WO2016052928A1 - 알파-아미노아미드 유도체 화합물 및 이를 포함하는 약학적 조성물 - Google Patents
알파-아미노아미드 유도체 화합물 및 이를 포함하는 약학적 조성물 Download PDFInfo
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- WO2016052928A1 WO2016052928A1 PCT/KR2015/010104 KR2015010104W WO2016052928A1 WO 2016052928 A1 WO2016052928 A1 WO 2016052928A1 KR 2015010104 W KR2015010104 W KR 2015010104W WO 2016052928 A1 WO2016052928 A1 WO 2016052928A1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A61K31/16—Amides, e.g. hydroxamic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to an alpha-aminoamide derivative compound and a pharmaceutical composition comprising the same.
- Parkinson's disease is the second most common degenerative neurological disorder, with an incidence rate of about 6.3 million patients worldwide, and it is estimated that about 1 in 1,000 people develop Parkinson's disease. The incidence is usually high in older people, but it is now also in young people. Because Parkinson's disease progresses slowly, it is not easy to distinguish from other diseases, and it is difficult to detect at early stages and clinical features include tremor, stiffness, slow motion, postural instability, stooped posture, gaze freezing, depression, sleep disorders, urination disorder, and dementia. There are abnormal symptoms that accompany the back.
- Parkinson's disease is known to cause a lack of dopamine due to the destruction of nerve cells that secrete a neurotransmitter called dopamine in the brain.
- levodopa therapy which is a method of administering levodopa which is converted into dopamine in the body, is generally performed.
- levodopa is the most effective treatment for Parkinson's disease, there are cases in which the reduction of drug-related effects or various movement disorders occur during the treatment.
- Other drugs include COMT inhibitors and MAO-B inhibitors that inhibit dopamine metabolism and maintain dopamine levels in the brain.
- MAO-B is known to play an important role in dopamine metabolism in the brain, as well as inhibit brain nerve cell damage. There is no clear evidence that MAO-B inhibitors actually slow down Parkinson's progression, but playing an important role in the development of Parkinson's disease by MPTP or similar environmental toxicants inhibits MAO-B, which inhibits degeneration or death of dopamine neurons. It is known to act. In addition, MAO-B inhibitors, unlike other drugs, have been shown to have evidence of brain protection from animal and clinical studies.
- MAO-B inhibitor The most representative drug approved as MAO-B inhibitor is selegiline (selegiline), which is prescribed as a treatment for Parkinson's disease, but when taken, it is metabolized into amphetamine in the body, causing liver toxicity, and with various side effects as an irreversible inhibitor. Since it was first marketed in 2005 in 2005, azilect, which has a rasagiline ingredient, has been introduced in more than 50 countries including Europe and the United States. Agilent is said to have no amphetamine side effects in the body when taken and is better than other dopamine drugs. However, as with selegiline, lasazilline is an irreversible MAO-B inhibitor, so it has excellent MAO-B inhibitory effect but has a disadvantage of safety problems. Therefore, in recent years, drugs that can reversibly inhibit activity while having good effects have been developed as an alternative to supplement these disadvantages, but noteworthy reversible inhibitors have not been prescribed until now.
- obesity refers to a medical condition in which excessive fat is accumulated in the body to a negative effect on health. Due to the difference between the energy consumed and the energy used, excess body weight can be combined with various diseases, with excess energy remaining.
- glia which occupies the majority, is essential for a comprehensive understanding of brain function.
- astrocytes which have the highest number of glial cells, recently secrete various signaling agents such as gaba-gamma-aminobutyric acid (GABA), glutamate, D-serine, and ATP to activate or suppress surrounding neurons. It is emerging as a possible cell.
- GABA gaba-gamma-aminobutyric acid
- hypothalamic glial cells also interact closely with POMC (pro-opiomelanocortin) neurons and express leptin receptors, which may contribute to leptin signaling.
- POMC neurons that induce appetite depression and energy consumption.
- astrocytes help activate POMC neurons, which induce energy consumption in close proximity.
- GABA GABA
- MAO-B mono-aminoxidase B
- POMC neurons that induce energy consumption express GABAa receptors outside synapses, including a4, a5, and a6 subunits, due to excessive leptin signaling, and are affected by persistent Gaba secreted from anti-responsive glial cells. This inhibits POMC neurons, reducing energy consumption and causing fat accumulation.
- Maobi the causative agent of Gaba production
- inhibits Gaba production and secretion relieves the inhibition of POMC neurons, and activates again to promote energy consumption.
- POMC neurons which induce anorexia
- GABAa receptors outside the synapse do not express GABAa receptors outside the synapse and are not affected by persistent Gaba.
- Maobi inhibitors act on POMC neurons, which selectively induce energy expenditure, resulting in the effect of obesity treatment.
- the conventional Maobi inhibitors have a problem that the various irreversible inhibitors are accompanied by various side effects. Therefore, drugs that can reversibly inhibit Maobia have been researched and developed, but noteworthy reversible Maobia inhibitors that can effectively act on obesity have not been prescribed until now.
- An object of the present invention is to overcome the disadvantages of existing drugs used as MAO-B inhibitors.
- a therapeutic agent that reversibly inhibits MAO-B through non-covalent bonds.
- a composition comprising the same and a method for preparing the same.
- One aspect of the present invention is to provide an alpha-aminoamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R and X are as defined in the present invention.
- Another aspect of the present invention relates to a monoamine oxidase B (MAO-B) inhibitor comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.
- MAO-B monoamine oxidase B
- Another aspect of the present invention relates to a pharmaceutical composition for treating or preventing degenerative neurological disease, including an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.
- Another aspect of the invention relates to the use of an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof in accordance with various embodiments of the invention for the manufacture of a medicament for the treatment or prevention of degenerative neurological diseases.
- Another aspect of the present invention is to treat a degenerative neurological disease by administering to a mammal an alpha-aminoamide derivative according to various embodiments of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising the same. It is about how to prevent.
- Another aspect of the present invention relates to a pharmaceutical composition for treating or preventing obesity, comprising as an active ingredient an alpha-aminoamide derivative or a pharmaceutically acceptable salt thereof or a solvate thereof according to various embodiments of the present invention.
- Another aspect of the present invention relates to a method for preparing an alpha-aminoamide derivative having the structure of Formula 1 below.
- the present invention it is possible to overcome the shortcomings of the existing drugs used as MAO-B inhibitors, and in particular, side effects of the existing drugs exhibiting therapeutic effects by irreversibly acting through covalent bonds with MAO-B. It is possible to provide a therapeutic agent that reversibly inhibits MAO-B through non-covalent binding to alleviate or eliminate. In particular, it is possible to provide new compounds with greater stability and efficacy than existing reversible MAO-B inhibitors.
- FIG. 1 is a flowchart of a reversibility verification experiment for Mao-B (MAO-B; Monoamine Oxydase-B) of an alpha-aminoamide derivative according to an embodiment of the present invention.
- MAO-B Monoamine Oxydase-B
- Figure 2a shows the dopaminergic neuron protective effect (Pre-treatment) of compound 9 in medulla and striatum.
- Figure 2b shows the post-treatment neuroprotective effect of compound 9 in black matter and striatum.
- FIG. 2C shows the dopaminergic neuronal protective effect (30-day pre-treatment) of compound 9 in medulla and striatum.
- Figure 3a shows the spike probability according to stimulus intensity in APP / PS1 mice (Jo et al., Nature Medicine, 2014).
- Figure 3b shows the spike probability according to stimulus intensity in the APP / PS1 mouse of compound 9.
- Figure 4 shows the excitability verification results in DGGCs (dentate gyrus granule cells) of compound 9.
- Figure 5 shows the binding mode prediction results of the compound 9 and the sapinamide.
- Figure 6 shows the weight change of the mice ingested the normal diet and high fat diet.
- Figure 7 is a result showing the change in the reactive glial cells of the mice ingested the normal diet and high fat diet according to an embodiment of the present invention.
- Figure 9 is a result showing the change in the amount of reactive glia cells and GABA of the normal diet intake mice, high fat diet intake mice, high fat diet intake mice provided with alpha-aminoamide derivatives in accordance with an embodiment of the present invention.
- the present invention relates to an alpha-aminoamide derivative represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof.
- R is hydrogen or an alkyl group
- X is selected from hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group and a halogenated alkoxy group.
- the asterisk (*) means optical activity.
- said R is selected from hydrogen, a C 1 -C 7 alkyl group
- X is selected from hydrogen, a halogen group, a C 1 -C 7 alkyl group, a halogenated C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, a halogenated C 1 -C 7 alkoxy group.
- R is selected from hydrogen, methyl group, ethyl group, n -propyl group, isopropyl group, cyclopropyl group, n -butyl group, isobutyl group, sec -butyl group, tert -butyl group;
- X is selected from halogen group, halogenated methyl group, halogenated ethyl group, halogenated methoxy group, halogenated ethoxy group, methoxy group and ethoxy group.
- R is selected from hydrogen, methyl group, isopropyl group, isobutyl group;
- X is selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy and methoxy groups.
- R and X are the same as above, there is little channel inhibitory effect, and in particular, it shows a significantly lower channel inhibitory effect than the conventional product sapinamide, which is well known as a Maobi inhibitor. It has the advantage of ensuring stability.
- R is selected from hydrogen, methyl group, isopropyl group, isobutyl group;
- X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- It is selected from a methoxy group, p -fluoro group, m -fluoro group.
- R is selected from hydrogen, methyl group, isopropyl group, isobutyl group;
- X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- It is selected from methoxy group.
- said R is hydrogen or methyl group;
- X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- It is selected from methoxy group.
- said R is hydrogen or methyl group;
- X is p-it is selected from trifluoromethoxy Messenger group-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree methyl group, m fluoro.
- R and X are the same as above, it was confirmed that additionally showing the effect of blocking the antibody-dependent cytotoxicity completely, otherwise.
- said R is hydrogen or methyl group
- X is a p -trifluoromethyl group or p -trifluoromethoxy.
- said R is a methyl group
- X is a p -trifluoromethyl group or p -trifluoromethoxy.
- said R is a methyl group
- X is a p -trifluoromethyl group
- the alpha-aminoamide derivative is selected from the following compounds.
- the alpha-aminoamide derivative according to various embodiments of the present invention may be an (S) -isomer.
- the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate or sulfate and organic acid salts such as carboxylic acid salts or sulfonic acid salts.
- the kinds of carboxylates include, but are not limited to, acetate, maleate, fumarate, malate, citrate, tartarate, lactate or benzoate.
- the type of sulfonate includes but is not limited to methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or naphthalenedi sulfonate.
- the present invention provides a method for preparing an alpha-aminoamide derivative comprising the following steps.
- R and X are as defined above.
- the preparation method may be represented by the following [Scheme 1].
- the R-type compound and the S-type compound may be separately synthesized through the synthesis process of the following steps.
- the present invention provides a Maobi- (MAO-B; monoamine Oxidase B) inhibitor comprising the alpha-aminoamide derivative or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
- MAO-B monoamine Oxidase B
- the alpha-aminoamide derivative according to the present invention has an excellent effect of inhibiting the activity of monoamine oxidase B and can be usefully used as a Maobi inhibitor.
- the present invention also provides a pharmaceutical composition for treating or preventing degenerative neurological diseases comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
- Examples of degenerative neurological diseases in the present invention include, but are not limited to, Parkinson's disease, Alzheimer's disease, and the like.
- Another aspect of the invention relates to the use of an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof in accordance with various embodiments of the invention for the manufacture of a medicament for the treatment or prevention of degenerative neurological diseases.
- Another aspect of the present invention is to treat a degenerative neurological disease by administering to a mammal an alpha-aminoamide derivative according to various embodiments of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising the same. It is about how to prevent.
- the present invention also provides a gamma amino butyric acid (GABA) production inhibitor comprising the alpha-aminoamide derivative or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
- GABA gamma amino butyric acid
- the alpha-aminoamide derivatives according to the present invention can inhibit GABA production and secretion by inhibiting Maobi, a causative agent of GABA production, and thus can be usefully used as inhibitors of GABA production.
- the alpha-aminoamide derivative according to the present invention may exhibit an anti-obesity effect by promoting energy consumption by eliminating or activating the inhibition of POMC neurons, which selectively induce energy consumption. It can be usefully used as a pharmaceutical composition for treatment or prevention.
- L-Alaninamide hydrochloride or D-Alaninamide hydrochloride was used to conduct an inductive reaction with the compound of step (a) to obtain an imine compound (step b, scheme 1b), followed by reduction with sodium cyanoborohydride to obtain an amine compound (step c, Scheme 1c).
- the organic layer was dried over sodium sulfate, concentrated in vacuo, and the concentrated reaction solution was dissolved in anhydrous methanol at 1.0 molar concentration, and 4.0 equivalents of sodium cyanoborohydride was added at 0 ° C. After reaction at room temperature for 18 hours, and after the reaction, the reaction solution was washed with ethyl acetate and distilled water. The organic layer was dried over sodium sulfate, concentrated in vacuo, separated and purified via silica gel column chromatography.
- the preparation step of the salt is an optional and optional step which may be carried out as necessary or may be omitted.
- Compounds in salt form are synthesized to improve the solubility of the amine compounds synthesized in this step.
- the salt form of the compound may be synthesized using an acid, and the type of the acid is as described above, but is not limited thereto.
- a salt compound was synthesized using methanesulfonic acid.
- Ethyl acetate was heated to 50 to 55 ° C. to dissolve all 1.0 equivalents of step (c) compound, and then 1.25 equivalents of methanesulfonic acid were added. After 1 hour, the reaction mixture was cooled to room temperature and filtered using a vacuum filter. The filtrate was washed with ethyl acetate and dried without further purification.
- safinamide which is well known as a reversible Maobi inhibitor
- sapinamide is a benzyloxyphenyl group instead of a biphenyl group in alpha-aminoamide according to the present invention, the structure is as shown in [Formula 2].
- Sapinamide is well known as a material which shows excellent maobia inhibitory effect and efficacy in animals. However, since it also acts as a calcium channel and sodium channel inhibitor, there is a limit to use as a selective Maobi inhibitor.
- BBB blood-brain barrier
- the position of the X substituent is preferably in the order of para, meta, ortho, and especially the position of para is most preferred in terms of Maobi inhibitory activity, and in contrast to the case of ortho and meta, The effect of remarkably lowering dependent cytotoxicity is also obtained, which is preferable.
- the S type isomer is preferable in terms of Maobi inhibitory activity than the R type isomer, and the recovered Maobi activity is remarkably superior, and the metabolic stability and cytotoxicity are significantly lower, which is preferable.
- R substituents are -CH 3 and -H excellent in Maobi activity, especially -CH 3 compared to -H or -CH (CH 3 ) 2 and -CH 2 CH (CH 3 ) 2 Not only is it superior in Maobi activity, it is preferable because it can further obtain a result of easier passage of the blood brain barrier.
- Monoamine oxidase B human-derived enzyme at a concentration of 5 mg / mL was diluted 1/40 with 0.05 M sodium phosphate (pH 7.4) buffer to prepare an enzyme buffer, and 441 ⁇ L of the enzyme buffer and 0.1 mM of the compound of Example 9 were prepared. 9 ⁇ L was mixed and reacted for 2 hours.
- the reacted compound solution was divided into two 200 ⁇ L portions, one was transferred to a 96 well plate (A), the other was placed in a centrifugal filtration filter (Amicon® Ultra-3K), and centrifuged at 14,000 g for 20 minutes using a centrifuge (B). . 500 ⁇ L of 0.05 M sodium phosphate (pH 7.4) buffer was added to the centrifugal filter, followed by centrifugation at 14000 g for 20 minutes, and the procedure was repeated twice.
- both compounds showed an inhibitory effect of 80% or more when treated with 1 ⁇ M.
- Maobi Enzyme After washing Maobi Enzyme three times using a buffer and then again verifying the activity of Maobi, selegiline that inhibits irreversibly retained the inhibitory effect, but the compound of the present invention was washed out in the washing process to inhibit the inhibitory effect Did not look.
- the inhibitor compound was removed by washing, it was confirmed that the compound of the present invention is a reversible inhibitor based on the recovery of Maobienzyme activity.
- Compound 9 was compared with Safinamide, an existing Maobi inhibitor, in the MPTP mouse model of Parkinson's disease animal model.
- MPTP was intraperitoneally injected with 20 mg / kg
- various Maobi inhibitors including Compound 9 were orally administered with 10 mg / kg.
- Maobi inhibitors were administered for 3 days from the day before the injection of MPTP, and in order to confirm the effect, TH (tyrosine hydroxylase), which is a marker of dopaminergic neurons, was quantitatively analyzed by immunohistochemical method.
- TH tyrosine hydroxylase
- Example 4 the experiment was conducted using Compound 9 to confirm the efficacy of the reversible Maobi inhibitors in APP / PS1 mice.
- Compound 9 was mixed with drinking water of APP / PS1 mice to be ingested freely for 2 weeks at a 10 mg / kg / day dose.
- brain tissue sections were prepared and the electrodes were connected to the granule cells of the dentate gyrus by the patch-clamp technique. Through this electrode, it is possible to detect changes in cell membrane potential and granulation of granule neurons.
- the spike probability was calculated by counting the number of granulation neuronal ignition reactions to the teeth and 10 electrical stimulations. Thus, after treating Compound 9 for 2 weeks, the ignition probability according to the stimulus was measured while changing the intensity of the electrical stimulus. As shown in FIG.
- Sapinamide a conventional reversible Maobi inhibitor
- Sapinamide is well known as an inhibitor of sodium channels and calcium channels as well as Maobi inhibitory effects. While minimizing such channel inhibition, Parkinson's disease and Alzheimer's disease treatment through selective Maobi inhibition can secure stability as a treatment for brain disease. In order to verify this channel inhibition effect, it was confirmed by electrophysiology experiment how to inhibit the excitability of the channel using DGGCs (dentate gyrus granule cells) of the hippocampus.
- DGGCs dentate gyrus granule cells
- sapinamide showed about 40% excitability inhibitory effect at 10 ⁇ M, while Compound 9 hardly inhibited. Even at high concentrations of 50 ⁇ M, Compound 9 showed a lower inhibitory effect than that of sapinamide, indicating that the excitability inhibitory effect of DGGCs in hippocampus was significantly lower than that of sapinamide. This result shows that Compound 9 secured stability as a selective Maobi inhibitor through a significantly lower channel inhibitory effect than sapinamide.
- the binding mode was predicted by docking experiment of compound 9 against Maobi.
- the binding force was excellent in the pocket known as Maobi's active site (SP score:- 10.862 kcal / mol).
- SP score -11.795 kcal / mol.
- mice The 7-week-old mice were divided into two groups to provide a normal diet (white, Chow) and high fat diet (blue, HFD), respectively, and observed for 8 weeks.
- the total calories provided to the normal diet and high fat diet mice were to be the same.
- the average weight of the dietary mice group was measured to be 3 g after 8 weeks, which increased by about 20% from the initial weight of 2.5 g.
- the average weight of the mice fed the high-fat diet was about 4.8 g, which was about doubled. Increased.
- mice fed a high-fat diet for eight weeks observed changes in reactive glia in the arch nucleus.
- GFAP which is a biomarker of reactive glial cells
- GABA gamma-aminobutyric acid
- the weight loss effect of the compound of Example 9 was verified in a high fat diet (HFD) mouse model, an obese animal model. As shown in FIG. 8, as a result of administering the compound of Example 9 at various concentrations, the weight increase was suppressed by high fat intake in a concentration-dependent manner. Specifically, the high-fat diet mouse model was confirmed that the weight is increased by more than 20% compared to the normal mouse (control), the weight of the overall weight was administered by administering the compound of Example 9. In particular, 10 mg / kg / day group and 100 mg / kg / day group was confirmed the effect of weight loss in a concentration-dependent manner.
- HFD high fat diet
- the alpha-aminoamide derivative according to the present invention can reversibly inhibit MAO-B and exhibit efficacy in anti-obesity treatment, and thus a composition including the same as an active ingredient may be usefully used as an anti-obesity therapeutic agent. have.
- the alpha-aminoamide derivatives can prevent overproduction of GABA in hypothalamic reactive glia by inhibiting maobia, thus acting on POMC neurons to selectively induce energy consumption, thereby exhibiting a therapeutic effect on obesity. Therefore, it is possible to overcome the side effects and lack of efficacy of the conventional central nervous system and sugar / fat metabolic control function centered on obesity treatments can be usefully applied as a new obesity treatment. In addition, because it can act to inhibit the degeneration or death of dopamine neurons, it can be usefully applied as a therapeutic agent for degenerative nervous system diseases such as Parkinson's disease, Alzheimer's disease.
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Abstract
Description
구분 | stereo | R | X | MAO-B(IC50, ㎛) | MAO-A(IC50, ㎛) |
실시예 1 | S | CH3 | 2'-F | >10 | >100 |
실시예 2 | S | CH3 | 3'-F | >10 | >100 |
실시예 3 | S | CH3 | 4'-F | >10 | >100 |
실시예 4 | S | CH3 | 2'-Cl | >10 | >100 |
실시예 5 | S | CH3 | 3'-Cl | 0.442 | >100 |
실시예 6 | S | CH3 | 4'-Cl | 0.416 | >100 |
실시예 7 | S | CH3 | 2'-CF3 | >10 | >100 |
실시예 8 | S | CH3 | 3'-CF3 | 0.316 | >100 |
실시예 9 | S | CH3 | 4'-CF3 | 0.042 | >500 |
실시예 10 | S | CH3 | 3'-OCF3 | 0.216 | >100 |
실시예 11 | S | CH3 | 4'-OCF3 | 0.098 | >100 |
실시예 12 | S | CH3 | 3'-OCH3 | 3.33 | >100 |
실시예 13 | S | CH3 | 4'-OCH3 | 1.06 | >100 |
실시예 14 | R | CH3 | 3'-F | >10 | >100 |
실시예 15 | R | CH3 | 4'-CF3 | 0.082 | >100 |
실시예 16 | S | H | 4'-CF3 | 0.126 | >100 |
실시예 17 | S | CH(CH3)2 | 4'-CF3 | 4.073 | >100 |
실시예 18 | S | CH2CH(CH3)2 | 4'-CF3 | 5.302 | >100 |
s-safinamide | - | - | - | 0.12 | >100 |
selegilne | - | - | - | 0.009 | ~1 |
구분 | 용량 | A. 마오비 저해효능 | B. 마오비 저해효능 | 복구된 마오비 활성 | 가역성 |
Selegiline | 1 μM | > 90% | > 90% | 0% | 비가역 |
실시예 9 | 1 μM | 82% | <15% | >85% | 가역 |
Claims (20)
- 제1항에 있어서, 상기 R은 수소, C1-C7 알킬기 중에서 선택되고;상기 X는 수소, 할로겐기, C1-C7 알킬기, 할로겐화 C1-C7 알킬기, C1-C7 알콕시기, 할로겐화 C1-C7 알콕시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염:
- 제1항에 있어서, 상기 R은 수소, 메틸기, 에틸기, n-프로필기, 이소프로필기, 시클로프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 중에서 선택되고;상기 X는 할로겐기, 할로겐화 메틸기, 할로겐화 에틸기, 할로겐화 메톡시기, 할로겐화 에톡시기, 메톡시기, 에톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소, 메틸기, 이소프로필기, 이소부틸기 중에서 선택되고;상기 X는 플루오로기, 클로로기, 트리클로로메틸기, 트리클로로메톡시기, 메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소, 메틸기, 이소프로필기, 이소부틸기 중에서 선택되고;상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기, p-플루오로기, m-플루오로기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소, 메틸기, 이소프로필기, 이소부틸기 중에서 선택되고;상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소 또는 메틸기인 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소 또는 메틸기이고;상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소 또는 메틸기이고;상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 수소 또는 메틸기이고;상기 X는 p-트리클로로메틸기 또는 p-트리클로로메톡시인 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 메틸기이고;상기 X는 p-트리클로로메틸기 또는 p-트리클로로메톡시인 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R은 메틸기이고;상기 X는 p-트리클로로메틸기인 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- 제1항에 있어서, 상기 알파-아미노아미드 유도체는 하기 화합물 중에서 선택된 것임을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염:(S)-2-(((2'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((3'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((4'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((2'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((3'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((4'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((2'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((3'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((3'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((4'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((3'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S)-2-(((4'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(R)-2-(((3'-플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)아세트아미드 메탄설포네이트,(R)-3-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)부탄아미드 메탄설포네이트,(R)- 4-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)펜탄아미드 메탄설포네이트.
- 제1항에 있어서, 상기 알파-아미노아미드 유도체는 (S)-이성질체인 것을 특징으로 하는 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용가능한 염.
- (A) 하기 화학식 1a의 화합물과 하기 화학식 1b의 화합물을 반응시켜 하기 화학식 1c의 화합물을 합성하는 단계:[화학식 1a][화학식 1b][화학식 1c](B) 상기 화학식 1c의 화합물과 하기 화학식 1d의 화합물을 반응시켜 하기 화학식 1e의 화합물을 합성하는 단계:[화학식 1d][화학식 1e](C) 상기 화학식 1e의 화합물을 하기 화학식 1의 알파-아미노아미드 유도체로 변환시키는 단계를 포함하는 것을 특징으로 하는 알파-아미노아미드 유도체의 제조방법:[화학식 1]상기 R은 수소, 메틸기, 에틸기, n-프로필기, 이소프로필기, 시클로프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 중에서 선택되고;상기 X는 할로겐기, 할로겐화 메틸기, 할로겐화 에틸기, 할로겐화 메톡시기, 할로겐화 에톡시기, 메톡시기, 에톡시기 중에서 선택된다.
- 제1항 내지 제14항 중 어느 한 항에 따른 알파-아미노아미드 유도체 또는 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 모노아민 옥시다아제 B(MAO B) 저해제.
- 제1항 내지 제14항 중 어느 한 항에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물을 포함하는 퇴행성 신경계 질환 치료 또는 예방용 약학 조성물.
- 제17항에 있어서, 상기 퇴행성 신경계 질환은 파킨슨병, 알츠하이머병, 뇌전증, 우울증 중에서 선택된 것임을 특징으로 하는 신경계 뇌질환 치료 또는 예방용 약학 조성물.
- 제1항 내지 제14항 중 어느 한 항에 따른 알파-아미노아미드 유도체 또는 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 감마아미노 뷰티르산(γ-Aminobutyric acid; GABA) 생성 저해제.
- 제1항 내지 제14항 중 어느 한 항에 따른 알파-아미노아미드 유도체 또는 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 비만 치료 또는 예방용 약학 조성물.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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CN201580053824.8A CN106795098B (zh) | 2014-10-02 | 2015-09-24 | α-氨基酰胺衍生化合物及包含其的药物组合物 |
EP15847985.7A EP3202759B1 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition containing the same |
CA2963371A CA2963371C (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition containing the same |
RU2017114506A RU2673622C2 (ru) | 2014-10-02 | 2015-09-24 | Соединения альфа-аминоамидных производных и содержащие их фармацевтические композиции |
BR112017006690-4A BR112017006690B1 (pt) | 2014-10-02 | 2015-09-24 | Derivado de ?-aminoamida ou um sal aceitável farmaceuticamente do mesmo, método para a preparação de um derivado de ?-aminoamida, uso do inibidor da monoamina-oxidase b (mao-b) e uso do inibidor da produção de ácido g-aminobutírico (gaba) |
AU2015324914A AU2015324914B2 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition containing the same |
JP2017518101A JP6446131B2 (ja) | 2014-10-02 | 2015-09-24 | α−アミノアミド誘導体化合物及びこれを含む薬学的組成物 |
US15/516,395 US10676425B2 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
ES15847985T ES2774800T3 (es) | 2014-10-02 | 2015-09-24 | Compuesto derivado de alfa-aminoamida y composición farmacéutica que contiene el mismo |
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EP3750529A4 (en) * | 2018-02-07 | 2021-12-01 | Neurobiogen Co., Ltd. | COMPOSITION FOR THE PREVENTION AND TREATMENT OF SPINAL MARSION LESIONS |
US20210401782A1 (en) * | 2018-04-04 | 2021-12-30 | Neurobiogen Co.,Ltd | Composition for preventing and treatment of stroke |
US11261186B2 (en) | 2014-12-24 | 2022-03-01 | Lg Chem. Ltd. | Biaryl derivative as GPR120 agonist |
KR20220038232A (ko) * | 2020-09-18 | 2022-03-28 | 한국과학기술연구원 | 류마티스 관절염 예방 또는 치료용 조성물 |
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CN109251155A (zh) * | 2017-07-14 | 2019-01-22 | 广东东阳光药业有限公司 | α-氨基酰胺衍生物及其用途 |
CN108912029B (zh) * | 2017-08-25 | 2021-10-01 | 广东东阳光药业有限公司 | 含氮杂环酰胺衍生物及其用途 |
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WO2007071311A1 (en) | 2005-12-22 | 2007-06-28 | Newron Pharmaceuticals S.P.A. | 2 -phenylethylamino derivatives as calcium and/or sodium channel modulators |
WO2012078994A1 (en) | 2010-12-09 | 2012-06-14 | Janssen Pharmaceutica Nv | Imidazo [1, 2-a] pyridine sulfonamides as trpm8 modulators |
KR101679568B1 (ko) | 2014-10-02 | 2016-11-28 | 한국과학기술연구원 | 알파-아미노아미드 유도체 화합물 및 이를 포함하는 약학적 조성물 |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11261186B2 (en) | 2014-12-24 | 2022-03-01 | Lg Chem. Ltd. | Biaryl derivative as GPR120 agonist |
EP3750529A4 (en) * | 2018-02-07 | 2021-12-01 | Neurobiogen Co., Ltd. | COMPOSITION FOR THE PREVENTION AND TREATMENT OF SPINAL MARSION LESIONS |
US20210401782A1 (en) * | 2018-04-04 | 2021-12-30 | Neurobiogen Co.,Ltd | Composition for preventing and treatment of stroke |
RU2765151C1 (ru) * | 2018-04-04 | 2022-01-26 | Нейробайоджен Ко., Лтд. | Композиция для предотвращения или лечения инсульта |
EP3777848A4 (en) * | 2018-04-04 | 2022-05-11 | Neurobiogen Co., Ltd. | COMPOSITION FOR THE PREVENTION OR TREATMENT OF STROKE |
KR20220038232A (ko) * | 2020-09-18 | 2022-03-28 | 한국과학기술연구원 | 류마티스 관절염 예방 또는 치료용 조성물 |
KR102531540B1 (ko) | 2020-09-18 | 2023-05-16 | 한국과학기술연구원 | 류마티스 관절염 예방 또는 치료용 조성물 |
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US20170298011A1 (en) | 2017-10-19 |
AU2015324914A1 (en) | 2017-05-04 |
JP2017531647A (ja) | 2017-10-26 |
EP3202759A1 (en) | 2017-08-09 |
CN106795098B (zh) | 2020-07-14 |
ES2774800T3 (es) | 2020-07-22 |
RU2017114506A3 (ko) | 2018-11-05 |
EP3202759A4 (en) | 2018-05-09 |
RU2017114506A (ru) | 2018-11-05 |
PT3202759T (pt) | 2020-03-06 |
US20200308104A1 (en) | 2020-10-01 |
EP3202759B1 (en) | 2019-12-18 |
AU2015324914B2 (en) | 2018-10-04 |
US10676425B2 (en) | 2020-06-09 |
CN106795098A (zh) | 2017-05-31 |
BR112017006690A2 (ko) | 2018-01-02 |
BR112017006690A8 (pt) | 2018-02-06 |
US11053190B2 (en) | 2021-07-06 |
BR112017006690B1 (pt) | 2023-11-21 |
CA2963371A1 (en) | 2016-04-07 |
RU2673622C2 (ru) | 2018-11-29 |
JP6446131B2 (ja) | 2018-12-26 |
CA2963371C (en) | 2020-06-02 |
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