Phenylamino propanamide derivative and pharmaceutical composition comprising same

Abstract

The present invention relates to a phenylamino propanamide derivative and a pharmaceutical composition comprising same and can be used as an MAO-B inhibitor and for preventing or treating diseases induced by oxidative stress.

Description

Phenylaminopropanamide derivatives and pharmaceutical compositions containing the same

[0001] The present invention relates to a phenylaminopropanamide derivative and a pharmaceutical composition comprising the same, which can be used as an MAO-B inhibitor and for the prevention or treatment of diseases induced by oxidative stress.

[0002] Parkinson's disease (PD) is a progressive disease, the second most common neurodegenerative disorder. It is estimated that approximately 6.3 million people worldwide develop the disease, affecting approximately 1 in 1,000 people. While it typically occurs more frequently in older adults, it is now also affecting younger individuals. Because Parkinson's disease progresses slowly, it is difficult to distinguish from other conditions, making early detection challenging. Clinically, it is characterized by unusual symptoms such as tremor, rigidity, bradykinesia, postural instability, stooped posture, freezing of gait, depression, sleep disturbances, urinary incontinence, and dementia.

[0003] Although the cause of Parkinson's disease is unknown, it is known to be a disease caused by a deficiency of the neurotransmitter dopamine, which is caused by the destruction of nerve cells in the brain that secrete it. The most widely developed and used medication is levodopa therapy, which is commonly administered by administering levodopa, which is converted to dopamine in the body. While levodopa is the most effective treatment for Parkinson's disease, it can sometimes cause a decrease in drug-related effects or various movement disorders during treatment. Other medications used include COMT inhibitors and MAO-B inhibitors, which work to maintain dopamine concentration in the brain by inhibiting dopamine metabolism.

[0004] MAO-B plays a crucial role in dopamine metabolism in the brain and is known to suppress neuronal damage. While there is no clear evidence that MAO-B inhibitors actually slow the progression of Parkinson's disease, it is known to play a key role in the pathogenesis of Parkinson's disease caused by MPTP or similar environmental toxins, and inhibiting MAO-B is known to have a protective effect against dopaminergic neuronal degeneration or death. Furthermore, animal and clinical studies have shown that MAO-B inhibitors, unlike other drugs, have a brain-protective effect.

[0005] The most representative approved MAO-B inhibitor is selegiline, prescribed as a treatment for Parkinson's disease. However, it is metabolized into amphetamine in the body when taken, causing liver toxicity. As an irreversible inhibitor, it carries various side effects. Azilect, containing rasagiline, was first marketed in Israel in 2005 and has recently been released in over 50 countries, including Europe and the United States. Azilect has no amphetamine side effects and is said to be more effective than other dopaminergic drugs. However, rasagiline, like selegiline, is an irreversible MAO-B inhibitor. While it exhibits excellent MAO-B inhibition, it also carries safety concerns. Therefore, drugs that are both effective and reversibly inhibit activity are being developed to address these shortcomings. However, no notable reversible inhibitors are currently available.

[0006]

[0007] Oxidative stress is a representative cause of diseases that appear in humans living in a rapidly changing modern society, and is caused by pollutants, pollutants, bad eating habits, or mental stress.

[0008] Cytochrome P450 (hereinafter referred to as CYP) is an enzyme involved in drug metabolism, such as breaking down substrates such as drugs absorbed from outside the cell. It is distributed evenly throughout body cells, mainly existing in the endoplasmic reticulum and mitochondria. Cytochrome P450 is not a single form, but a complex form composed of several isoenzymes with different molecular structures, such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. The activities of these CYP isoenzymes show various differences between individuals. This difference in enzyme activity between individuals is mainly due to various genetic polymorphisms, including single nucleotide polymorphisms (SNPs), and acquired factors such as food, cytokines, hormones, and various drugs are also related. These differences in CYP isoenzyme activity reflect individual differences in blood drug concentrations and can lead to serious adverse effects, depending on the drug type. Therefore, assessing the activity of CYP isoenzymes can be applied not only in academic fields such as drug interaction studies and genotype-based phenotype studies, but also in industrial applications such as new drug development.

[0009]

[0010] <Prior Art Literature>

[0011] 1. International Patent Publication No. WO 2016052928

[0012] 2. International Patent Publication No. WO 2016052928

[0013] 3. Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease. Science advances. 2019; 5:eaav0316.

[0014] 4. KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson's disease. Neurotherapeutics. 2021; doi: 10.1007 / s13311-021-01097-4.

[0015]

[0016] The present invention aims to provide a novel phenylaminopropanamide derivative, a method for preparing the same, and a pharmaceutical composition comprising the same.

[0017] In addition, the present invention seeks to use a pharmaceutical composition comprising the novel phenylaminopropanamide derivative for the prevention or treatment of diseases induced by MAO-B inhibitors and oxidative stress.

[0018] The purpose of the present invention is to provide a phenylamino propanamide derivative represented by the following chemical formulas 1 and 2.

[0019]

[0020]

[0021]

[0022]

[0023] wherein R is hydrogen or an alkyl group;

[0024] A phenylamino propanamide derivative characterized in that the above X is selected from hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.

[0025]

[0026] The above derivative may include a pharmaceutically acceptable salt or solvate thereof.

[0027] Furthermore, the present invention relates to an MAO-B inhibitor comprising the phenylaminopropanamide derivative or a pharmaceutically acceptable salt or solvate thereof.

[0028] In addition, the present invention relates to a cytochrome P450 activity inhibitor comprising the phenylaminopropanamide derivative or a pharmaceutically acceptable salt or solvate thereof.

[0029] It also relates to a cytochrome P450 activity inhibitor that selectively inhibits the activity of CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 among the above cytochrome P450.

[0030]

[0031] The novel phenylaminopropanamide derivative of the present invention has an excellent effect of selectively inhibiting MAO-B and has excellent CYP enzyme activity, and thus can be used for the prevention or treatment of diseases related thereto, more specifically, diseases induced by oxidative stress.

[0032] The present inventors have developed KDS2010, a new, selective candidate substance that reversibly binds to the active site of MAO-B to minimize the side effects of existing drugs and minimizes off-target activity that causes other neurological side effects besides the target.

[0033] The candidate substance KDS2010 was confirmed to be able to continuously improve cognitive function over a long period of time by not activating the in vivo alternative mechanism even when administered long-term. Furthermore, when administered to genetically modified experimental mice with Alzheimer's disease, cognitive function was restored through various behavioral experiments. Furthermore, a long-term administration test at a low dose also confirmed superior cognitive function improvement efficacy. Clinical trials are currently underway, and to enable rapid entry into global clinical trials, it is necessary to identify backup compounds for the candidate substance and expand research into other indications. To minimize clinical risks, the inventors are conducting research to identify backup compounds with excellent MAO-B inhibition. A total of 37 backup compounds were synthesized, and optimization was required to identify a representative backup compound with inhibitory efficacy and pharmacological activity comparable to KDS2010.

[0034]

[0035] The figure below shows that the number of carbon atoms in the A portion of candidate material KDS2010 is 1 or 2, but in the present invention, the number of carbon atoms in that portion is limited to 0. In addition, the structure of portion B of the existing candidate material was expanded and diversified to include phenoxybenzene, benzyloxybenzene, biphenyl, etc. The left side is KDS2010, and the right side is the material of the present invention.

[0036]

[0037]

[0038] The present invention aims to provide a novel phenylaminopropanamide derivative, a method for preparing the same, and a pharmaceutical composition comprising the same.

[0039] In addition, the present invention seeks to use a pharmaceutical composition comprising the novel phenylaminopropanamide derivative for the prevention or treatment of diseases induced by MAO-B inhibitors and oxidative stress.

[0040]

[0041] The purpose of the present invention is to provide a phenylamino propanamide derivative represented by the following chemical formulas 1 and 2.

[0042] <Chemical Formula 1>

[0043]

[0044]

[0045] <Chemical Formula 2>

[0046]

[0047]

[0048] wherein R is hydrogen or an alkyl group;

[0049] The above X can be selected from hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.

[0050] wherein R is selected from hydrogen and C -C alkyl groups;

[0051] A phenylamino propanamide derivative, characterized in that the above X is selected from hydrogen, a halogen group, a C1-C7 alkyl group, a halogenated C1-C7 alkyl group, a C1-C7 alkoxy group, and a halogenated C1-C7 alkoxy group.

[0052] In addition, the R is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group; and the X can be selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group, and an ethoxy group.

[0053] In addition, the above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group;

[0054] The above X can be selected from a fluoro group, a chloro group, a trichloromethyl group, a trichloromethoxy group, and a methoxy group.

[0055] In addition, the above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group;

[0056] The above X can be selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, a m-methoxy group, a p-fluoro group, and a m-fluoro group.

[0057] In addition, the above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group;

[0058] The above X can be selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, and a m-methoxy group.

[0059] Additionally, the above R may be hydrogen or a methyl group.

[0060] In addition, the R is hydrogen or a methyl group; and the X can be selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, and a m-methoxy group.

[0061] In addition, the R is hydrogen or a methyl group; and the X can be selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, and a m-trichloromethoxy group.

[0062] In addition, the R may be hydrogen or a methyl group, and the X may be p-trichloromethyl group or p-trichloromethoxy.

[0063] In addition, the above R may be a methyl group; and the above X may be a p-trichloromethyl group or p-trichloromethoxy.

[0064] Additionally, the above R may be a methyl group; and the above X may be a p-trichloromethyl group.

[0065] In addition, the compound of the above chemical formula 1 may be selected from the following compounds.

[0066] 2-((4-(4-(trifluoromethyl)phenoxy)phenyl)amino)propanamide methanesulfonate

[0067] 2-((4-(3,4-dichlorophenoxy)phenyl)amino)propanamide methanesulfonate

[0068] 2-((4-((4-(trifluoromethyl)benzyl)oxy)phenyl)amino)propanamide methanesulfonate

[0069] 2-((4-((3,4-difluorobenzyl)oxy)phenyl)amino)propanamide methanesulfonate

[0070] 2-((4-((3,4-dichlorobenzyl)oxy)phenyl)amino)propanamide methanesulfonate

[0071] In addition, the compound of the above chemical formula 2 may be selected from the following compounds.

[0072] 2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)propanamide methanesulfonate

[0073] 2-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)propanamide methanesulfonate

[0074] The present invention may be an MAO-B inhibitor comprising the phenylaminopropanamide derivative or a pharmaceutically acceptable salt or solvate thereof.

[0075] In addition, the present invention may be a cytochrome P450 activity inhibitor comprising the phenylaminopropanamide derivative or a pharmaceutically acceptable salt or solvate thereof.

[0076] Additionally, it may be a cytochrome P450 activity inhibitor that selectively inhibits the activity of CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6 among the above cytochrome P450.

[0077]

[0078] Next, we will look at the synthesis process of the above phenylaminopropanamide derivative.

[0079]

[0080] <Reaction Scheme 1>

[0081]

[0082]

[0083] Substituted (tert-butyl (4-phenoxyphenyl)carbamate) was synthesized according to the above reaction scheme. Specifically, tert-butyl (4-hydroxyphenyl)carbamate (1.0 eq) and boronic acid (2.0 eq) substituted with a trifluoromethyl group or chlorine at the 3- or 4-position were dissolved in DCM, and copper acetate (1.0 eq), triethylamine (TEA, 5.0 eq), and pyridine (5.0 eq) were added, and the mixture was stirred at room temperature for 18 hours. When the reaction was completed, the reaction solution was diluted with diethyl ether, filtered through celite, and the filtrate was distilled under reduced pressure. The residue was washed with a 0.5 M HCl solution, water, and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by medium pressure liquid chromatography (MPLC) using a mixed solvent of ethyl acetate and n-hexane to obtain 3- or 4-substituted tert-butyl (4-phenoxyphenyl)carbamate derivatives.

[0084]

[0085] <Reaction Formula 2>

[0086]

[0087]

[0088] Substituted (4-phenoxyaniline hydrochloride) was synthesized according to the above reaction scheme. Specifically, the compound (1.0 eq) synthesized from the above reaction scheme 1 was dissolved in EA, HCl (6.0 eq, 4.0 M dioxane solution) was added, and the mixture was stirred at room temperature for 3 days. Upon completion of the reaction, the reaction solution was filtered and washed with ethyl acetate, thereby obtaining a 3- or 4-substituted 4-phenoxyaniline hydrochloride derivative.

[0089]

[0090] <Reaction Formula 3>

[0091]

[0092]

[0093] According to the above reaction scheme, (2-((4-phenoxyphenyl)amino)propanamide) was synthesized. Specifically, the compound (1.0 eq) synthesized in the above reaction scheme 2 was dissolved in ACN, potassium carbonate (4.0 eq) was added, and the mixture was stirred at room temperature for 15 minutes. Then, bromopropanamide (2-Bromopropanamide, 1.5 eq) was added at the same temperature, and the mixture was stirred with reflux at 85 °C for 18 hours. Upon completion of the reaction, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by medium pressure liquid chromatography (MPLC) to obtain 3- or 4-substituted 2-((4-bromophenyl)amino)propanamide.

[0094]

[0095] <Reaction Scheme 4>

[0096]

[0097]

[0098] Substituted (2-([1,1'-biphenyl]-4- ylamino)propanamide methanesulfonate) was synthesized according to the above reaction scheme. Specifically, the compound (1.0 eq) synthesized in the above reaction scheme 3 was dissolved in ethyl acetate, methane sulfonic acid (1.2-1.5 eq) was added, and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was filtered and washed with ethyl acetate, thereby obtaining 3- or 4-substituted 2-((4-phenoxyphenyl)amino)propanamide methanesulfonate derivatives.

[0099]

[0100] <Reaction Formula 5>

[0101]

[0102]

[0103] According to the above reaction scheme, (tert-butyl (4-(benzyloxy)phenyl)carbamate) was synthesized. Specifically, tert-butyl (4-hydroxyphenyl)carbamate (1.0 eq) and potassium carbonate (4.0 eq) were dissolved in acetone, and bromomethylbenzene (2.0 eq) substituted with trifluoromethyl, fluorine, or chlorine at the 3- and 4-positions was added, followed by stirring at 60°C for 5 hours with reflux. Upon completion of the reaction, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified through column chromatography using a mixed developing solvent of ethyl acetate and n-hexane to obtain 3- or 4-substituted 2-((4-bromophenyl)amino)propanamide.

[0104]

[0105] <Reaction Formula 6>

[0106]

[0107]

[0108] Substituted (4-(benzyloxy)aniline hydrochloride) was synthesized according to the above reaction scheme. Specifically, the compound (1.0 eq) synthesized from the above reaction scheme 5 was dissolved in EA, HCl (6.0 eq, 4.0 M dioxane solution) was added, and the mixture was stirred at room temperature for 18 hours. Upon completion of the reaction, the reaction solution was filtered and washed with ethyl acetate, thereby obtaining a 3- or 4-substituted 4-phenoxyaniline hydrochloride derivative.

[0109]

[0110] <Reaction Formula 7>

[0111]

[0112]

[0113] According to the above reaction scheme, (2-((4-(benzyloxy)phenyl)amino)propanamide) was synthesized. Specifically, the compound (1.0 eq) synthesized in the above reaction scheme 6 was dissolved in ACN, potassium carbonate (4.0 eq) was added, and the mixture was stirred at room temperature for 15 minutes. Then, bromopropanamide (2-Bromopropanamide, 1.5 eq) was added at the same temperature, and the mixture was stirred with reflux at 85 °C for 18 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography to obtain 3- or 4-substituted 2-((4-benzyloxy)phenyl)amino)propanamide.

[0114]

[0115] <Reaction Formula 8>

[0116]

[0117]

[0118] Substituted (2-((4-(benzyloxy)phenyl)amino)propanamide methanesulfonate) was synthesized according to the above reaction scheme. Specifically, the compound synthesized in the above reaction scheme 7 (1.0 eq) was dissolved in ethyl acetate, methane sulfonic acid (1.2-1.5 eq) was added, and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was filtered and washed with ethyl acetate, thereby obtaining 3- or 4-substituted 2-((4-phenoxyphenyl)amino)propanamide methanesulfonate derivatives.

[0119]

[0120] <Reaction Formula 9>

[0121]

[0122]

[0123] 2-((4-bromophenyl)amino)propanamide was synthesized according to the above reaction formula. Specifically, 4-bromoaniline (1.0 eq) was dissolved in (Acetonitrile; ACN), potassium carbonate (4.0 eq) was added, and the mixture was stirred at room temperature for 15 minutes.

[0124] After that, bromopropanamide (2-Bromopropanamide, 1.5 eq) was added at the same temperature and stirred at 85 °C for 18 hours with reflux. When the reaction was complete, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was distilled off under reduced pressure, and the residue obtained was purified by medium-pressure liquid chromatography (MPLC) using a mixed solvent of ethyl acetate and n-hexane to obtain 2-((4-bromophenyl)amino)propanamide.

[0125]

[0126] <Reaction Scheme 10>

[0127]

[0128]

[0129] Substituted (2-([1,1'-biphenyl]-4- ylamino)propanamide) was synthesized according to the above reaction scheme. Specifically, the compound synthesized from the above reaction scheme 9 (1.0 eq), boronic acid substituted with a trifluoromethyl group or chlorine at the 3- or 4-position (3.0 eq), sodium carbonate (5.0 eq), and tetrakis (0.04 eq) were added to degassed toluene / distilled water (Toluene / DW), and the mixture was stirred under reflux at 140°C for 18 hours. Upon completion of the reaction, the reaction solution was filtered through celite, diluted with ethyl acetate (EtOAc), washed with water, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by medium pressure liquid chromatography (MPLC), and 3- or 4-substituted 2-([1,1'-biphenyl]-4-ylamino)propanamide derivatives were obtained.

[0130]

[0131] <Reaction Formula 11>

[0132]

[0133]

[0134] Substituted (2-([1,1'-biphenyl]-4- ylamino)propanamide methanesulfonate) was synthesized according to the above reaction scheme. Specifically, the compound (1.0 eq) synthesized in the above reaction scheme 10 was dissolved in ethyl acetate EA and a small amount of methanol MeOH, methane sulfonic acid (1.2-1.5 eq) was added, and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was filtered and washed with ethyl acetate to obtain 3- or 4-substituted 2-([1,1'-biphenyl]-4-ylamino)propanamide methanesulfonate derivatives.

[0135]

[0136] Through the above-described synthetic method, compounds of chemical formulas 3 to 9 below were synthesized.

[0137] (1) 2-((4-(4-(trifluoromethyl)phenoxy)phenyl)amino)propanamide methanesulfonate

[0138]

[0139]

[0140] 1 H NMR (400 MHz, DMSO-d6) δ7.70 (d, 8.6 Hz, 2 ArH), 7.53 (br s, C(O)NHH'), 7.20 (br s, C(O)NHH'), 7.08-6.98 (m, 4 ArH), 6.91-6.83 (m, 2 ArH), 3.87 (q,J= 6.3 Hz, CH), 2.35 (s, SCH3) 1.35 (d,J= 6.7 Hz, CH3).

[0141]

[0142] (2) 2-((4-(3,4-dichlorophenoxy)phenyl)amino)propanamide methanesulfonate

[0143]

[0144]

[0145] 1 H NMR (400 MHz, DMSO-d6)δ7.59 (d, 8.9 Hz, 2 ArH), 7.52 (br s, C(O)NHH'), 7.18-7.17 (m, 2 ArH), 7.01-6.98 (m, 2 ArH), 6.94-6.86 (m, 2 ArH, C(O)NHH'), 3.87 (q,J= 6.0 Hz, CH), 2.35 (s, SCH3) 1.34 (d,J= 6.8 Hz, CH3).

[0146]

[0147] (3) 2-((4-((4-(trifluoromethyl)benzyl)oxy)phenyl)amino)propanamide methanesulfonate

[0148]

[0149]

[0150] 1 H NMR (400 MHz, DMSO-d6)δ10.0 (br s, + NH2), 7.86 (br s, C(O)NHH'), 7.73 (dd,J= 29.9, 8.1 Hz, 4 ArH), 7.55 (br s, C(O)NHH'), 7.37 (d,J= 8.7 Hz, 2 ArH), 7.14 (d,J= 8.8 Hz, 2 ArH), 5.25 (s, OCH2), 4.15 (q,J= 6.9 Hz, CH), 2.38 (s, SCH3) 1.40 (d,J= 6.8 Hz, CH3); 13 C NMR (75 MHz, DMSO-d6)δ171.4 (C(O)), 157.7, 142.1, 129.7, 128.9 (q,J C-F= 31.6 Hz), 128.5, 125.8 (q,J C-F = 3.8 Hz), 124.7 (q,J C-F = 270.4 Hz, CF3), 124.4, 116.2 (ArC), 69.2 (OCH2), 59.0 (CH), 40.3 (SCH3), 16.4 (CH3).

[0151]

[0152] (4) 2-((4-((3,4-difluorobenzyl)oxy)phenyl)amino)propanamide methanesulfonate

[0153]

[0154]

[0155] 1 H NMR (300 MHz, DMSO-d6)δ10.3 (br s, + NH2), 7.85 (br s, C(O)NHH'), 7.57-7.35 (m, 3 ArH, C(O)NHH'), 7.36 (d,J= 8.9 Hz, 2 ArH), 7.12 (d,J= 8.7 Hz, 2 ArH), 5.11 (s, OCH2), 4.15 (q,J= 6.4 Hz, CH), 2.38 (s, SCH3) 1.40 (d,J= 6.8 Hz, CH3).

[0156]

[0157] (5) 2-((4-((3,4-dichlorobenzyl)oxy)phenyl)amino)propanamide methanesulfonate

[0158]

[0159]

[0160] 1 H NMR (400 MHz, DMSO-d6)δ10.1 (br s, +NH2), 7.86 (br s, C(O)NHH'), 7.73-7.66 (m, 2 ArH), 7.54 (br s, C(O)NHH'), 7.47-7.44 (m, 1 ArH), 7.36 (d,J= 8.9 Hz, 2 ArH), 7.13 (d,J= 9.0 Hz, 2 ArH), 5.14 (s, OCH2), 4.14 (q,J= 6.9 Hz, CH), 2.38 (s, SCH3) 1.40 (d,J= 6.9 Hz, CH3); 13 C NMR (75 MHz, DMSO-d6)δ170.9 (C(O)), 157.1, 137.9, 131.1, 130.7, 130.4, 129.5, 129.3, 127.9, 123.8, 115.7 (ArC), 68.0 (OCH2), 58.5 (CH), 39.7 (SCH3), 15.9 (CH3).

[0161]

[0162] (6) 2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)propanamide methanesulfonate

[0163]

[0164]

[0165] 1 H NMR (400 MHz, DMSO-d6)δ7.75 (dd,J= 29.6, 8.3 Hz, 4 ArH), 7.56-7.53 (m, 2 ArH), 7.42 (br s, C(O)NHH'), 7.06 (br s, C(O)NHH'), 6.75-6.71 (m, 2 ArH), 3.85 (q,J= 6.8 Hz, CH), 2.36 (s, SCH3) 1.34 (d,J= 6.9 Hz, CH3).

[0166]

[0167] (7) 2-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)propanamide methanesulfonate

[0168]

[0169]

[0170] 1 H NMR (400 MHz, DMSO-d6) δ7.80-7.79 (m, 1 ArH), 7.61-7.54 (m, 2 ArH), 7.48 (d, J= 8.5 Hz, 2 ArH), 7.37 (br s, C(O)NHH'), 7.01 (br s, C(O)NHH'), 6.66 (d,J= 8.3 Hz, 2 ArH), 3.82 (q,J= 6.9 Hz, CH), 2.32 (s, SCH3) 1.33 (d,J= 7.0 Hz, CH3).

[0171]

[0172] <Experimental Example 1: Evaluation of Monoamine Oxidase B (MAO-B) Activity Inhibition>

[0173] The MAO-B inhibitory efficacy of the above seven compounds was tested. The MAO-B inhibitory efficacy assay was conducted together with selegiline, a well-known irreversible MAO-B inhibitor, and the existing candidate substance KDS2010.

[0174] Compounds according to the examples of the present invention were diluted in DMSO solution and prepared at five concentrations of 1 mM, 0.1 mM, 0.01 mM, 0.001 mM, and 0.0001 mM, respectively, and 0.05 M sodium phosphate buffer (pH 7.4) was prepared. 5 mg / mL monoamine oxidase type B human enzyme was diluted 1 / 200 with 0.05 M sodium phosphate buffer, and then mixed with 1 μL of the compound solutions of the five concentrations to make a total of 100 μL to prepare an enzyme buffer, which was placed in a 96-well plate and reacted at 37°C for 15 minutes. 100 μL of working buffer made by adding 20 mM Amplex red (200 μL), 100 mM benzylamine substrate (200 μL), and 200 U / mL horseradish peroxidase (100 μL) to 0.05 M sodium phosphate buffer (pH 7.4, 9.5 mL) was mixed 1:1 with the enzyme buffer reacted in the above step, incubated at 37°C for 20 minutes, and then measured by fluorescence (absorption; 545 nm, emission; 590 nm), and the activity of the compound of the present invention was verified to be the concentration that inhibits the activity of MAO-B by 50% (IC 50 ) are shown in Table 1 below. As a control group, selegiline, which is well known as an MAO-B inhibitor, and the candidate substance KDS2010 were used together.

[0175]

[0176] Compound number MAO-B inhibitory potency (IC 50, nM)1>10002>1000327.8416.154.0618.07106.7Selegiline14.5KDS20109.3

[0177]

[0178] Compounds 1 and 2 showed some MAO-B inhibitory efficacy at high concentrations, and compounds 3-7 all showed excellent MAO-B inhibitory efficacy. In particular, compounds 3-6 showed inhibitory efficacy comparable to or superior to that of selegiline, an MAO-B inhibitor, and candidate substance KDS2010, confirming that the compounds of the present invention have excellent efficacy compared to prior art.

[0179]

[0180] <Experimental Example 2: Evaluation of CYP activity inhibition>

[0181] The CYP enzyme inhibition ability was tested for the same 7 compounds as in Experimental Example 1 above to evaluate pharmacological activity, and the results are shown in Table 2 below.

[0182] To confirm the applicability of compounds according to embodiments of the present invention as drugs for actual in vivo administration, CYP activity inhibition was determined. Specifically, for the compounds of the present invention, activity inhibition was evaluated using the P450-Glo™ Assays (Promega) kit targeting five isoenzymes, 2C19, 2D6, 2C9, 1A2, and 3A4, which are reported to account for more than 90% of total metabolism by CYP.

[0183] The 10 mM compound was diluted 250-fold in luciferin-free water and 12.5 μL was added to a 96-well white plate. Each CYP isoenzyme and corresponding substrate were mixed in a potassium phosphate buffer (pH 7.4) to prepare a 4-fold concentrated CYP reaction solution (for 1A2, 0.5 pmol 1A2, 400 mM potassium phosphate, 400 μM luciferin-ME; for 2C9, 0.5 pmol 2C9, 100 mM potassium phosphate, 400 μM luciferin-H; for 2C19, 0.25 pmol 2C19, 200 mM potassium phosphate, 40 μM luciferin-H EGE; for 2D6, 0.25 pmol 2D6, 400 mM potassium phosphate, 120 μM luciferin-ME EGE; for 3A4, 0.1 pmol 3A4, 400 mM potassium phosphate, Luciferin-IPA 12 μM) was prepared and 12.5 μL was added to a 96-well plate and pre-incubated at room temperature for 10 minutes. After that, 25 μL of NADPH generation system solution was added and reacted at 37°C for the incubation time according to the CYP isozyme (10 minutes for 1A2 and 3A4, 20 minutes for 2C19, and 30 minutes for 2C9 and 2D6). Then, 50 μL of luciferin detection reagent was added and incubated at room temperature for 20 minutes under light protection. Luminescence signals were measured using a SpectraMax®i3 microplate reader from Molecular Devices, and well-known inhibitors for each CYP isoenzyme (lansoprazole for 2C19, quinidine for 2D6, sulfaphenazole for 2C9, α-naphtoflavone for 1A2, and ketoconazole for 3A4) were used as positive controls.The activity inhibition capacity for each CYP isoenzyme was converted into % activity relative to the negative control group to which the compounds were not added.

[0184]

[0185] Compound number CYP enzyme activity (% remaining) 1A2 / 3A1 / 2C9 / 2C19 / 2D6 11 12.7 / 77.0 / 103.3 / 77.1 / 84.0 21 20.3 / 44.3 / 13 5.2 / 72.4 / 80.6 31 06.8 / 94.6 / 102.0 / 62.4 / 94.5 41 04.6 / 69.1 / 100.0 / 75.8 / 88.4 5101 .7 / 76.8 / 117.6 / 62.6 / 95.86109.9 / 91.9 / 101.2 / 83.2 / 101.8789.3 / 73.3 / 99.5 / 75.4 / 98.7Selegiline83.2 / 98.7 / 103.3 / 48.1 / 68.1KDS201053.1 / 88.4 / 101.2 / 81.3 / 80.7

[0186] Compounds 3-7 with excellent activity were confirmed to have excellent drug stability as they showed >60% of the activity of all five CYP enzymes. Compounds 3-7 improved 2C19 compared to selegiline, an MAO-B inhibitor, and improved 1A2 compared to candidate substance KDS2010.

[0187]

[0188] The present invention has been described above, focusing on preferred embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from the essential characteristics thereof. Therefore, the disclosed embodiments should be considered illustrative rather than restrictive. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being included within the present invention.

Claims

1. A phenylamino propanamide derivative having a structure represented by the following chemical formula 1; <Chemical Formula 1> wherein R is hydrogen or an alkyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.

2. In paragraph 1, wherein R is selected from hydrogen and C -C alkyl groups; A phenylamino propanamide derivative, characterized in that the above X is selected from hydrogen, a halogen group, a C1-C7 alkyl group, a halogenated C1-C7 alkyl group, a C1-C7 alkoxy group, and a halogenated C1-C7 alkoxy group.

3. In paragraph 1, The above R is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group, and an ethoxy group.

4. In paragraph 1, The above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a fluoro group, a chloro group, a trichloromethyl group, a trichloromethoxy group, and a methoxy group.

5. In paragraph 1, The above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group; A phenylamino propanamide derivative characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, a m-methoxy group, a p-fluoro group, and a m-fluoro group.

6. In paragraph 1, The above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, and a m-methoxy group.

7. In paragraph 1, A phenylamino propanamide derivative, characterized in that the above R is hydrogen or a methyl group.

8. In paragraph 1, wherein R is hydrogen or a methyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, and a m-methoxy group.

9. In paragraph 1, wherein R is hydrogen or a methyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, and a m-trichloromethoxy group.

10. In paragraph 1, wherein R is hydrogen or a methyl group; A phenylamino propanamide derivative, characterized in that the above X is a p-trichloromethyl group or p-trichloromethoxy.

11. In paragraph 1, wherein R is a methyl group; A phenylamino propanamide derivative, characterized in that the above X is a p-trichloromethyl group or p-trichloromethoxy.

12. In paragraph 1, wherein R is a methyl group; An alpha-aminoamide derivative, characterized in that the above X is a p-trichloromethyl group.

13. In paragraph 1, A phenylamino propanamide derivative characterized in that the above phenylamino propanamide derivative is selected from the following compounds. 2-((4-(4-(trifluoromethyl)phenoxy)phenyl)amino)propanamide methanesulfonate 2-((4-(3,4-dichlorophenoxy)phenyl)amino)propanamide methanesulfonate 2-((4-((4-(trifluoromethyl)benzyl)oxy)phenyl)amino)propanamide methanesulfonate 2-((4-((3,4-difluorobenzyl)oxy)phenyl)amino)propanamide methanesulfonate 2-((4-((3,4-dichlorobenzyl)oxy)phenyl)amino)propanamide methanesulfonate 14. A phenylamino propanamide derivative having a structure represented by the following chemical formula 2; <Chemical Formula 2> wherein R is hydrogen or an alkyl group; A phenylamino propanamide derivative characterized in that the above X is selected from hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.

15. In paragraph 14, wherein R is selected from hydrogen and C -C alkyl groups; A phenylamino propanamide derivative, characterized in that the above X is selected from hydrogen, a halogen group, a C1-C7 alkyl group, a halogenated C1-C7 alkyl group, a C1-C7 alkoxy group, and a halogenated C1-C7 alkoxy group.

16. In paragraph 14, The above R is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group, and an ethoxy group.

17. In paragraph 14, The above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a fluoro group, a chloro group, a trichloromethyl group, a trichloromethoxy group, and a methoxy group.

18. In paragraph 14, The above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group; A phenylamino propanamide derivative characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, a m-methoxy group, a p-fluoro group, and a m-fluoro group.

19. In paragraph 14, The above R is selected from hydrogen, a methyl group, an isopropyl group, and an isobutyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, and a m-methoxy group.

20. In paragraph 14, A phenylamino propanamide derivative, characterized in that the above R is hydrogen or a methyl group.

21. In paragraph 14, wherein R is hydrogen or a methyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, a m-trichloromethoxy group, a p-chloro group, a m-chloro group, a p-methoxy group, and a m-methoxy group.

22. In paragraph 14, wherein R is hydrogen or a methyl group; A phenylamino propanamide derivative, characterized in that the above X is selected from a p-trichloromethyl group, a p-trichloromethoxy group, a m-trichloromethyl group, and a m-trichloromethoxy group.

23. In paragraph 14, wherein R is hydrogen or a methyl group; A phenylamino propanamide derivative, characterized in that the above X is a p-trichloromethyl group or p-trichloromethoxy.

24. In paragraph 14, wherein R is a methyl group; A phenylamino propanamide derivative, characterized in that the above X is a p-trichloromethyl group or p-trichloromethoxy.

25. In paragraph 14, wherein R is a methyl group; An alpha-aminoamide derivative, characterized in that the above X is a p-trichloromethyl group.

26. In paragraph 14, A phenylamino propanamide derivative characterized in that the above phenylamino propanamide derivative is selected from the following compounds. 2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)propanamide methanesulfonate 2-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)propanamide methanesulfonate 27. An MAO-B inhibitor comprising a phenylaminopropanamide derivative according to any one of claims 1 to 26 or a pharmaceutically acceptable salt or solvate thereof.

28. A cytochrome P450 activity inhibitor comprising a phenylaminopropanamide derivative according to any one of claims 1 to 26 or a pharmaceutically acceptable salt or solvate thereof.

29. In paragraph 28, A cytochrome P450 activity inhibitor that selectively inhibits the activity of CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 among the above cytochrome P450.

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