KR101859074B1 - Novel glycine amide compound or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of diseases induced by activation of sodium channel containing the same as an active ingredient - Google Patents
Novel glycine amide compound or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of diseases induced by activation of sodium channel containing the same as an active ingredient Download PDFInfo
- Publication number
- KR101859074B1 KR101859074B1 KR1020160010605A KR20160010605A KR101859074B1 KR 101859074 B1 KR101859074 B1 KR 101859074B1 KR 1020160010605 A KR1020160010605 A KR 1020160010605A KR 20160010605 A KR20160010605 A KR 20160010605A KR 101859074 B1 KR101859074 B1 KR 101859074B1
- Authority
- KR
- South Korea
- Prior art keywords
- acetamide
- methylamino
- indol
- pharmaceutically acceptable
- compound
- Prior art date
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- -1 glycine amide compound Chemical class 0.000 title claims abstract description 65
- 150000003839 salts Chemical class 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 239000004480 active ingredient Substances 0.000 title claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 17
- 201000010099 disease Diseases 0.000 title abstract description 16
- 108010052164 Sodium Channels Proteins 0.000 title abstract description 15
- 102000018674 Sodium Channels Human genes 0.000 title abstract description 15
- 230000002265 prevention Effects 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title description 25
- 230000004913 activation Effects 0.000 title 1
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- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 27
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- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
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Images
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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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
Abstract
The present invention relates to a novel glycine amide compound or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating a sodium channel activity-related disease, Inhibitory activity and excellent neuropathic pain inhibiting activity, it can be usefully used as a pharmaceutical composition for the prevention and treatment of neuropathic pain containing it.
Description
The present invention relates to a novel glycine amide compound or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating a sodium channel activity-related disease.
Pain is a useful warning system that protects the life of an individual from harmful environments, or a pathologic pain that lasts for many years, which is the cause of physical and mental deprivation of the patient and is classified as serious enough to attempt suicide . In addition, chronic pathological pain is the most common disease, with a direct medical cost of $ 600 billion a year and an estimated 100 million US adults. Chronic pathological pain is a universal disease that has been receiving medical attention for a long time and its incidence is steadily increasing due to the recent increase in traffic accidents and safety accidents.
On the other hand, neuropathic pain refers to pathologic pain caused by nerve damage or abnormal nerve function (postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, spinal cord injury, etc.) It is known to be the most painful pain. The lesions affecting the peripheral nerves cause axonopathy and dehydration, resulting in neuropathic changes. They also affect the damaged area by initiating membrane repair, Excessive ion release is induced to constitute an early neuropathic pain signal, and chronic pain is caused by excessively inducing spontaneous pain to continuously increase dislocation.
Since neuropathic pain is caused by excessive ion release, it is possible to treat neuropathic pain using drugs that control or inhibit ion release of ion channels.
Gabapentin, a second-generation anticonvulsant recently developed as a representative neuropathic pain medication, is the first-line medication for neuropathic pain, which reduces central sensation and affects neuropathic pain Is an anticonvulsant agent. Specifically, gabapentin binds to the alpha-2-delta subunit of the dislocation-dependent calcium channel at the periphery of the pain receptor and exhibits pharmacological action, including peripheral neuropathic pain (PNP) Neuropathy (PHN) and diabetic neuropathy (PDN) are effective drugs for relieving pain immediately after starting treatment. However, side effects are dizziness, insomnia, rarely gastrointestinal symptoms and peripheral edema.
On the other hand, a method for suppressing VGSCs (Voltage-gated sodium channels) can be used for the treatment of neuropathic pain. Because VGSCs are ion channels that play a fundamental role in the regulation of cellular stimulation and abnormal activity associated with several pathologies, including cardiac arrhythmias, epilepsy, neuropathic disorders, ankylosing spondylitis, chronic and neuropathic pain, treatment of neuropathic pain , Which can be a good target of the drug for the neuronal cell, and specifically using a drug that regulates the voltage-gated pore of VGSCs that selectively pass the sodium ion to determine electrical stimulation of sensory neurons, Thereby controlling neuropathic pain by controlling or inhibiting stimulation (Non-Patent Document 1).
In addition, recent neuropathic pain is associated with the channels of Nav1.3, Nav1.7, Nav1.8, and Nav1.9 among VGSCs, and NaV1.7 in particular is directly correlated with pain acne and severe paroxysmal pain disorders And the development of drugs that target pain-associated VGSCs is becoming more urgent.
Accordingly, the present inventors have made efforts to develop a therapeutic agent for neuropathic pain through regulation and inhibition of VGSCs, the compound of the present invention has a remarkably excellent inhibitory effect on Nav1.7, among VGSCs, And the present invention was completed.
It is an object of the present invention to provide a novel glycineamide compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a novel glycine amide compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by the activity of the sodium channel containing the novel glycine amide compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .
Another object of the present invention is to provide a health functional food for preventing or ameliorating a disease caused by the activity of a sodium channel containing the novel glycine amide compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient .
In order to achieve the above object,
The present invention provides a novel glycineamide compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The present invention also provides a process for preparing the novel glycine amide compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases caused by the activity of the sodium channel containing the novel glycineamide compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides a health functional food for preventing or ameliorating a disease caused by the activity of a sodium channel containing the novel glycine amide compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient .
The present invention relates to a novel glycine amide compound or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating a sodium channel activity-related disease, Inhibitory activity and excellent neuropathic pain inhibiting activity, it can be usefully used as a pharmaceutical composition for the prevention and treatment of neuropathic pain containing it.
FIG. 1 is a graphical representation of the pain sensitivity of rats, which were obtained by injecting the compound of Example 14 at 5, 10 and 50 μg, respectively.
The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
(In the formula 1,
R 1 is an unsubstituted or substituted C 6-15 aryl, or an unsubstituted or substituted 3-15-membered heteroaryl comprising one or more heteroatoms selected from the group consisting of N, O and S,
The substituted C 6-15 aryl or substituted 3-15 heteroaryl is optionally substituted with one or more substituents selected from the group consisting of:
Halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, -NO 2 , unsubstituted or substituted C 6-10 aryl, (N, O and S Unsubstituted or substituted 4-8 atoms containing one or more heteroatoms), (unsubstituted or substituted 4-8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, Lt; / RTI > heteroaryl), unsubstituted or substituted C6-10 aryloxy, and unsubstituted or substituted C6-10 -benzyloxy,
The substituted C 6-10 aryl, the substituted 4-8 membered heterocycloalkyl, the substituted 4-8 membered heteroaryl, the substituted C 6-10 aryloxy, or the substituted C 6-10 benzyl Oxy,
Straight -chain or branched alkyl of C 1-5 , C 1-5 straight-chain or branched alkoxy unsubstituted or substituted with one or more halogens, halogen and -CN).
Preferably, in Formula 1, R 1 is an unsubstituted or substituted C 6 aryl, or an unsubstituted or substituted 5-9 atom containing one or more hetero atoms selected from the group consisting of N, O and S Lt; / RTI >
The substituted C 6 aryl or substituted 5-9-membered heteroaryl is optionally substituted with one or more substituents selected from the group consisting of:
Halogen, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, -NO 2 , unsubstituted or substituted C 6-9 aryl, N, O and S An unsubstituted or substituted 5-7 membered heterocycloalkyl containing one or more heteroatoms, an unsubstituted or substituted 5-7 membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, , Unsubstituted or substituted C 6-9 aryloxy, and unsubstituted or substituted C 6-9 benzyloxy,
The substituted C 6-9 aryl, the substituted 5-7 membered heterocycloalkyl, the substituted 5-7 membered heteroaryl, the substituted C 6-9 aryloxy, or the substituted C 6-9 benzyl Oxy,
Straight or branched alkyl having 1 to 3 carbon atoms, unsubstituted or substituted with one or more halogens, straight or branched alkyl having 1 to 3 carbon atoms, substituted or unsubstituted alkoxy having 1 to 3 carbon atoms, halogen and -CN.
More preferably, R 1 of Formula 1,
Most preferably, the compounds represented by the above formula (1) according to the present invention include the following compounds.
(1) 2 - ((5- (3- (Trifluoromethyl) phenyl) furan-2-yl) methylamino) acetamide;
(2) 2- (4- (4-Methylpiperazin-1-yl) benzylamino) acetamide;
(3) 2- (4-morpholinobenzylamino) acetamide;
(4) 2 - ((5- (4-Chlorophenyl) furan-2-yl) methylamino) acetamide;
(5) 2- (4- (Pyridin-4-yl) benzylamino) acetamide;
(6) 2 - ((5- (4-chlorophenyl) isooxazol-3-yl) methylamino) acetamide;
(7) 2 - ((5- (3-Chloro-4-methoxyphenyl) furan-2-yl) methylamino) acetamide;
(8) 2- (4- (Pyrimidin-5-yl) benzylamino) acetamide;
(9) 2- (4- (4-thiophenoxy) benzylamino) acetamide;
(10) 2 - ((5-chloro-1H-indol-3-yl) methylamino) acetamide;
(11) 2 - ((lH-indol-3-yl) methylamino) acetamide;
(12) 2 - ((2-phenyl-1H-indol-3-yl) methylamino) acetamide;
(13) 2- (4- (4-Fluorophenoxy) benzylamino) acetamide;
(14) 2- (4- (4-Chlorophenoxy) benzylamino) acetamide;
(15) 2 - ((5- (Benzyloxy) -1H-indol-3-yl) methylamino) acetamide;
(16) 2 - ((5-Bromo-1H-indol-3-yl) methylamino) acetamide;
(17) 2 - ((6-fluoro-1H-indol-3-yl) methylamino) acetamide;
(18) 2 - ((5-methoxy-1H-indol-3-yl) methylamino) acetamide; And
(19) 2 - ((7-Nitro-1H-indol-3-yl) methylamino) acetamide.
The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.
In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.
The present invention also relates to a process for preparing a compound represented by the general formula (1), which comprises reacting a compound represented by the general formula (2) and a compound represented by the general formula (3) ≪ / RTI >
[Reaction Scheme 1]
(In the above Reaction Scheme 1,
R 1 is the same as defined in the above formula (1)).
Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.
In the process for preparing a compound represented by the formula 1 according to the present invention, the above step is a step of reacting a compound represented by the formula 2 and a compound represented by the
The organic solvent may be an organic solvent such as dichloromethane (DCM), tetrahydrofuran, dioxane, ethyl ether, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloroethane, acetonitrile , Toluene, chlorobenzene, and acetone. Preferably, the organic solvent may be dichloromethane.
In addition, the above-mentioned preparation step can be carried out according to the following reaction scheme 1, but is not limited thereto.
(In the above Scheme 1-1, R 1 is the same as defined in Formula 1)
The present invention also provides a pharmaceutical composition for the prevention or treatment of diseases caused by the activity of the sodium channel, which comprises the compound represented by the above-mentioned formula (1), its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient do. At this time, the disease caused by the activity of the sodium channel is preferably neuropathic pain.
Furthermore, the present invention provides a health functional food for preventing or ameliorating diseases caused by the activity of the sodium channel containing the compound represented by the above-mentioned formula (1), its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient do. At this time, the disease caused by the activity of the sodium channel is preferably neuropathic pain.
Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.
However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto.
Example 1 Preparation of 2 - ((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methylamino) acetamide
Dry methylene chloride was added to a flask containing 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde (1 eq) under nitrogen gas displacement. Glycinamide (2-aminoacetamide) was added thereto and stirred for 30 minutes. Sodium triacetoxyborohydride (1.5 eq) was then added to the mixture and stirred at ambient temperature for 16 hours. The methylene chloride solvent of the reaction mixture was then evaporated under reduced pressure. Then, the product was purified by column chromatography (EA: Hex = 3: 1) to obtain the target compound.
1 H NMR (400MHz, DMSO- d 6) δ 7.96-7.95 (m, 2H), 7.62 (dd, J = 4.4Hz, J = 2.8Hz, 2H), 7.23-7.17 (m, 1H), 7.13 (d , J = 3.2Hz, 1H), 6.34 (d, J = 3.2Hz, 2H) 5.75 (s, 1H) 3.85 (s, 2H), 3.14 (s, 2H) HR-FABMS Calcd for C 14 H 13 F 3 N 2 O 2 .
Example 2 Preparation of 2- (4- (4-methylpiperazin-1-yl) benzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (4-methylpiperazinyl) benzaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2- , The target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 7.25 (brs, 1H) 7.20-7.01 (m, 2H), 6.89-6.86 (m, 2H), 6.28 (s, 1H) 3.17-2.98 (m, 7H) , 2.43 (t, J = 4.8Hz , 2H), 2.21 (s, 1H), 1.84 (s, 5H) HR-FABMS Calcd for C 14 H 22 N 4 O.
≪ Example 3 > Preparation of 2- (4-morpholinobenzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (4-formylphenyl) morpholine was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde of Example 1 The objective compound was prepared in the same manner as in the preparation method.
1 H NMR (400MHz, DMSO- d 6) δ 7.16 (d, J = 8.4Hz, 2H), 6.90-6.87 (m, 2H), 4.97 (brs, 1H) 3.723 (t, J = 4.8Hz, 3H) , 3.32-3.27 (m, 9H), 3.06 (t, J = 4.8Hz, 2H) HR-FABMS Calcd for C 13 H 19 N 3 O 2.
Example 4 Preparation of 2 - ((5- (4-chlorophenyl) furan-2-yl) methylamino) acetamide
Except that 5- (4-chlorophenyl) furan-2-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde in Example 1, The procedure of Example 1 was repeated to produce the desired compound.
1 H NMR (400MHz, DMSO- d 6) δ 7.68 (dd, J = 6.8Hz, J = 2Hz, 2H), 7.48 (dd, J = 6.6Hz J = 2Hz, 2H), 6.95 (d, J = 2Hz , 1H), 6.50 (d, J = 3.6Hz, 1H), 5.76 (s, 2H), 3.81 (s, 2H) 3.22 (s, 1H) 3.11 (s, 1H) HR-FABMS Calcd for C 13 H 13 ClN 2 O 2 .
Example 5 Preparation of 2- (4- (pyridin-4-yl) benzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (4-formylphenyl) pyridine was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2- The objective compound was prepared in the same manner as in the production method.
1 H NMR (400MHz, DMSO- d 6) δ 8.62 (dd, J = 4.4Hz, J = 1.6Hz, 1H), 7.80-7.75 (m, 1H), 7.72-7.70 (m, 1H), 7.47 (t , 7.28 (d, J = 6.6 Hz, 2H), 7.04 (s, 1H), 6.95 (s, 2H), 6.28 (brs, 2H) 3.03 Calcd for C 14 H 15 N 3 O
Example 6 Preparation of 2 - ((5- (4-chlorophenyl) isooxazol-3-yl) methylamino) acetamide
Except that 5- (4-chlorophenyl) isooxazole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan- The procedure of Example 1 was repeated to produce the target compound.
1 H NMR (400MHz, DMSO- d 6) δ 7.92-7.88 (m, 2H), 7.62-7.59 (m, 2H), 7.05 (s, 1H), 6.28 (s, 1H), 5.56 (brs, 1H) , 4.55 (s, 2H), 3.01 (s, 2H) HR-FABMS Calcd for C 12
Example 7 Preparation of 2 - ((5- (3-chloro-4-methoxyphenyl) furan-2-yl) methylamino) acetamide
It was found that 5- (3-chloro-4-methoxyphenyl) furan-2-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) , The target compound was prepared in the same manner as in the preparation method described in Example 1 above.
1 H NMR (400MHz, DMSO- d 6) δ 7.72 (d, J = 1.2Hz, 1H), 7.56 (dd, J = 8.8Hz, J = 2.4Hz, 1H), 7.21 (brd, J = 2.8Hz, 1H), 7.17 (s, 1H), 7.15 (s, 1H), 6.85 (d, J = 2 Hz, 1H), 6.46 , 1H) 3.88 (s, 3H ), 3.79 (s, 2H) HR-FABMS Calcd for C 14
Example 8 Preparation of 2- (4- (pyrimidin-5-yl) benzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (pyrimidin-5-yl) benzaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) , The target compound was prepared.
1 H NMR (400MHz, CDCl 3 ) δ 9.22 (d, J = 3.2Hz, 1H), 8.96 (d, J = 2.4Hz, 2H), 7.61-7.46 (m, 6H), 4.80 (s, 1H), 3.89 (s, 1H), 3.77 (s, 1H), 3.37 (d, J = 6.8Hz, 1H), 3.19 (s, 1H) HR-FABMS Calcd for C 13 H 14 N 4 O.
Example 9 Preparation of 2- (4- (4-cyanophenoxy) benzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (4-formylphenoxy) benzonitrile was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2- , The target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 7.83-7.81 (m, 2H), 7.51 (d, J = 8.4Hz, 2H), 7.12-7.07 (m, 6H), 5.75 (s, 1H), 3.66 (s, 2H), 2.98 ( s, 2H) HR-FABMS Calcd for C 16 H 15 N 3 O 2.
Example 10 Preparation of 2 - ((5-chloro-1H-indol-3-yl) methylamino) acetamide
The procedure of Example 1 was repeated except that 5-chloro-lH-indole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan- , The target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 11.13 (s, 1H), 7.54 (t, J = 2Hz, 1H), 7.39 (d, J = 2Hz, 1H), 7.35 (d, J = 8.8Hz, 1H), 7.05 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 6.99 (s, ) HR-FABMS Calcd for C 11
Example 11 Preparation of 2 - ((1H-indol-3-yl) methylamino) acetamide
The procedure of Example 1 was followed except that 1H-indole-3-carbaldehyde was used instead of 5- (3- (trifluoromethyl) phenyl) furan-2- The target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 10.95 (s, 1H), 7.36-7.34 (m, 1H), 7.32-7.22 (m, 1H), 7.12-7.04 (m, 2H), 7.02-6.91 ( m, 2H), 6.28 (s , 1H), 3.06 (s, 2H), 3.02 (s, 2H), 2.90 (s, 1H) HR-FABMS Calcd for C 11 H 13 N 3 O.
Example 12 Preparation of 2 - ((2-phenyl-1H-indol-3-yl) methylamino) acetamide
Phenyl-1H-indole-3-carbaldehyde in place of 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde in Example 1, , The target compound was prepared.
1 H NMR (400 MHz, DMSO-d 6 )? 9.95 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.79 -7.49 (m, 4H), 7.27-7.22 (m, 2H), 5.75 (s, 2H), 4.10 (brs, 4H) HR-FABMS Calcd for C 17 H 17 N 3 O.
Example 13 Preparation of 2- (4- (4-fluorophenoxy) benzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (4-fluorophenoxy) benzaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2- , The target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 7.40 (d, J = 8.8Hz, 1H), 7.33 (s, 1H), 7.21 (t, J = 8.8Hz, 3H), 7.07-7.03 (m, 2H ), 6.95-6.93 (m, 3H) , 6.28 (s, 1H), 3.58 (s, 2H), 3.51 (s, 2H) HR-FABMS Calcd for C 15
Example 14 Preparation of 2- (4- (4-chlorophenoxy) benzylamino) acetamide
The procedure of Example 1 was repeated except that 4- (4-chlorophenoxy) benzaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2- The objective compound was prepared in the same manner as in the preparation process.
1 H NMR (400MHz, DMSO- d 6) δ 7.44-7.35 (m, 3H), 7.23 (brs, 1H), 7.11 (brs, 1H), 7.03-6.99 (m, 5H), 6.28 (s, 1H) , 3.61 (s, 2H), 3.02 (s, 1H), 2.94 (s, 1H) HR-FABMS Calcd for C 15
Example 15 Preparation of 2 - ((5- (benzyloxy) -1H-indol-3-yl) methylamino) acetamide
Except that 5- (benzyloxy) -1H-indole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan- The procedure of Example 1 was repeated to produce the desired compound.
1 H NMR (400MHz, DMSO- d 6) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.68 (d, J = 1.2Hz, 1H), 7.50-7.38 (m, 6H), 7.34-7.18 2H), 6.97 (dd, J = 6.4 Hz, J = 2.4 Hz, 2H), 5.13 (s, 2H), 4.10 (s, 2H), 3.01 (s, 2H) HR-FABMS Calcd for C18 H 19 N 3 O 2 .
Example 16 Preparation of 2 - ((5-bromo-1H-indol-3-yl) methylamino) acetamide
Except that 5-bromo-1H-indole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde in Example 1, 1, the target compound was prepared.
1 H NMR (400 MHz, DMSO-d 6 )? 11.15 (s, 1H), 7.68 (d, J = 2 Hz, 1H), 7.37 -7.25 (m, 2H), 7.18-7.15 (m, 2H), 4.09 (s, 2H) 3.77 (d, J = 2.8Hz, 2H) HR-FABMS Calcd for C 11
Example 17 Preparation of 2 - ((6-fluoro-1H-indol-3-yl) methylamino) acetamide
Fluoro-lH-indole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde in Example 1, 1, the target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 11.02 (s, 1H), 7.54 (dd, J = 8.4Hz, J = 2.8Hz, 1H), 7.31 (d, J = 2.4Hz, 1H), 7.23 ( s, 2H), 6.28 (s , 1H) 3.77 (d, J = 7.6Hz, 4H) HR-FABMS Calcd for C 11
Example 18 Preparation of 2 - ((5-methoxy-1H-indol-3-yl) methylamino) acetamide
Except that 5-methoxy-lH-indole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde in Example 1, 1, the target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 10.77 (s, 1H), 7.22 (d, J = 8.8Hz, 3H), 6.68 (dd, J = 4.4Hz, J = 2.4Hz, 3H), 3.78- 3.66 (m, 7H) HR- FABMS Calcd for C 12 H 15 N 3 O 2.
Example 19 Preparation of 2 - ((7-nitro-1H-indol-3-yl) methylamino) acetamide
The procedure of Example 1 was repeated except that 7-nitro-lH-indole-3-carbaldehyde was used in place of 5- (3- (trifluoromethyl) phenyl) furan- , The target compound was prepared.
1 H NMR (400MHz, DMSO- d 6) δ 11.71 (s, 1H), 8.11-8.09 (m, 2H), 7.523 (d, J = 2.8Hz, 1H), 7.43 (dd, J = 4.8Hz, J = 2.4Hz, 1H), 7.26-7.18 ( m, 2H) 6.28 (s, 1H), 4.69 (s, 1H) 3.88 (d, J = 2Hz, 3H) HR-FABMS Calcd for C 11 H 12 N 4 O 3 .
The chemical structures of the compounds prepared in Examples 1-19 are shown in Table 1 below.
Experimental Example 1 Evaluation of Inhibitory Effect on Nav 1.7
In order to evaluate the inhibitory effect of the compound according to the present invention on Nav 1.7, the following VIPR (voltage / ion probe reader) analysis experiment was conducted.
Nav 1.7-channel expressing HEK cells were plated on poly-D-lysine coated black-wall, white-bottomed 96-well bio-coated plates and cultured in 100 μL culture for 24 hours prior to analysis. The following day, membrane potential dyeing was performed according to the manufacturer's instructions. That is, the content of a single dye was dissolved in 10 ml of Hepes-HBSS buffer (pH 7.4) or 100 ml of a large amount of dye. Hepes-HBSS and dye solutions were pre-warmed to 37 ° C and 90 μl dye was added to the wells (total 190 μl) and incubated for 60 min at 37 ° C. Standard inhibitors were tested with each assay. 10 [mu] l of compound was added 10 minutes before reading the plate. The Flexstation was set up to add 50 μl of channel activator and veratridine, and the fluorescence was read at 530 nm excitation and 565 nm emission. Each well was read at 1.52 second intervals for 120 seconds and the degree of inhibition of each of the compounds by sodium channel 1.7 is shown in Table 2 as a percentage.
As shown in Table 2, the compound of Example 1-19 according to the present invention was found to have superior Nav 1.7 channel inhibitory activity. In particular, the compounds of Examples 5, 9 and 11-14 were found to have a Nav 1.7 channel inhibitory activity of 80% or more, showing excellent inhibitory activity.
Therefore, the compounds according to the present invention are excellent in Nav 1.7 channel inhibitory activity and can be usefully used for treating pathological pain related thereto.
≪ Experimental Example 2 >
<2-1> Preparation of an animal model of central neuropathic pain
Chloral hydrate (500 mg / kg) was anesthetized by intraperitoneal injection into the rats, and the spinal cord T8-T10 was exposed. We used a NYU impactor designed to quantify the traumatic intensities in a computerized manner, with a 10-gram weight placed at a constant height on an animal model of spinal cord injury. Specifically, the rat was fixed to the clamp of the NYU impactor, and a weight of 10 g at a height of 25 mm was freely dropped to damage the spinal cord T9. The data on the damage intensity appearing on the computer were used to confirm that a certain amount of damage was applied within a predetermined error range, and then the wound area was sealed. The injured area was disinfected with povidone solution and two cages were placed in a cage. The bladder was artificially massaged three times a day to help urinate.
≪ 2-2 > Evaluation of the inhibitory effect of central neuropathic pain
Behavioral response tests were performed to confirm the inhibitory effect of the compound of Example 14 on the central neuropathic pain in spinal injured centripetal pain rats. Specifically, BBB locomotor test (BBB locomotor test) and post-injury pain response were observed until about 28 days after spinal cord injury. The rats were placed under a transparent plastic box (10 cm x 10 cm) on a wire mesh (3 mm x 3 mm) for 20 minutes and von-Frey filaments were applied to both soles of the rats. The tactile (mechanical) sensitivity was measured using a stiff nylon bone-fray single filament series (Stoelting, WoodDale, IL, USA specification: 0.4 g (3.61 mN), 0.6 g (3.84 mN), 1.0 g The avoidance response of the foot was evaluated with increasing mechanical stimulation using g (4.31 mN), 4.0 g (4.56 mN), 6.0 g (4.74 mN), 8.0 g (4.93 mN) and 15.0 g (5.18 mN). The prefilament was applied to each foot for 3-4 seconds to a complete bend, stimulation was done at 2 second intervals, and the 50% threshold was confirmed using the up-down method (Chaplan et al., 1994). The experimental method started with sequential identification of the most sensitive areas at various sites using eight bouffray filaments of 0.4 - 15 g. In the case where the evasion reaction of the foot does not occur, the experiment is repeated with the filament of the next size. In the case of the reaction, the weaker filament is applied and the result is shown in FIG.
FIG. 1 is a graphical representation of the pain sensitivity of rats, which were obtained by injecting the compound of Example 14 at 5, 10 and 50 μg, respectively.
FIG. 1 shows that as the content of the compound of Example 14 is increased, the pain of the rat is alleviated and the reaction occurs at a high intensity.
Accordingly, the compound according to the present invention is excellent in neuropathic pain-suppressing activity, and thus can be usefully used as a pharmaceutical composition for the prevention and treatment of neuropathic pain containing it.
Claims (10)
(1) 2 - ((5- (3- (Trifluoromethyl) phenyl) furan-2-yl) methylamino) acetamide;
(2) 2- (4- (4-Methylpiperazin-1-yl) benzylamino) acetamide;
(3) 2- (4-morpholinobenzylamino) acetamide;
(4) 2 - ((5- (4-Chlorophenyl) furan-2-yl) methylamino) acetamide;
(5) 2- (4- (Pyridin-4-yl) benzylamino) acetamide;
(6) 2 - ((5- (4-chlorophenyl) isooxazol-3-yl) methylamino) acetamide;
(7) 2 - ((5- (3-Chloro-4-methoxyphenyl) furan-2-yl) methylamino) acetamide;
(8) 2- (4- (Pyrimidin-5-yl) benzylamino) acetamide;
(9) 2- (4- (4-thiophenoxy) benzylamino) acetamide;
(10) 2 - ((5-chloro-1H-indol-3-yl) methylamino) acetamide;
(11) 2 - ((lH-indol-3-yl) methylamino) acetamide;
(12) 2 - ((2-phenyl-1H-indol-3-yl) methylamino) acetamide;
(13) 2- (4- (4-Fluorophenoxy) benzylamino) acetamide;
(14) 2- (4- (4-Chlorophenoxy) benzylamino) acetamide;
(15) 2 - ((5- (Benzyloxy) -1H-indol-3-yl) methylamino) acetamide;
(16) 2 - ((5-Bromo-1H-indol-3-yl) methylamino) acetamide;
(17) 2 - ((6-fluoro-1H-indol-3-yl) methylamino) acetamide;
(18) 2 - ((5-methoxy-1H-indol-3-yl) methylamino) acetamide; And
(19) 2 - ((7-Nitro-1H-indol-3-yl) methylamino) acetamide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11952347B2 (en) | 2016-10-11 | 2024-04-09 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
| US11964945B2 (en) | 2020-05-29 | 2024-04-23 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
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