1 was prepared according to Examples 1 to 8 below.

[0122]

[0123] Example 1: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate

[0124]

[0125] Dichloromethane (4.25 ml) and triethylamine (0.23 g, 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, acetyl chloride (0.22 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

[0126] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (Samjeon Pure Chemical Industry Co., Ltd.) (15% MC:MeOH) to obtain 0.58 g (yield: 80%) of a white solid compound.

[0127] 1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.53(t, 2H), 2.31(s, 2H), 2.24(q, 2H), 2.12(s, 3H)

[0128]

[0129] Example 2: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate

[0130]

[0131] Dichloromethane (4.25 ml) and triethylamine (0.23 g, 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, propanoyl chloride (0.35 g, 3.78 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

[0132] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.60 g (yield: 80%) of a white solid compound.

[0133] 1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.61-2.53(m, 4H), 2.24(q, 2H), 2.12(s, 3H), 1.28(t, 3H)

[0134]

[0135] Example 3: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate

[0136]

[0137] Dichloromethane (4.25 ml) and triethylamine (0.23 g 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, isobutyryl chloride (0.29 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

[0138] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.61 g (yield: 78%) of a white solid compound.

[0139] 1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.55-2.53(m, 3H), 2.24(q, 2H), 2.12(s, 3H), 1.19(d, 6H)

[0140]

[0141] Example 4: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate

[0142]

[0143] Dichloromethane (4.25 ml) and triethylamine (0.23 g 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, cyclopropanecarbonyl chloride (0.29 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction mixture to terminate the reaction, and the organic layer was extracted.

[0144] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.54 g (yield: 69%) of a white solid compound.

[0145] 1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.53(t, 3H), 2.24(q, 2H), 2.12(s, 3H), 1.61(m, 1H), 1.12-0.86(m, 4H)

[0146]

[0147] Example 5: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate

[0148]

[0149] Dichloromethane (4.25 ml) and triethylamine (0.23 g 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, dimethylcarbamoyl chloride (0.30 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

[0150] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.49 g (yield: 62%) of a white solid compound.

[0151] 1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.27(s, 6H), 3.26(s, 3H), 2.53(t, 3H), 2.24(q, 2H), 2.12(s, 3H)

[0152]

[0153] Example 6: Synthesis of 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaniate

[0154]

[0155] To tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.30 g, 0.81 mmol) was added dichloromethane (6.0 ml), acetyl-L-alanine (0.12 g, 0.89 mmol), and 4-dimethylaminopyridine (0.02 g, 0.20 mmol), followed by adding 1-ethyl-3-carbodiimide hydrochloride (0.23 g, 1.21 mmol), and the mixture was stirred at room temperature for 3 hours. Afterwards, water (6.0 ml) was added to terminate the reaction, and the aqueous layer was removed.

[0156] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.28 g, 2.42 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.06 g (yield: 19%) of a colorless viscous substance.

[0157] 1H NMR δ: 8.51(d, 1H), 7.32-7.25(m, 5H), 6.50-6.37(m, 3H), 5.11(t, 1H), 4.40-4.06(m,1H), 2.96(s,1H), 2.74(s, 3H), 2.18(s, 3H), 2.05-1.85(m, 2H), 1.83(s, 3H), 1.30-1.14(m, 5H)

[0158]

[0159] Example 7: Synthesis of 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate

[0160]

[0161] To tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.30 g, 0.81 mmol) was added dichloromethane (6.0 ml), acetyl-L-valine (0.14 g, 0.89 mmol), and 4-dimethylaminopyridine (0.02 g, 0.20 mmol), followed by adding 1-ethyl-3-carbodiimide hydrochloride (0.23 g, 1.21 mmol), and the mixture was stirred at room temperature for 3 hours. Afterwards, water (6.0 ml) was added to terminate the reaction, and the aqueous layer was removed.

[0162] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.28 g, 2.42 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.08 g (yield: 24%) of a colorless viscous substance.

[0163] 1H NMR δ: 8.32(d, 1H), 7.37-7.25(m, 5H), 6.84-6.72m, 3H), 5.53(t, 1H), 4.25(t,1H), 3.03-2.88(m,2H), 2.54(s, 3H), 2.26(s, 3H), 2.10-1.99(m, 2H), 1.89(s, 3H), 0.96(d, 6H)

[0164]

[0165] Example 8: Synthesis of 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate

[0166]

[0167] To tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.30 g, 0.81 mmol) were added dichloromethane (6.0 ml), acetyl-L-leucine (0.15 g, 0.89 mmol), and 4-dimethylaminopyridine (0.02 g, 0.20 mmol), followed by adding 1-ethyl-3-carbodiimide hydrochloride (0.23 g, 1.21 mmol), and the mixture was stirred at room temperature for 3 hours. Water (6.0 ml) was added to the reaction mixture to terminate the reaction, and the aqueous layer was removed.

[0168] The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.28 g, 2.42 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction mixture to perform extraction. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.07 g (20%) of a colorless viscous substance.

[0169] 1H NMR δ: 8.37 (d, 1H), 7.37-7.25(m, 5H), 6.84-6.72m, 3H), 5.53(t, 1H), 4.25(t,1H), 3.03-2.88(m,2H), 2.54(s, 3H), 2.26(s, 3H), 2.10-1.99(m, 2H), 1.86(s, 3H),1.67-1.59(m, 3H), 0.99-0.91(m, 7H)

[0170]

[0171] Experimental Example 1: Pharmacokinetic Evaluation

[0172] To investigate the absorption, distribution, metabolism, and excretion of drugs in vivo, rats (Coatech Co., Ltd.) (n=3 per group) were purchased and, after a one-week acclimatization period, pharmacokinetic evaluation was conducted. The experiment was conducted in five groups administered orally (atomoxetine, 4-hydroxy atomoxetine, Examples 1, 2, and 3).

[0173] The concentration of drug administration was converted and administered based on the human equivalent dose calculation method, and was set as the ratio of equal molar numbers based on 40 mg / day of atomoxetine. Accordingly, 4.1 mg / kg of atomoxetine, 4.4 mg / kg of 4-hydroxy atomoxetine, 5.0 mg / kg of the compound of Example 1, 5.3 mg / kg of the compound of Example 2, and 5.5 mg / kg of the compound of Example 3 were orally administered.

[0174] The fasting plate was replaced 12 hours before drug administration, and only water was supplied, and the experiment was conducted after 12 hours of fasting. In the oral administration group, a single dose was administered using an oral administration plate. Blood samples were collected before (0 hr) and after administration, and 300 to 400 μl of blood was collected from 10 points through the jugular vein at 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr from the time of administration. After that, the plasma was separated by centrifugation at 3000 × g for 10 minutes and analyzed by LC-MS / MS. The analysis contents and pharmacokinetic results are shown in Tables 3 and 4 below.

[0175] Animal SD rats, 8 weeks old, weight: 180 to 200 g, n=3 Fasting time 12 hr Group 1. Atomoxetine (4.1 mg / kg) 2. 4-hydroxy atomoxetine (4.4 mg / kg) 3. Compound of Example 1 (5.0 mg / kg) 4. Compound of Example 2 (5.3 mg / kg) 5. Compound of Example 3 (5.5 mg / kg) Route of administration Oral Blood sampling Time Before administration: 0 hr After administration: 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr

[0176] Parameter Atomoxetine 4-OH ATX Example 1 Example 2 Example 3t 1 / 2 (hr)4.04 ±2.436.95±0.405.54±0.7813.95±6.4610.03±4.31T max0.33 ±0.180.67±0.240.150.150.60±0.64C max 6.82 ±3.393.71±1.849.68±6.4510.63±7.0315.43±13.13AUC 0-24 (ng / ml*h)13.86 ±1.356.93±0.8812.22±3.3311.11±4.1020.81±12.49AUC 0-inf 25.61 ±0.327.72±0.8613.43±3.5214.38±2.8923.13±13.51Vz / F939.14 ±572.375755.36 ±447.493257.24 ±1153.09788.71±3715.205021.25 ±3569.21CI / F160.13 ±1.99577.08 ±65.45406.46±130.09384.59±80.09387.36 ±279.36

[0177] As a result of oral administration of a total of five compounds of Examples 1, 2, and 3, which are prodrugs of atomoxetine, 4-hydroxy atomoxetine, and 4-hydroxy atomoxetine, the blood half-lives of the compounds of the examples were significantly longer than those of atomoxetine and 4-hydroxy atomoxetine. Example 1 showed a longer half-life than atomoxetine, and Examples 2 and 3 showed half-lives that were 2-fold and 1.4-fold longer than those of 4-hydroxy atomoxetine, respectively.

[0178] For AUC0-24, the compounds of Examples 1 and 2 showed an approximately 2-fold increase compared to 4-hydroxy atomoxetine, and the compound of Example 3 showed an approximately 1.5-fold increase compared to atomoxetine and an approximately 3-fold increase compared to 4-hydroxy atomoxetine.

[0179] As such, all of the compounds of the present invention showed better pharmacokinetic results compared to atomoxetine and / or 4-hydroxy atomoxetine.

[0180]

[0181] Experimental Example 2: Measurement of norepinephrine reuptake inhibition rate (IC50)

[0182] We aimed to determine the norepinephrine reuptake capacity in cell lines expressing the norepinephrine transporter using a kit (Neurotransmitter Transporter Uptake Assay Kit, Molecular Devices) consisting of a fluorescent substance mimicking an amine neurotransmitter and a masking dye.

[0183] HEK-293T cells stably expressing the norepinephrine transporter were seeded in a 96-well Black / Clear Bottom Plate with 6 x 104 cells in 100 μl of cell culture medium per well. After culturing for 20 h in a 37℃5% CO2 incubator to ensure proper attachment and stabilization on the plate, the cell culture medium was removed, and 100 μl of a 20 mM HEPES solution with the drug dissolved at the desired concentration in HBSS+0.1% BSA was dispensed to each well. For the control group, 100 μl was dispensed to each well without dissolving the drug in the same buffer solution. The cells were incubated for 30 min in a 37℃5% CO2 incubator to ensure sufficient reaction of the drug with the transporter.

[0184] Afterwards, fluorescence plate reader (SpectraMax ® ) was used to measure fluorescence for a total of 30 minutes in Kinetic reading mode at Ex / Em=440 nm / 520 nm. The measured fluorescence intensity values ​​were converted to the value of "absorption inhibition rate (%)" using the following formula, and then a dose-response curve was drawn using 4-parameter (Log) logistic regression to obtain the IC of each drug. 50 After calculating the values, they were compared. The inhibition of intracellular norepinephrine reuptake through the antagonistic effect of atomoxetine, 4-hydroxy atomoxetine, and norepinephrine transporters of Examples 1, 2, and 3 was determined through a dose-concentration curve, as shown in the table below. 50The values ​​were calculated and shown in Table 5.

[0185]

[0186] Atomoxetine 4-hydroxy atomoxetine Example 1 Example 2 Example 3 IC 50 (nM)67.46104.9105.476.0172.98

[0187] It was confirmed that the compounds of Examples 2 and 3 exhibited inhibitory activity similar to that of atomoxetine in the degree of norepinephrine reuptake and superior to that of 4-hydroxy atomoxetine. This indicates that the compounds of the examples are easily converted to the active substance, 4-hydroxy atomoxetine, by enzymes in the body.

Claims

1. A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In chemical formula 1, Z is any one amino acid selected from the group consisting of glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine, or W; W is and; R is H, halogen, C1-20 alkyl, C 1-20 Alkoxy, -OC 1-20 Alkyl, -SC 1-20 Alkyl, C 1-20 Alkenyl, C 1-20 alkynyl, C 3-12 Cycloalkyl, heterocycloalkyl having 3 to 12 ring atoms, C 5-10 Aryl, heteroaryl having 5 to 10 ring atoms, hydroxy (OH), thiol, amine, ester, carboxyl (COOH), or cyano (CN); At this time, the amino acid, alkyl, alkenyl, alkynyl and amine are unsubstituted or each independently C 1-20 C substituted with one or more alkyl or halogens 1-20 Alkyl, -OC 1-20 Alkyl, -SC 1-20 C substituted with alkyl, ester, or cyano 1-20 Alkyl, C 1-20 Alkyl-substituted amines, carboxyl (COOH), halogen, cyano (CN), and C 1-20 which may be substituted with one or more substituents selected from the group consisting of alkylcarbonyl; The above n is an integer from 0 to 20.

2. In paragraph 1, A compound represented by chemical formula 1A or a pharmaceutically acceptable salt thereof: [Chemical Formula 1A] In chemical formula 1A, The above amino acid is any one amino acid selected from the group consisting of substituted or unsubstituted glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine.

3. In paragraph 1, A compound represented by chemical formula 1B or a pharmaceutically acceptable salt thereof: [Chemical Formula 1B] In chemical formula 1B, The above R is H, halogen, C 1-20 C substituted with one or more alkyl or halogens 1-20 Alkyl, -OC 1-20 Alkyl, -SC 1-20 C substituted with alkyl, cyano (CN) 1-20 Alkyl, hydroxy (OH), thiol, C 1-20 Alkyl substituted or unsubstituted amine, ester, carboxyl (COOH), cyano (CN), substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted heterocycloalkyl having 3 to 12 ring atoms, substituted or unsubstituted C 5-10 Aryl, or substituted or unsubstituted heteroaryl having 5 to 10 ring atoms; wherein n is an integer from 0 to 20.

4. In paragraph 1, A compound represented by chemical formula 1C or a pharmaceutically acceptable salt thereof: [Chemical Formula 1C] In chemical formula 1C, A is , or And, R2 is hydrogen, C 1-20 C substituted with one or more alkyl or halogens 1-20 Alkyl, -OC 1-20 Alkyl, -SC 1-20 C substituted with alkyl, ester, or cyano 1-20 Alkyl, C 1-20 Amine substituted with alkyl, carboxyl (COOH), halogen or cyano (CN).

5. In paragraph 1, The above Z is C 1-10 An amino acid substituted with an alkylcarbonyl; or The above Z is W, and the above R is C 1-10 Alkyl, C 3-7 Cycloalkyl, or C 1-10 An amine substituted with alkyl, wherein n is 0. A compound or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, A compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is any one selected from the group below: 1) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate; 2) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate; 3) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate; 4) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate; 5) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate; 6) 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaninate; 7) 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate; and 8) 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate.

7. A method for producing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising a step of deprotecting a compound represented by the following chemical formula 2. [Chemical Formula 1] [Chemical Formula 2] 8. In paragraph 7, A manufacturing method comprising using any one compound selected from the group consisting of: , , , , , , and .

9. In any one of paragraphs 1 to 6, A compound or a pharmaceutically acceptable salt thereof, wherein the compound is capable of providing 4-hydroxy atomoxetine, which is an active metabolite of atomoxetine, by an enzyme.

10. A pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction, or ischemic stroke, comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

11. In paragraph 10, A pharmaceutical composition, wherein the cognitive dysfunction is any one selected from the group consisting of Alzheimer's disease, Parkinson's disease, agnosia, aphasia, apraxia, and mild cognitive impairment.

12. In paragraph 10, The pharmaceutical composition above can be administered orally or topically.

13. A method for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction, or ischemic stroke, comprising administering to a subject a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

14. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

15. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction, or ischemic stroke.

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