WO2023163555A1 - Novel hydantoin derivatives and uses thereof - Google Patents
Novel hydantoin derivatives and uses thereof Download PDFInfo
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- WO2023163555A1 WO2023163555A1 PCT/KR2023/002720 KR2023002720W WO2023163555A1 WO 2023163555 A1 WO2023163555 A1 WO 2023163555A1 KR 2023002720 W KR2023002720 W KR 2023002720W WO 2023163555 A1 WO2023163555 A1 WO 2023163555A1
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- A—HUMAN NECESSITIES
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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- A—HUMAN NECESSITIES
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to novel hydantoin derivatives and uses thereof.
- NADPH oxidases are a family of enzymes that have 6 trans-membrane domains and transport electrons across biological membranes. These enzymes broadly and specifically regulate redox-sensitive signaling pathways and are implicated in a variety of pathogenesis.
- the electron acceptor is oxygen
- the product of the electron transfer reaction is superoxide.
- ROS reactive oxygen species
- ROS Reactive oxygen species
- oxygen radicals super-oxide anions [*O 2 ], hydroxyl [HO*], peroxyl [ROO*], alkoxyl [RO*] and hydroperoxyl [HOO*]
- other oxidizing agents and/or non-radical compounds that are readily converted to radicals such as hydrogen peroxide (H 2 O 2 ).
- Nox1, Nox2, and Nox4 were increased in the brains of Parkinson's disease patients, Alzheimer's disease patients, amyotrophic lateral sclerosis patients, etc., and disease-induced experimental animals (Parkinson's animal models by herbicides, LPS, MPP +, etc., Alzheimer's animals overexpressing APP)
- a neuroprotective effect has been reported when Nox is knocked out or genetically inactivated in a SOD1 mutant amyotrophic lateral sclerosis animal model).
- NOX is known to play an important role in cancer growth, angiogenesis, and metastasis, and NOX is overexpressed in epithelial cancer, especially in colorectal cancer, prostate cancer, and breast cancer, and it has been reported that it is related to active mutations in K-Ras.
- the anti-cancer effect of substances that inhibit Nox has also been confirmed through animal experiments.
- NADPH oxidase is the main source of cell ROS generation along with mitochondria, but ROS generated by NADPH oxidase is not a by-product of an enzymatic reaction, but a single product. point. This suggests that NADPH oxidase plays an important role in cellular function.
- the present inventors have confirmed that the novel hydantoin derivative has an excellent effect as a Nox inhibitor.
- degenerative brain diseases such as Parkinson's disease and Alzheimer's disease, cancer including various brain carcinomas, and various diseases related to the inhibition of angiogenesis through the Nox inhibitory action, thereby discovering the present invention. completed.
- An object to be solved by the present invention is to provide a novel hydantoin derivative or a pharmaceutically acceptable salt thereof.
- the present invention provides a use of the novel hydantoin derivative or a pharmaceutically acceptable salt thereof.
- the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R 1 is a hydrogen atom, a C 1 -C 6 alkyl group or a halogen
- L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;
- R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));
- R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing substituted or unsubstituted heteroatoms selected from oxygen, nitrogen and sulfur.
- the compound represented by Formula 1 may be a compound represented by Formula 2 below or a pharmaceutically acceptable salt thereof.
- L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;
- R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));
- R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing substituted or unsubstituted heteroatoms selected from oxygen, nitrogen and sulfur.
- R 1 is a C 1 -C 6 alkyl group
- L is a single bond, -C 1 -C 6 alkylene or -SO 2 -;
- R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl (wherein, when C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 12 aryl, or C 6 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)-R 3 , or -O-(C 1 -C 4 haloalkyl));
- R 3 may be substituted or unsubstituted C 6 -C 12 aryl.
- R 1 may be a methyl group or an ethyl group.
- R 2 is , or and here , or is unsubstituted or one or more H is each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)-R 3 , or -O-(C 1 - C 4 haloalkyl).
- LR 2 is , , , , , , , or can be
- LR 2 is preferably
- the compound of Formula 1 may be any one selected from the group consisting of the following compounds:
- the compound of Formula 1 may be any one selected from the group consisting of the following compounds.
- pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, for example, inorganic ion salts prepared with calcium, potassium, sodium and magnesium; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid organic acid salts prepared from acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid
- single bond means that the N atom of the thioxoimidazoline of Formula 1 and R 2 are directly bonded.
- Cx-Cy means having more than x and less than y carbon atoms.
- substituted refers to a moiety having a substituent replacing hydrogen on one or more carbons of the main chain. “Substitution” or “substituted with” is contingent on whether such substitution is permissible on the atom and substituent being substituted, and refers to compounds that are stable by substitution, such as compounds that are not naturally modified by rearrangement, cyclization, elimination, etc. It is defined as including the implicit condition that induces
- C 1 -C 6 alkyl means a C 1 -C 6 straight-chain or branched-chain saturated hydrocarbon such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl.
- Preferred alkyl groups contain about 1, 2, 3, 4, 5 or 6 carbon atoms in the chain.
- Side chain means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkyl chain.
- “Lower alkyl” means a group having from about 1 to about 6 carbon atoms in the chain, which may be straight or branched.
- Alkyl may be unsubstituted or optionally substituted by one or more substituents, which may be the same or different, each substituent being halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkyl thio, amino, carboxy, and the like.
- substituents Preferably alkyl can be methyl or ethyl.
- 'methyl (methyl group, methyl group)' is a structure in which three hydrogen atoms are bonded to one carbon atom, and is the smallest alkyl group. This methyl group can exist in three forms: anionic, cationic, and free.
- C 1 -C 6 alkylene refers to a divalent functional group derived from C 1 -C 6 alkyl, including divalent functional groups such as -CH 2 - or -CH 2 -CH 2 -. can do.
- C 1 -C 4 haloalkyl refers to a C 1 -C 4 straight-chain or branched-chain saturated hydrocarbon, wherein at least one hydrogen is substituted with a halogen compound (ie, F, Cl, Br, or I). It means a C 1 -C 4 straight-chain or branched-chain saturated hydrocarbon. For example, it may be CF 3 .
- C 3 -C 8 cycloalkyl refers to a saturated hydrocarbon ring containing 3 to 8 carbon atoms, and the saturated hydrocarbon ring is monocyclic and polycyclic, and two or more rings share one or more pairs of carbon atoms. This means that all structures are included. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, and the like, and may preferably be cyclopentyl or cyclohexyl, but is not limited thereto.
- C 3 -C 8 heterocycloalkyl refers to saturated monocyclic and polycyclic heterocycles containing 1 to 4 heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S). Or a ring structure in which two or more rings share one or more pairs of carbon atoms.
- Heterocycloalkyl includes oxiranyl, oxetanyl, mophorinyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the like. And, preferably, it may be piperidinyl, and may also be piperidinyl in which benzyl is substituted at the N atom, but is not limited thereto.
- C 6 -C 12 aryl refers to an aromatic hydrocarbon containing 6 to 12 carbon atoms.
- monocyclic eg, phenyl
- ring systems such as bicyclic (eg, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl).
- aryl has a chemical formula of C 6 H 5 and may be a phenyl group in which 6 carbon atoms are arranged in a cyclic ring structure.
- the phenyl group is a very stable, aromatic hydrocarbon found in many organic compounds.
- the simplest compound containing a phenyl group is phenol (C 6 H 5 OH), which has a structure in which a hydroxy group is bonded.
- hydrogen at the ortho, meta, and para positions of the phenyl ring is a halogen atom, C 1 -C 4 haloalkyl.
- -O-(C 1 -C 4 haloalkyl) may be substituted, preferably F, Cl, -O-CF 3 or CF 3 may be substituted.
- C 2 -C 12 heteroaryl is a heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S), at least one of the ring carbon atoms is replaced, 2 to 12 carbon atoms or an aromatic ring (e.g., a bicyclic or tricyclic ring system) fused to more than one ring, such as a heteroaryl ring, aryl ring, heterocyclic ring, or carbocyclic ring, containing , each of which may have an optional substituent.
- an aromatic ring e.g., a bicyclic or tricyclic ring system
- Examples include, but are not limited to, isoquinolinyl, pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, furanyl, thiophenyl, indolyl, benzopyridinyl, pyrazolyl, and the like.
- halogen means a substituent selected from fluorine (F), chloro (Cl), bromo (Br) and iodo (I).
- halogen can be fluorine or chloro.
- the present invention provides a use of a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- R 1 is a hydrogen atom, a C 1 -C 6 alkyl group or a halogen
- L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;
- R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));
- R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing substituted or unsubstituted heteroatoms selected from oxygen, nitrogen and sulfur.
- the matters related to Chemical Formula 1 may be applied to the matters related to Chemical Formula 2 and specific compounds thereof mentioned above within the scope of use of the present invention.
- the present invention provides a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
- a Nox inhibitor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is provided.
- the compounds according to the present invention exhibit excellent effects on inhibiting Nox (NADPH oxidase) and can be used for various therapeutic purposes.
- the present invention provides a pharmaceutical composition for preventing or treating NADPH oxidase (Nox)-related diseases, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Nox NADPH oxidase family
- Nox was identified as an upstream factor regulating both oxidative stress and neuroinflammation. Therefore, inactivation or pharmacological inhibition of Nox can be expected to have a strong neuroprotective effect (eg, dopaminergic neuron protection, improvement of microglia pathology, etc.) and behavioral improvement in a wide range of neurological diseases.
- Nox is well known in various carcinomas, especially brain carcinoma, and its suppression can exhibit excellent effects in disease treatment.
- Reactive oxygen species generated by Nox are closely related to the pathophysiology of cancer because they are related to altered signal transduction, tumor formation and growth-related environment, angiogenesis, gene instability, and metastasis.
- Nox1 has been reported to be associated with colon cancer proliferation
- Nox2 is associated with breast cancer, colorectal cancer, gastric cancer, prostate cancer, and myelomonocytic leukemia
- Nox4 has been reported to be associated with non-small cell lung cancer, gastric cancer, and neuroblastoma
- Nox5 with prostate cancer, breast cancer, melanoma, and lung cancer
- Duox1 with lung cancer and liver cancer.
- Nox inhibitors may have anti-tumor effects, restore sensitivity to immunotherapy, and/or improve responsiveness to immunotherapy. In addition, it may exhibit an angiogenesis inhibitory effect. In addition, expression of inflammatory factors and the like can be inhibited.
- NADPH oxidase (Nox) related diseases include, for example, psoriasis, rheumatoid arthritis, osteoarthritis, restenosis, atherosclerosis, ulcers, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy , organ transplant rejection, diabetes, hypertension, cardiac hypertrophy, heart failure, restenosis, cancer, autoimmune disease, inflammatory disease, degenerative brain disease, and retinal disease.
- Nox NADPH oxidase
- Autoimmune diseases include alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, autoimmune orchitis, autoimmune thrombocytopenia, Behcet's disease, Bullous pemphigoid, cardiomyopathy, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, scarring pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic Pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA neuritis, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type I or immune
- inflammatory diseases examples include asthma, encephalitis, inflammatory enteritis, chronic obstructive pulmonary disease, allergy, septic shock, pulmonary fibrosis, undifferentiated spondyloarthrosis, and undifferentiated joints. conditions, arthritis, inflammatory osteolysis, and chronic inflammation due to chronic viral or bacterial infection.
- the cancers that can be prevented or treated by the composition of the present invention include brain cancer, neuroendocrine cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, including but not limited to bladder, adrenal, colorectal, colon, cervical, prostate, bone, skin, thyroid, parathyroid and ureter cancers
- the cancer may in particular be brain cancer.
- brain cancers include, for example, astrocytoma, glioblastoma, ependymoma, oligodendroglioma, mixed glioma, brain stem glioma, and optic nerve glioma.
- glioma pituitary adenoma, craniopharyngioma, medulloblastoma, primitive neuroectodermal tumors, pineal tumors, meningioma, schwannoma
- metastatic It may be any one or more selected from the group consisting of metastatic brain tumors, CNS lymphoma, neurofibromatosis, pseudotumor cerebri, and tuberous sclerosis.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention is useful for preventing or treating degenerative brain diseases.
- the present invention provides a pharmaceutical composition for preventing or treating degenerative brain disease comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Non-limiting examples of degenerative brain diseases in the present invention include Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette's Syndrome (Tourette's Syndrome), Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, progressive supranuclear palsy (Progressive Supranuclear Palsy) and Frontotemporal Dementia.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention is useful for preventing or treating retinal diseases.
- the present invention provides a pharmaceutical composition for preventing or treating retinal diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Non-limiting examples of retinal diseases in the present invention include glaucoma, retinopathy of prematurity, proliferative retinopathy, corneal transplant rejection, proliferative vitreoretinopathy, diabetic retinopathy, macular degeneration, choroidal neovascularization or retinal edema.
- the macular degeneration may be wet macular degeneration or dry macular degeneration.
- the hydantoin derivative according to the present invention exhibits an excellent effect on Nox inhibition.
- the hydantoin derivative according to the present invention exhibits excellent effects in preventing or treating NADPH oxidase (Nox)-related diseases.
- the hydantoin derivative according to the present invention can exhibit excellent effects in treating diseases by inhibiting the migratory ability of microglial cell lines.
- the hydantoin derivative according to the present invention exhibits molecular biological and histological improvement effects through protection of dopaminergic neurons and improvement of pathology of microglia in a Parkinson's disease model, and through such action effects It shows the effect of behavioral treatment together.
- the hydantoin derivative according to the present invention reduces amyloid plaque deposition in an Alzheimer's disease model, inhibits the activity of astrocytes and microglia, and improves cognitive function, spatial memory, and short-term and long-term memory. shows excellent effect.
- the compounds according to the present invention exhibit excellent effects on blood-brain barrier (BBB, Brain Barrier Blood) permeability, and thus can be used for the treatment of the aforementioned diseases.
- BBB blood-brain barrier
- the compounds according to the present invention have excellent BBB permeability, they have excellent delivery effect to the target site and thus have excellent therapeutic efficacy as actual drugs.
- the compounds according to the present invention exhibit excellent metabolic stability and can be used for the treatment of the aforementioned diseases.
- the compounds according to the present invention have excellent metabolic stability and thus have excellent efficacy as actual drugs.
- the pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for administration.
- a pharmaceutically acceptable carrier may be a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and, if necessary, antioxidants and buffers. , bacteriostatic agents and other conventional additives may be added.
- diluents such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
- the pharmaceutical composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository or the like.
- These formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on each disease or component It can be.
- the pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage is determined according to the patient's weight, age, sex, health The range varies depending on the condition, diet, administration time, administration method, excretion rate, and disease type and severity.
- the daily dose of the compound of Formula 1 of the present invention is about 0.01 to 1000 mg/kg, preferably 0.1 to 100 mg/kg, and may be administered once or several times a day.
- the administration route of the composition may be administered through any general route as long as it can reach the target tissue, but subcutaneous injection using an osmotic pump, intradermal injection, intravenous injection ( It may be administered through intravein injection, intraperitoneal injection, or intravitreal injection.
- the pharmaceutical composition of the present invention may further contain at least one active ingredient exhibiting the same or similar efficacy in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention is directed to treating or preventing NADPH oxidase (Nox) related diseases, comprising administering a therapeutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. provides a way
- the present invention provides a method for treating or preventing a degenerative brain disease, comprising administering a therapeutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
- the present invention provides a method for treating or preventing cancer, comprising administering a therapeutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
- terapéuticaally effective amount refers to an amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof effective for preventing or treating the disease.
- the treatment method of the present invention includes not only addressing the disease itself prior to the onset of symptoms, but also inhibiting or avoiding its symptoms, by administering the compound of Formula 1 above.
- the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dosing will vary according to the age, weight and response of the individual patient. A suitable dosage regimen can be readily selected by those skilled in the art who take these factors into account.
- the treatment method of the present invention may further include the administration of a therapeutically effective amount of an additional active agent to help treat a disease together with the compound of Formula 1, the additional active agent together with the compound of Formula 1 They may exhibit synergistic or auxiliary effects.
- the present invention provides a food composition for preventing or alleviating NADPH oxidase (Nox)-related diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention provides a food composition for preventing or improving degenerative brain disease comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention provides a food composition for preventing or improving cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the food composition of the present invention can be used as a health functional food.
- health functional food refers to food manufactured and processed using raw materials or ingredients having functional properties useful for the human body in accordance with the Health Functional Food Act No. 6727, and “functional” refers to the structure of the human body. And it refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients for functions or physiological functions.
- the food composition of the present invention may contain conventional food additives, and the suitability as the "food additive" is determined in accordance with the General Rules of the Code of Food Additives and General Test Methods approved by the Korea Food and Drug Administration, unless otherwise specified. It is judged according to the standards and standards for
- the food composition of the present invention may contain the compound of Formula 1 in an amount of 0.01 to 95%, preferably 1 to 80%, based on the total weight of the composition.
- it can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, beverages, and the like.
- the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of NADPH oxidase (Nox)-related diseases.
- the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of degenerative brain diseases.
- the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of cancer.
- the compound of Formula 1 for the preparation of a drug may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
- the present invention provides a food composition for enhancing cognitive function comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Treatment of the above-mentioned diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as defined in any embodiment described herein. method;
- Nox inhibitors comprising a compound represented by Formula 1 as defined in any of the embodiments described herein or a pharmaceutically acceptable salt thereof;
- an antioxidant comprising a compound represented by Formula 1 as defined in any of the embodiments described herein or a pharmaceutically acceptable salt thereof;
- prevention used in the present invention refers to any action that inhibits the formation of the disease or delays the onset of the disease by administration of the composition.
- treatment refers to all activities that improve or beneficially change the symptoms of the disease by administration of the composition.
- subject of the present invention means any animal that has or may develop the disease, and typically has a beneficial effect by treatment with the compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof. It may be an animal that can show, but includes without limitation any individual that has symptoms of the disease or is likely to have these symptoms. As described above, the aforementioned diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject.
- the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent, administered in combination with existing therapeutic agents, or sequentially or simultaneously with conventional therapeutic agents.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent Nox inhibitory effect. In particular, it exhibits excellent effects in the treatment of NADPH oxidase (Nox)-related diseases, including degenerative brain diseases and cancer.
- Nox NADPH oxidase
- Figure 1a shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds E7240-13 and E7240-17-24 according to the present invention.
- Figure 1b shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds E7240-17-27 and LMT-1894 according to the present invention.
- Figure 1c shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds LMT-2132 and LMT-1895 according to the present invention.
- Figure 1d shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds LMT-1896 and LMT-2144 according to the present invention.
- Figure 1e shows the results of measuring IC 50 values for confirming the Nox inhibitory effect of the compounds LMT-2154 and LMT-2156 according to the present invention.
- High-resolution mass spectrometry was performed using a Joel JMS-700 mass spectrometer based on electrical ionization.
- Sarcosine 89.1 mg, 1.0 mmol
- tosyl isothiocyanate 237.2 mg, 1.0 mmol
- ethanol 10 mL
- a Teflon-sealed glass container 20 mL volume
- the container was heated at 135 °C and 3.5 °C. It was placed in a 60W microwave cavity at -5.0 Bar for 6 minutes.
- the reaction was then cooled to room temperature.
- 4-(diethylamino)-2-hydroxybenzaldehyde 212.5 mg, 1.1 mmol
- piperidine 170.3 mg, 2.0 mmol
- Human Nox isozymes were provided from transgenic flies expressing human Nox isozymes under the daughterless (Da)-GAL4 promoter. The genotype of each fly line is shown below.
- Transgenic flies were homogenized with PBS containing protease inhibitors (Aprotinin, Leupeptin) to obtain Drosophila membranes of each Nox isozyme.
- Membranes were incubated with compounds (100 ⁇ M, 10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M, 0.001 ⁇ M, 0 ⁇ M) for 10 min on a shaker.
- NADPH b-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate; Sigma-Aldrich
- 1X HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- lucigenin N,N′-dimethyl-9,9′-biacridinium dinitrate; Sigma-Aldrich
- IC 50 values were calculated with Graph-Pad Prism 5 (GraphPad Software).
- Lucigenin chemiluminescence assays were performed with Drosophila membranes expressing hNox1, hNox2 and hNox4. The assay was repeated three times and the average of the IC 50 values was determined.
- Table 1 and FIGS. 1a to 1e show the results of confirming the Nox2 and Nox4 inhibitory effects of Examples 1 to 10 according to the present invention.
- Example 1 Nox2 Nox4 Example 1 (E7240-13) 1.655 2.350 Example 2 (E7240-17-24) 0.222 0.550 Example 3 (E7240-17-27) 0.829 0.799 Example 4 (LMT-1894) 0.906 1.099 Example 5 (LMT-2132) 1.401 1.757 Example 6 (LMT-1895) 0.787 0.717 Example 7 (LMT-1896) 0.852 0.839 Example 8 (LMT-2144) 1.023 0.840 Example 9 (LMT-2154) 1.083 0.950 Example 10 (LMT-2156) 1.379 0.779
- Double sink (Pion, BBB PAMPA)
- the stability of the drug in vivo was confirmed by measuring the degree of drug metabolism in the liver, a major organ of drug metabolism, using Liver microsomes.
- the specific test method is as follows:
- the amount of substrate remaining through the reaction was analyzed using an Agilent 1290 infinity series pump system (Agilent, USA) and a Triple Quad 5500 LC-MS/MS system (Applied Biosystems, USA).
- As the HPLC column an Acquity UPLC BEH Amide column (2.1 ⁇ 100 mm, 1.7 ⁇ m particle size; Waters, Ireland) was used.
- the mobile phase was distilled water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B). Data analysis was performed using Analyst software (version 1.6.3).
- the hydantoin derivative compound of the present invention has the ability to pass through the BBB.
- the microsomal stability evaluation criteria according to the % remaining value which is the result of the reaction experiment for 30 minutes, when the half-life is 70-90%, it is judged to be a stable compound with a half-life of about 1 to 3 hours, and the hydantoin derivative compound of the present invention has metabolic stability. It was confirmed that this excellent compound.
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Abstract
The present invention relates to a novel hydantoin derivative and a composition comprising same for preventing or treating NADPH oxidase (NOX)-related diseases. The present invention can be used for the treatment of NADPH oxidase (NOX)-related diseases through an excellent action on NOX inhibition.
Description
본 발명은 신규 히단토인 유도체 및 이의 용도에 관한 것이다.The present invention relates to novel hydantoin derivatives and uses thereof.
NADPH 옥시다아제 (NOX)는 6 막통관영역(trans-membrane domain)을 갖고 생물학적 막을 가로질러 전자들을 이송하는 효소 패밀리이다. 이들 효소는 산화환원-민감성 신호전달 경로를 폭넓게 및 특이적으로 조절하여 다양한 발병 기전과 연관되어 있다. 일반적으로 전자수용체는 산소이고, 전자전이반응의 산물은 슈퍼 산화물 (superoxide)이다. 따라서 Nox 효소의 주된 생물학적 기능은 산소로부터 반응성 산소종 (reactive oxygen species: ROS)의 생성이다. 반응성 산소종 (ROS)는 산소로부터 유도된 작은 분자물로, 산소라디칼 (슈퍼-산화물 음이온 [*O2], 히드록실 [HO*], 퍼옥실 [ROO*], 알콕실[RO*] 및 히드로퍼옥실 [HOO*])을 포함하며, 다른 산화제 및/또는 쉽게 과산화수소 (H2O2)와 같은 라디칼로 전환되는 비라디칼 화합물도 포함된다.NADPH oxidases (NOX) are a family of enzymes that have 6 trans-membrane domains and transport electrons across biological membranes. These enzymes broadly and specifically regulate redox-sensitive signaling pathways and are implicated in a variety of pathogenesis. In general, the electron acceptor is oxygen, and the product of the electron transfer reaction is superoxide. Thus, the main biological function of Nox enzymes is the production of reactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS) are small molecules derived from oxygen, including oxygen radicals (super-oxide anions [*O 2 ], hydroxyl [HO*], peroxyl [ROO*], alkoxyl [RO*] and hydroperoxyl [HOO*]), other oxidizing agents and/or non-radical compounds that are readily converted to radicals such as hydrogen peroxide (H 2 O 2 ).
파킨슨 병, 알츠하이머 병 등을 포함한 중추신경계의 여러 질병은 병증의 발병과 진행에 산화 스트레스, 염증, 미세아교세포 활성화, 진행성 신경세포 사멸이 공통적으로 나타난다. 파킨슨 병 환자, 알츠하이머 병 환자, 근위축성 측삭경화증 환자 등의 뇌에서 Nox1, Nox2, Nox4의 발현이 증가되었고 질병 유발 실험동물(제초제나 LPS, MPP+등에 의한 파킨슨 동물모델, APP를 과발현시킨 알츠하이머 동물모델, SOD1 돌연변이 근위축성 측삭경화증 동물모델)에서 Nox를 녹아웃 또는 유전적 비활성화 시켰을 때 신경보호 효과가 보고된 바 있다. 또한, NOX가 암의 성장, 혈관신생, 전이에도 중요한 역할을 하는 것으로 알려지고 있으며, NOX는 상피암 특히 대장암, 전립선암, 유방암 등에서 과발현되어 있으며 이는 K-Ras의 활성형 변이와 관련됨이 보고되었고, Nox를 억제하는 물질의 항암효과도 동물 실험을 통해 확인한 바 있다. Various diseases of the central nervous system, including Parkinson's disease and Alzheimer's disease, commonly show oxidative stress, inflammation, microglia activation, and progressive neuronal cell death in the onset and progression of the disease. The expression of Nox1, Nox2, and Nox4 was increased in the brains of Parkinson's disease patients, Alzheimer's disease patients, amyotrophic lateral sclerosis patients, etc., and disease-induced experimental animals (Parkinson's animal models by herbicides, LPS, MPP +, etc., Alzheimer's animals overexpressing APP) A neuroprotective effect has been reported when Nox is knocked out or genetically inactivated in a SOD1 mutant amyotrophic lateral sclerosis animal model). In addition, NOX is known to play an important role in cancer growth, angiogenesis, and metastasis, and NOX is overexpressed in epithelial cancer, especially in colorectal cancer, prostate cancer, and breast cancer, and it has been reported that it is related to active mutations in K-Ras. , The anti-cancer effect of substances that inhibit Nox has also been confirmed through animal experiments.
특히, 위와 같은 질환과 NADPH oxidase과의 관계에서 중요하게 고려하여야 하는 점은 NADPH oxidase가 미토콘드리아와 함께 세포 ROS 생성의 주요 source이지만, NADPH oxidase에 의해 발생되는 ROS가 효소 반응의 부산물이 아니라 단일 산물이라는 점이다. 이는 NADPH oxidase가 세포 기능에 중요한 역할을 함을 암시한다. In particular, an important point to consider in the relationship between the above diseases and NADPH oxidase is that NADPH oxidase is the main source of cell ROS generation along with mitochondria, but ROS generated by NADPH oxidase is not a by-product of an enzymatic reaction, but a single product. point. This suggests that NADPH oxidase plays an important role in cellular function.
이러한 배경하에 NADPH oxidase에 관한 연구들이 최근 들어 많이 증가하고 특히, NOX에 관한 미국에서의 관련 연구 개발비 지원도 상당히 증가하고 있는 추세이다. 그러나, Nox의 신규 저해제로 우수한 효능을 가지는 저해제에 대한 연구 개발 속도는 상당히 더디어 질환 표적으로의 우수한 장점에도 불구하고 현재까지의 개발 결과는 상당히 미진한 실정이다. Under this background, studies on NADPH oxidase have recently increased a lot, and in particular, related R&D support for NOX in the US is also on the rise. However, the speed of research and development on inhibitors with excellent efficacy as novel inhibitors of Nox is quite slow, and despite the excellent merits as a disease target, the development results to date have been quite poor.
위와 같은 문제점 하에, 본 발명자들은 신규 히단토인 유도체가 Nox 억제제로 우수한 작용 효과가 있음을 확인하였다. 특히, 이러한 Nox 억제 작용을 통하여 파킨슨 병, 알츠하이머병 등과 같은 퇴행성 뇌질환, 다양한 뇌암종을 포함하는 암, 혈관 형성 억제와 관련되는 다양한 질환들의 예방 및/또는 치료 효과가 있음을 확인하여 본 발명을 완성하였다.Under the above problems, the present inventors have confirmed that the novel hydantoin derivative has an excellent effect as a Nox inhibitor. In particular, it was confirmed that there is an effect of preventing and/or treating degenerative brain diseases such as Parkinson's disease and Alzheimer's disease, cancer including various brain carcinomas, and various diseases related to the inhibition of angiogenesis through the Nox inhibitory action, thereby discovering the present invention. completed.
본 발명이 해결하고자 하는 과제는 신규 히단토인 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.An object to be solved by the present invention is to provide a novel hydantoin derivative or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 신규 히단토인 유도체 또는 이의 약학적으로 허용가능한 염의 용도를 제공하는 것이다.In addition, the present invention provides a use of the novel hydantoin derivative or a pharmaceutically acceptable salt thereof.
화학식 1의 화합물Compound of Formula 1
본 발명은 전술한 기술적 과제를 해결하기 위해, 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 제공한다.In order to solve the above-described technical problem, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 수소원자, C1-C6 알킬기 또는 할로겐이고, R 1 is a hydrogen atom, a C 1 -C 6 alkyl group or a halogen;
L은 단결합, -O-, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;
R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C2-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, -O-(C1-C6 알킬) 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));
R3은 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이다.R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing substituted or unsubstituted heteroatoms selected from oxygen, nitrogen and sulfur.
보다 구체적으로, 상기 화학식 1로 표시되는 화합물은 하기 화학식 2로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염일 수 있다.More specifically, the compound represented by Formula 1 may be a compound represented by Formula 2 below or a pharmaceutically acceptable salt thereof.
[화학식 2][Formula 2]
상기 화학식 2에서,In Formula 2,
L은 단결합, -O-, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;
R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C2-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, -O-(C1-C6 알킬) 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));
R3은 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이다.R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing substituted or unsubstituted heteroatoms selected from oxygen, nitrogen and sulfur.
다른 구현예에서, 상기 화학식 1에서, In another embodiment, in Formula 1,
R1은 C1-C6 알킬기이고, R 1 is a C 1 -C 6 alkyl group;
L은 단결합, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -C 1 -C 6 alkylene or -SO 2 -;
R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C6-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl (wherein, when C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 12 aryl, or C 6 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)-R 3 , or -O-(C 1 -C 4 haloalkyl));
R3은 치환 또는 비치환된 C6-C12 아릴일 수 있다.R 3 may be substituted or unsubstituted C 6 -C 12 aryl.
다른 구현예에서, R1은 메틸기 또는 에틸기일 수 있다.In other embodiments, R 1 may be a methyl group or an ethyl group.
다른 구현예에서, R2는 , 또는 이고, 여기서 , 또는 는 비치환 또는 하나 이상의 H가 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, 또는 -O-(C1-C4 할로알킬)로 치환될 수 있다.In other embodiments, R 2 is , or and here , or is unsubstituted or one or more H is each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)-R 3 , or -O-(C 1 - C 4 haloalkyl).
다른 구현예에서, L-R2는 바람직하게는 In another embodiment, LR 2 is preferably
본 발명의 구체예에 따르면, 상기 화학식 1의 화합물은 하기 화합물들로 이루어진 군으로부터 선택된 어느 하나일 수 있다:According to an embodiment of the present invention, the compound of Formula 1 may be any one selected from the group consisting of the following compounds:
(E)-3-사이클로헥실-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온;( E )-3-cyclohexyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one;
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-3-((4-플루오로페닐)술포닐)-1-메틸-2-티옥소이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidene)-3-((4-fluorophenyl)sulfonyl)-1-methyl-2-thioxoimidazolidine- 4-one;
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-1-메틸-2-티옥소-3-토실이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidene)-1-methyl-2-thioxo-3-tosylimidazolidin-4-one;
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-페닐-2-티오옥소이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenyl-2-thioxoimidazolidin-4-one;
(E)-3-(1-벤질피페리딘-4-닐)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온;( E )-3-(1-benzylpiperidin-4-yl)-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidine -4-one;
(E)-3-벤질-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온;( E )-3-benzyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one;
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-펜에틸-2-티오옥소이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenethyl-2-thioxoimidazolidin-4-one;
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메틸)벤질)이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethyl)benzyl)imidazolidine- 4-one;
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(3-(트리플루오로메틸)벤질)이미다졸리딘-4-온; 및( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(3-(trifluoromethyl)benzyl)imidazolidine- 4-one; and
(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메톡시)벤질)이미다졸리딘-4-온.( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethoxy)benzyl)imidazolidine- 4-on.
본 발명의 구체예에 따르면, 상기 화학식 1의 화합물은 하기 화합물들로 이루어진 군으로부터 선택된 어느 하나일 수 있다.According to an embodiment of the present invention, the compound of Formula 1 may be any one selected from the group consisting of the following compounds.
본 발명에서, 약학적으로 허용가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 포타슘, 소듐 및 마그네슘 등으로 제조된 무기이온염; 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 및 황산 등으로 제조된 무기산염; 아세트산, 트라이플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염; 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염; 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염; 및 트리메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.In the present invention, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, for example, inorganic ion salts prepared with calcium, potassium, sodium and magnesium; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid organic acid salts prepared from acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; amino acid salts made of glycine, arginine, lysine, and the like; and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited by these listed salts.
본 명세서를 통하여 화학식 1의 화합물을 정의함에 있어서는 다음과 같이 정의된 개념들이 사용된다. 하기 정의는 특별히 달리 지시되지 않는 한, 본 명세서 전체에 걸쳐서 개별적으로 도는 더욱 큰 군의 일부로서 사용되는 용어에도 적용된다.In defining the compound of Formula 1 throughout this specification, the concepts defined as follows are used. The following definitions apply also to terms used throughout this specification, either individually or as part of a larger group, unless specifically indicated otherwise.
본 발명에 있어서, 용어 "단결합"은 화학식 1의 티옥소이미다졸린의 N 원자와 R2가 직접적으로 결합하는 것을 의미한다.In the present invention, the term "single bond" means that the N atom of the thioxoimidazoline of Formula 1 and R 2 are directly bonded.
본 발명에서, "Cx-Cy"는 탄소수 x 이상 y 이하를 갖는 것을 의미한다.In the present invention, "Cx-Cy" means having more than x and less than y carbon atoms.
본 발명에서, 용어 "치환된"은 주쇄의 하나 이상의 탄소상의 수소를 대체하는 치환기를 갖는 부분을 나타낸다. "치환" 또는 "~로 치환된"은 이러한 치환이 치환된 원자 및 치환체의 허용되는 가에 따르며, 치환에 의해 안정한 화합물 예를 들어, 재배열, 고리화, 제거 등에 의해 자연적으로 변형되지 않는 화합물을 유도한다는 암묵적 조건을 포함하는 것으로 정의한다.In the present invention, the term "substituted" refers to a moiety having a substituent replacing hydrogen on one or more carbons of the main chain. "Substitution" or "substituted with" is contingent on whether such substitution is permissible on the atom and substituent being substituted, and refers to compounds that are stable by substitution, such as compounds that are not naturally modified by rearrangement, cyclization, elimination, etc. It is defined as including the implicit condition that induces
본 발명에서 용어 "C1-C6 알킬"은 예를 들어 메틸, 에틸, 프로필, 이소프로필, 부틸, 펜틸, 헥실과 같은 C1-C6의 직쇄 또는 분지쇄의 포화 탄화수소를 의미한다. 바람직한 알킬 그룹은 상기 쇄 내에 약 1개, 2개, 3개, 4개, 5개 또는 6개의 탄소 원자를 포함한다. 측쇄는 하나 이상의 저급 알킬 그룹, 예를 들면, 메틸, 에틸 또는 프로필이 선형 알킬 쇄에 부착되어 있는 것을 의미한다. "저급 알킬"은 직쇄 또는 측쇄일수 있는 쇄 내에 약 1개 내지 약 6개의 탄소 원자를 갖는 그룹을 의미한다. "알킬"은 치환되지 않을 수 있거나 또는, 동일하거나 또는 상이할 수 있는 하나 이상의 치환체에 의해 임의로 치환될 수 있고, 각 치환체는 할로겐, 알킬, 아릴, 사이클로알킬, 시아노, 하이드록시, 알콕시, 알킬티오, 아미노, 카르복시 등일 수 있다. 바람직하게 알킬은 메틸 또는 에틸일 수 있다. 본 발명에서 '메틸(메틸기, methyl group)'는 탄소 원자 1개에 수소 원자 3개가 결합한 구조로 가장 작은 알킬기이다. 이 메틸기는 음이온, 양이온, 유리기라는 세 가지 형태로 존재할 수 있다.In the present invention, the term “C 1 -C 6 alkyl” means a C 1 -C 6 straight-chain or branched-chain saturated hydrocarbon such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl. Preferred alkyl groups contain about 1, 2, 3, 4, 5 or 6 carbon atoms in the chain. Side chain means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain, which may be straight or branched. “Alkyl” may be unsubstituted or optionally substituted by one or more substituents, which may be the same or different, each substituent being halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkyl thio, amino, carboxy, and the like. Preferably alkyl can be methyl or ethyl. In the present invention, 'methyl (methyl group, methyl group)' is a structure in which three hydrogen atoms are bonded to one carbon atom, and is the smallest alkyl group. This methyl group can exist in three forms: anionic, cationic, and free.
본 발명에서 용어 "C1-C6 알킬렌"은 C1-C6 알킬로부터 유도된 2가 작용기를 의미하며, 예로 -CH2- 또는 -CH2-CH2-와 같은 2가 작용기들을 포함할 수 있다.In the present invention, the term "C 1 -C 6 alkylene" refers to a divalent functional group derived from C 1 -C 6 alkyl, including divalent functional groups such as -CH 2 - or -CH 2 -CH 2 -. can do.
본 발명에서 용어 "C1-C4 할로알킬"은 C1-C4의 직쇄 또는 분지쇄의 포화 탄화수소의 적어도 하나의 수소가 할로겐 화합물 (즉, F, Cl, Br, 또는 I)로 치환된 C1-C4의 직쇄 또는 분지쇄의 포화탄화수소를 의미한다. 예컨대, CF3일 수 있다.In the present invention, the term "C 1 -C 4 haloalkyl" refers to a C 1 -C 4 straight-chain or branched-chain saturated hydrocarbon, wherein at least one hydrogen is substituted with a halogen compound (ie, F, Cl, Br, or I). It means a C 1 -C 4 straight-chain or branched-chain saturated hydrocarbon. For example, it may be CF 3 .
본 발명에서 용어 "C3-C8 시클로알킬"은 3 내지 8개의 탄소 원자를 함유하는 포화탄화수소 고리를 의미하며 포화탄화수소 고리는 일환 및 다환, 2개 이상의 고리가 한쌍 이상의 탄소원자를 공유하고 있는 고리 구조를 모두 포함하는 의미이다. 시클로알킬은 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵탄일, 시클로옥탄일 등을 포함하며, 바람직하게는 시클로펜틸 또는 시클로헥실일 수 있으며, 여기에 한정되는 것은 아니다.In the present invention, the term "C 3 -C 8 cycloalkyl" refers to a saturated hydrocarbon ring containing 3 to 8 carbon atoms, and the saturated hydrocarbon ring is monocyclic and polycyclic, and two or more rings share one or more pairs of carbon atoms. This means that all structures are included. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, and the like, and may preferably be cyclopentyl or cyclohexyl, but is not limited thereto.
본 발명에서, "C3-C8 헤테로시클로알킬"는 질소(N), 산소(O) 및 황(S)으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 함유하는 포화된 일환 및 다환의 헤테로 고리 또는 2개 이상의 고리가 한쌍 이상의 탄소원자를 공유하고 있는 고리 구조를 의미한다. 헤테로시클로알킬은 옥시란일, 옥세탄일, 모포리닐, 티에탄일, 피롤리디닐, 피페리디닐, 테트라하이드로퓨라닐, 테트라하이드로티오펜일, 테트라하이드로피라닐, 테트라하이드로티오피라닐 등을 포함하며, 바람직하게는 피페리디닐일 수 있으며, 또한 N 원자에 벤질이 치환된 피페리디닐일 수 있으며, 여기에 한정되는 것은 아니다.In the present invention, "C 3 -C 8 heterocycloalkyl" refers to saturated monocyclic and polycyclic heterocycles containing 1 to 4 heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S). Or a ring structure in which two or more rings share one or more pairs of carbon atoms. Heterocycloalkyl includes oxiranyl, oxetanyl, mophorinyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the like. And, preferably, it may be piperidinyl, and may also be piperidinyl in which benzyl is substituted at the N atom, but is not limited thereto.
본 발명에서 용어 "C6-C12 아릴"은, 6 내지 12개의 탄소 원자를 함유하는 방향족 탄화수소를 지칭한다. 예를 들어, 모노시클릭 (예컨대, 페닐); 바이시클릭 (예컨대, 인데닐, 나프탈레닐, 테트라하이드로나프틸, 테트라하이드로인데닐) 같은 고리계를 가리킬 수 있다. 바람직하게는 아릴은 C6H5의 화학식을 가지며 6개의 탄소 원자가 순환 고리 구조를 이루며 배열되어 있는 페닐기일 수 있다. 페닐기는 매우 안정적이며 방향족 탄화수소의 일종으로 많은 유기 화합물에서 발견된다. 페닐기를 포함하는 가장 단순한 화합물은 페놀(C6H5OH)로, 하이드록시기가 결합된 구조이다. 또한 페닐고리의 오쏘(ortho), 메타(meta), 파라(para)위치의 수소가 할로겐 원자, C1-C4 할로알킬. -O-(C1-C4 할로알킬)이 치환될 수 있으며, 바람직하게는 F, Cl, -O-CF3 또는 CF3가 치환된 것일 수 있다.In the present invention, the term "C 6 -C 12 aryl" refers to an aromatic hydrocarbon containing 6 to 12 carbon atoms. For example, monocyclic (eg, phenyl); ring systems such as bicyclic (eg, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl). Preferably, aryl has a chemical formula of C 6 H 5 and may be a phenyl group in which 6 carbon atoms are arranged in a cyclic ring structure. The phenyl group is a very stable, aromatic hydrocarbon found in many organic compounds. The simplest compound containing a phenyl group is phenol (C 6 H 5 OH), which has a structure in which a hydroxy group is bonded. In addition, hydrogen at the ortho, meta, and para positions of the phenyl ring is a halogen atom, C 1 -C 4 haloalkyl. -O-(C 1 -C 4 haloalkyl) may be substituted, preferably F, Cl, -O-CF 3 or CF 3 may be substituted.
본 발명에서 용어 "C2-C12 헤테로아릴"은, 산소(O), 질소(N) 및 황(S)으로부터 선택되는 헤테로원자로 고리 탄소 원자 중 적어도 하나가 대체된, 2 내지 12개의 탄소 원자를 함유하는 선택적으로 치환된 방향족 고리나, 또는 헤테로아릴 고리, 아릴고리, 헤테로사이클릭 고리, 또는 카보사이클 고리와 같이 하나 이상의 고리에 융합된 방향족 고리(예컨대, 이환 또는 삼환 고리계)를 지칭하며, 각각은 선택적인 치환기를 가질 수 있다. 예를 들어, 이소퀴놀린일, 피리디닐, 피리미디닐, 퀴놀리닐, 티아졸릴, 푸라닐, 티오페닐, 인돌릴, 벤조피리디닐, 피라졸일 등을 포함하며, 이에 제한되는 것은 아니다.In the present invention, the term "C 2 -C 12 heteroaryl" is a heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S), at least one of the ring carbon atoms is replaced, 2 to 12 carbon atoms or an aromatic ring (e.g., a bicyclic or tricyclic ring system) fused to more than one ring, such as a heteroaryl ring, aryl ring, heterocyclic ring, or carbocyclic ring, containing , each of which may have an optional substituent. Examples include, but are not limited to, isoquinolinyl, pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, furanyl, thiophenyl, indolyl, benzopyridinyl, pyrazolyl, and the like.
본 발명에서 용어 "할로겐"은 플루오르(F), 클로로(Cl), 브로모(Br) 및 아이오도(I)로 선택되는 치환체를 의미한다. 바람직하게 할로겐은 플루오르 또는 클로로일 수 있다.In the present invention, the term "halogen" means a substituent selected from fluorine (F), chloro (Cl), bromo (Br) and iodo (I). Preferably halogen can be fluorine or chloro.
이밖에 본 명세서에서 사용된 용어들과 약어들은 달리 정의되지 않는 한, 그 본래의 의미를 갖는다.In addition, terms and abbreviations used in this specification have their original meanings unless otherwise defined.
화학식 1의 화합물의 용도Uses of Compounds of Formula 1
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 용도를 제공한다. The present invention provides a use of a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 수소원자, C1-C6 알킬기 또는 할로겐이고, R 1 is a hydrogen atom, a C 1 -C 6 alkyl group or a halogen;
L은 단결합, -O-, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;
R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C2-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6알킬렌)-R3, -O-(C1-C6 알킬) 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));
R3은 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이다.R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing substituted or unsubstituted heteroatoms selected from oxygen, nitrogen and sulfur.
본 발명에 있어서 상기 화학식 1에 관한 사항은 앞서 언급된 화학식 2 및 이의 구체적 화합물에 대한 사항을 본 발명의 용도 범주 내에 적용할 수 있다. In the present invention, the matters related to Chemical Formula 1 may be applied to the matters related to Chemical Formula 2 and specific compounds thereof mentioned above within the scope of use of the present invention.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염; 및 약제학적으로 허용가능한 담체를 포함하는 약학적 조성물을 제공한다. The present invention relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 Nox 억제제를 제공한다. A Nox inhibitor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is provided.
본 발명에 따른 화합물들은 Nox(NADPH oxidase) 억제에 우수한 효과를 나타내어, 다양한 치료 용도에 이용될 수 있다. The compounds according to the present invention exhibit excellent effects on inhibiting Nox (NADPH oxidase) and can be used for various therapeutic purposes.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 NADPH 산화효소(Nox) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating NADPH oxidase (Nox)-related diseases, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
NADPH 옥시다아제 (Nox) 패밀리의 멤버는 주요 생성물로써 ROS를 생성하는 효소들이다. 이들은 일반적으로 과산화물 음이온을 생산하기 위해서 NADPH-의존적 방법으로 산소 분자를 감소시킨다. 이러한 Nox의 활성 제어를 통한 활성산소 생성의 조절기전은 궁극적으로 세포 전반의 신호전달체계와 밀접한 관계를 가지고 있기 때문에 세포 전반의 신호 전달 체계뿐만 아니라 다양한 질환의 발병에 대한 치료와도 관련이 높다. Members of the NADPH oxidase (Nox) family are enzymes that generate ROS as a major product. They generally reduce molecular oxygen in a NADPH-dependent manner to produce superoxide anions. Because the mechanism of regulation of reactive oxygen species production through the control of activity of Nox ultimately has a close relationship with the overall cell signal transduction system, it is highly related to the treatment of various diseases as well as the overall cell signal transduction system.
예를 들어, 파킨슨 병, 알츠하이머 병 등을 포함하는 퇴행성 뇌질환과 관련되는 중추신경계의 여러 질병은 병증의 발병과 진행에 산화 스트레스와 신경염증이 공통적으로 나타난다. 특히, Nox는 산화 스트레스와 신경염증을 모두 조절하는 상위 인자로 확인되었다. 따라서 Nox의 비활성화 또는 약리학적 억제는 광범위한 신경 질환의 강력한 신경보호 효과(예를 들어, 도파민성뉴런 보호, 미세아교세포의 병리 개선 등) 및 행동학적 개선 효과를 기대할 수 있다.For example, various diseases of the central nervous system associated with degenerative brain diseases, including Parkinson's disease and Alzheimer's disease, commonly show oxidative stress and neuroinflammation in the onset and progression of the disease. In particular, Nox was identified as an upstream factor regulating both oxidative stress and neuroinflammation. Therefore, inactivation or pharmacological inhibition of Nox can be expected to have a strong neuroprotective effect (eg, dopaminergic neuron protection, improvement of microglia pathology, etc.) and behavioral improvement in a wide range of neurological diseases.
또한 예를 들어, Nox의 과발현은 다양한 암종, 특히 뇌암종에서 많이 알려져 있는바, 이의 억제는 질환 치료에 우수한 효과를 나타낼 수 있다. Also, for example, overexpression of Nox is well known in various carcinomas, especially brain carcinoma, and its suppression can exhibit excellent effects in disease treatment.
Nox에 의해 생성된 활성산소종은 변경된 신호 전달, 종양 형성 및 성장과 관련된 환경, 혈관 신생, 유전자의 불안정성, 전이 등과 연관이 있어 암의 병리 생리적으로 관련이 깊다. Reactive oxygen species generated by Nox are closely related to the pathophysiology of cancer because they are related to altered signal transduction, tumor formation and growth-related environment, angiogenesis, gene instability, and metastasis.
장기 및 세포에 따라 주로 발현하는 Nox의 효소종류가 다르기 때문에 다양한 암에서 Nox 동질효소별 연구가 많이 이루어지고 있다. Nox1은 결장암 증식과 관련이 보고도고 있고, Nox2는 유방암, 결장직장암, 위암, 전립선암 및 골수단구성 백혈병 등과 관련이 있다. Nox4는 비소세포폐암, 위암, 신경모세포종과의 관련성이 보고되고 있고 Nox5는 전립선암, 유방암, 흑색종 및 폐암, Duox1은 폐암 및 간암과의 관련성이 보고되었다. Since the types of Nox enzymes that are mainly expressed in organs and cells are different, many studies on Nox isoenzymes are being conducted in various cancers. Nox1 has been reported to be associated with colon cancer proliferation, and Nox2 is associated with breast cancer, colorectal cancer, gastric cancer, prostate cancer, and myelomonocytic leukemia. Nox4 has been reported to be associated with non-small cell lung cancer, gastric cancer, and neuroblastoma, Nox5 with prostate cancer, breast cancer, melanoma, and lung cancer, and Duox1 with lung cancer and liver cancer.
또한, Nox 저해제가 항-종양 효과를 가지거나, 면역 치료에 대한 민감성을 회복시키거나 및/또는 면역치료에 대한 반응성을 개선할 수도 있다. 또한, 혈관 형성 억제 효과를 나타낼 수도 있다. 또한, 염증인자 등의 발현을 저해할 수 있다. In addition, Nox inhibitors may have anti-tumor effects, restore sensitivity to immunotherapy, and/or improve responsiveness to immunotherapy. In addition, it may exhibit an angiogenesis inhibitory effect. In addition, expression of inflammatory factors and the like can be inhibited.
이에 따라, NADPH 산화효소(Nox) 관련 질환은 예를 들어, 건선, 류마티스 관절염, 골관절염, 재발협착증, 아테롬성 경화증, 궤양, 간경병증, 사구체신염, 당뇨병성 신장병증, 악성 신경화증, 혈전성 미소혈관증, 기관 이식 거부, 당뇨병, 고혈압, 심장 비대증, 심부전증, 재발협착증, 암, 자가면역질환, 염증성 질환, 퇴행성 뇌질환, 망막 질환 등을 들 수 있다. Accordingly, NADPH oxidase (Nox) related diseases include, for example, psoriasis, rheumatoid arthritis, osteoarthritis, restenosis, atherosclerosis, ulcers, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy , organ transplant rejection, diabetes, hypertension, cardiac hypertrophy, heart failure, restenosis, cancer, autoimmune disease, inflammatory disease, degenerative brain disease, and retinal disease.
자가면역질환은 원형탈모증(alopecia areata), 강직성 척추염, 항인지질 증후군, 부신의 자가면역 질환, 자가면역 용혈성 빈혈, 자가면역 간염, 자가면역 난소염, 자가면역 고환염, 자가면역 혈소판감소증, 베체트병, 수포성 유천포창, 심근병증, 만성 피로 면역이상 증후군, 만성염증성 탈수초 다발성 신경병증, 반흔성유천포창, CREST 증후군, 한냉 응집소 질환, 크론씨병, 원판성 낭창, 그레이브스 질환, 귈레인 바레 증후군, 하시모토 갑상선염, 특발성 폐섬유화증, 특발성 혈소판 감소성 자반증, IgA 신경염, 연소자성 관절염, 편평태선, 홍반성 루푸스, 메니에르병, 혼합성 연결 조직 질환, 다발성 경화증, 타입 I 또는 면역-매개 당뇨병, 중증근무력증, 심상성 천포창, 악성 빈혈, 결정성 다발동맥염, 다발연골염, 자가면역성 다선 증후군, 류마티스 다발성근통, 다발성 근염과 피부근염, 일차성 무감마글로불린혈증, 일차성 담증성 간경변, 전신성 홍반성 루푸스, 홍반성 루푸스, 다가야스 동맥염, 일시적 동맥염, 거대세포 동맥염, 궤양성 대장염, 포도막염, 백반증 및 베게너 육아종증을 포함하나, 이에 한정되는 것은 아니다.Autoimmune diseases include alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, autoimmune orchitis, autoimmune thrombocytopenia, Behcet's disease, Bullous pemphigoid, cardiomyopathy, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, scarring pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic Pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA neuritis, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type I or immune-mediated diabetes, myasthenia gravis, vulgaris Pemphigus, pernicious anemia, polyarteritis crystallographic, polychondritis, autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, systemic lupus erythematosus, lupus erythematosus, Dagayas arteritis, transient arteritis, giant cell arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis.
본 발명의 조성물에 의해 예방 또는 치료될 수 있는 염증성 질환의 예는, 천식, 뇌염(encephalitis), 염증성 장염, 만성 폐쇄성 폐질환, 알러지, 폐혈병성 쇼크증, 폐섬유증, 미분화 척추관절증, 미분화 관절병증, 관절염, 염증성 골용해, 및 만성 바이러스 또는 박테리아 감염에 의한 만성 염증을 포함하나, 이에 한정되는 것은 아니다.Examples of inflammatory diseases that can be prevented or treated by the composition of the present invention include asthma, encephalitis, inflammatory enteritis, chronic obstructive pulmonary disease, allergy, septic shock, pulmonary fibrosis, undifferentiated spondyloarthrosis, and undifferentiated joints. conditions, arthritis, inflammatory osteolysis, and chronic inflammation due to chronic viral or bacterial infection.
본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물에 의해 예방 또는 치료될 수 있는 암은 뇌암, 신경 내분비 암, 위암, 폐암, 유방암, 난소암, 간암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 부신암, 대장암, 결장암, 자궁경부암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암 및 요관암을 포함하지만, 이에 한정되는 것은 아니다According to a preferred embodiment of the present invention, the cancers that can be prevented or treated by the composition of the present invention include brain cancer, neuroendocrine cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, including but not limited to bladder, adrenal, colorectal, colon, cervical, prostate, bone, skin, thyroid, parathyroid and ureter cancers
상기 암은 특히 뇌암일 수 있다. 이러한 뇌암은 예를 들어, 성상세포종(astrocytoma), 교모세포종(glioblastoma), 상의세포종(ependymoma), 핍지교종(oligodendroglioma), 혼합교종(mixed glioma), 뇌간 교종(brain stem glioma), 시신경 교종(optic nerve glioma), 뇌하수체 종양(pituitary adenoma), 두개인두종(craniopharyngioma), 수모세포종(medulloblastoma), 원시신경외배엽종양(primitive neuroectodermal tumors), 송과체 종양(pineal tumors), 수막종(meningioma), 신경초종(schwannoma), 전이성 뇌종양(metastatic brain tumors), 중추신경 임파종(CNS lymphoma), 신경섬유종증(neurofibromatosis), 가성뇌종양(pseudotumor cerebri), 및 결절성 경화증(tuberous sclerosis)로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다. The cancer may in particular be brain cancer. These brain cancers include, for example, astrocytoma, glioblastoma, ependymoma, oligodendroglioma, mixed glioma, brain stem glioma, and optic nerve glioma. glioma, pituitary adenoma, craniopharyngioma, medulloblastoma, primitive neuroectodermal tumors, pineal tumors, meningioma, schwannoma, metastatic It may be any one or more selected from the group consisting of metastatic brain tumors, CNS lymphoma, neurofibromatosis, pseudotumor cerebri, and tuberous sclerosis.
보다 구체적으로, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염은 퇴행성 뇌질환 예방 또는 치료에 유용하다. More specifically, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention is useful for preventing or treating degenerative brain diseases.
이에 따라 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating degenerative brain disease comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명에서 퇴행성 뇌질환의 비제한적인 예는 파킨슨 병, 헌팅턴 병, 알츠하이머 병, 경도인지장애, 노인성 치매, 근위축성 측삭경화증 (amyotrophic lateral sclerosis), 척수소뇌성 운동실조증(Spinocer ebellar Atrophy), 뚜렛 증후군(Tourette`s Syndrome), 프리드리히 보행실조(Friedrich`s Ataxia), 마차도-조셉 병(Machado-Joseph`s disease), 루이 소체 치매(Lewy Body Dementia), 근육긴장이상(Dystonia), 진행성 핵상 마비(Progressive Supranuclear Palsy), 전두측두엽 치매(Frontotemporal Dementia) 등을 들 수 있다. Non-limiting examples of degenerative brain diseases in the present invention include Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette's Syndrome (Tourette's Syndrome), Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, progressive supranuclear palsy (Progressive Supranuclear Palsy) and Frontotemporal Dementia.
보다 구체적으로, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염은 망막 질환 예방 또는 치료에 유용하다. More specifically, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention is useful for preventing or treating retinal diseases.
이에 따라 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 망막 질환 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating retinal diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명에서 망막질환의 비제한적인 예는 녹내장, 미숙아 망막증, 증식성 망막증, 각막 이식 거부, 증식성 유리체망막병증, 당뇨망막병증, 황반변성, 맥락막 신생혈관증 또는 망막부종 등을 들 수 있다. 구체적으로, 상기 황반변성은 습식 황반변성 또는 건식 황반변성일 수 있다.Non-limiting examples of retinal diseases in the present invention include glaucoma, retinopathy of prematurity, proliferative retinopathy, corneal transplant rejection, proliferative vitreoretinopathy, diabetic retinopathy, macular degeneration, choroidal neovascularization or retinal edema. Specifically, the macular degeneration may be wet macular degeneration or dry macular degeneration.
본 발명의 일실시양태에 따르면, 본 발명에 따른 히단토인 유도체는 Nox 억제에 대해 우수한 효과를 나타낸다. 특히, 미세아교세포주인 BV2를 포함하여 다양한 신경 세포주에서 Nox에 의한 활성산소종의 생성을 조절함으로써 NADPH 산화효소(Nox) 관련 질환의 예방 또는 치료에 우수한 효과를 나타낸다. According to one embodiment of the present invention, the hydantoin derivative according to the present invention exhibits an excellent effect on Nox inhibition. In particular, by controlling the production of reactive oxygen species by Nox in various nerve cell lines, including the microglial cell line BV2, it exhibits excellent effects in preventing or treating NADPH oxidase (Nox)-related diseases.
본 발명의 일실시양태에 따르면, 본 발명에 따른 히단토인 유도체는 미세아교세포주의 이동능을 억제함으로써 질환 치료에 우수한 효과를 나타낼 수 있다. According to one embodiment of the present invention, the hydantoin derivative according to the present invention can exhibit excellent effects in treating diseases by inhibiting the migratory ability of microglial cell lines.
본 발명의 일실시양태에 따르면, 본 발명에 따른 히단토인 유도체는 파킨슨병 모델에서 도파민성 뉴런 보호, 미세아교세포의 병리 개선 등을 통하여 분자생물학적, 조직학적 개선 효과를 나타내며, 이러한 작용 효과를 통해 행동학적 치료 효과를 함께 나타낸다. According to one embodiment of the present invention, the hydantoin derivative according to the present invention exhibits molecular biological and histological improvement effects through protection of dopaminergic neurons and improvement of pathology of microglia in a Parkinson's disease model, and through such action effects It shows the effect of behavioral treatment together.
본 발명의 일실시양태에 따르면, 본 발명에 따른 히단토인 유도체는 알츠하이머병 모델에서 아밀로이드 플라그 침착을 감소시키고, 별아교세포 및 미세아교세포의 활성을 억제하고 인지기능, 공간 기억력, 단기 및 장기 기억력 개선에 우수한 효과를 나타낸다. According to one embodiment of the present invention, the hydantoin derivative according to the present invention reduces amyloid plaque deposition in an Alzheimer's disease model, inhibits the activity of astrocytes and microglia, and improves cognitive function, spatial memory, and short-term and long-term memory. shows excellent effect.
또한, 본 발명에 따른 화합물들은 혈액-뇌 장벽 (BBB, Brain Barrier Blood) 투과성이 우수한 효과를 나타내어, 상기 전술된 질환의 치료 용도에 이용될 수 있다.In addition, the compounds according to the present invention exhibit excellent effects on blood-brain barrier (BBB, Brain Barrier Blood) permeability, and thus can be used for the treatment of the aforementioned diseases.
본 발명에 따른 화합물들은 BBB 투과성이 우수함에 따라 표적 부위로 전달 효과가 우수하여 실제 약물로서 치료적 효능이 우수하다.As the compounds according to the present invention have excellent BBB permeability, they have excellent delivery effect to the target site and thus have excellent therapeutic efficacy as actual drugs.
또한, 본 발명에 따른 화합물들은 대사 안정성이 우수한 효과를 나타내어, 상기 전술된 질환의 치료 용도에 이용될 수 있다.In addition, the compounds according to the present invention exhibit excellent metabolic stability and can be used for the treatment of the aforementioned diseases.
본 발명에 따른 화합물들은 대사 안정성이 우수하여 실제 약물로서의 효능이 우수하다.The compounds according to the present invention have excellent metabolic stability and thus have excellent efficacy as actual drugs.
본 발명의 약학 조성물은 투여를 위해서 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염 외에 추가로 약학적으로 허용가능한 담체를 1 종 이상 더 포함할 수 있다. 약학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 약학 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for administration. A pharmaceutically acceptable carrier may be a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and, if necessary, antioxidants and buffers. , bacteriostatic agents and other conventional additives may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare formulations for injections such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets. Accordingly, the pharmaceutical composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository or the like. These formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on each disease or component It can be.
본 발명의 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여 (예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환 종류 및 중증도 등에 따라 그 범위가 다양하다. 본 발명의 화학식 1의 화합물의 일일 투여량은 약 0.01 내지 1000 ㎎/㎏ 이고, 바람직하게는 0.1 내지 100 ㎎/㎏ 이며, 하루 일 회 내지 수 회에 나누어 투여할 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage is determined according to the patient's weight, age, sex, health The range varies depending on the condition, diet, administration time, administration method, excretion rate, and disease type and severity. The daily dose of the compound of Formula 1 of the present invention is about 0.01 to 1000 mg/kg, preferably 0.1 to 100 mg/kg, and may be administered once or several times a day.
즉, 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있으나, 삼투압 펌프(osmotic pump)를 이용한 피하주사(subcutaneous injection), 피내주사(intradermal injection), 정맥주사(intravein injection), 복강주사(intraperitoneal injection) 또는 안구 주사 (intravitreal injection) 등을 통해 투여될 수 있다. That is, the administration route of the composition may be administered through any general route as long as it can reach the target tissue, but subcutaneous injection using an osmotic pump, intradermal injection, intravenous injection ( It may be administered through intravein injection, intraperitoneal injection, or intravitreal injection.
본 발명의 약학 조성물은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상 더 포함할 수 있다.The pharmaceutical composition of the present invention may further contain at least one active ingredient exhibiting the same or similar efficacy in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 치료학적으로 유효한 양을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는, NADPH 산화효소(Nox) 관련 질환을 치료 또는 예방하는 방법을 제공한다. The present invention is directed to treating or preventing NADPH oxidase (Nox) related diseases, comprising administering a therapeutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. provides a way
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 치료학적으로 유효한 양을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는, 퇴행성 뇌질환을 치료 또는 예방하는 방법을 제공한다. The present invention provides a method for treating or preventing a degenerative brain disease, comprising administering a therapeutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 치료학적으로 유효한 양을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는, 암을 치료 또는 예방하는 방법을 제공한다. The present invention provides a method for treating or preventing cancer, comprising administering a therapeutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 상기 질환의 예방 또는 치료에 유효한 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 양을 나타낸다.The term "therapeutically effective amount" used in the present invention refers to an amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof effective for preventing or treating the disease.
본 발명의 치료방법은 상기 화학식 1의 화합물을 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서, 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성(nature)과 심각도, 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령, 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한, 본 발명의 치료방법은 상기 화학식 1의 화합물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 상기 화학식 1의 화합물과 함께 시너지 효과 또는 보조적 효과를 나타낼 수 있다.The treatment method of the present invention includes not only addressing the disease itself prior to the onset of symptoms, but also inhibiting or avoiding its symptoms, by administering the compound of Formula 1 above. In the management of disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dosing will vary according to the age, weight and response of the individual patient. A suitable dosage regimen can be readily selected by those skilled in the art who take these factors into account. In addition, the treatment method of the present invention may further include the administration of a therapeutically effective amount of an additional active agent to help treat a disease together with the compound of Formula 1, the additional active agent together with the compound of Formula 1 They may exhibit synergistic or auxiliary effects.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 NADPH 산화효소(Nox) 관련 질환 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or alleviating NADPH oxidase (Nox)-related diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or improving degenerative brain disease comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 암 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or improving cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명의 식품 조성물은 건강기능식품으로서 사용될 수 있다. 상기 "건강기능식품"이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The food composition of the present invention can be used as a health functional food. The term “health functional food” refers to food manufactured and processed using raw materials or ingredients having functional properties useful for the human body in accordance with the Health Functional Food Act No. 6727, and “functional” refers to the structure of the human body. And it refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients for functions or physiological functions.
본 발명의 식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안정청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The food composition of the present invention may contain conventional food additives, and the suitability as the "food additive" is determined in accordance with the General Rules of the Code of Food Additives and General Test Methods approved by the Korea Food and Drug Administration, unless otherwise specified. It is judged according to the standards and standards for
본 발명의 식품 조성물은 상기 질환의 예방 및/또는 개선을 목적으로, 조성물 총 중량에 대하여 상기 화학식 1의 화합물을 0.01 내지 95 %, 바람직하게는 1 내지 80 % 중량백분율로 포함할 수 있다. 또한, 상기 질환의 예방 및/또는 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환, 음료 등의 형태로 제조 및 가공할 수 있다.For the purpose of preventing and/or improving the disease, the food composition of the present invention may contain the compound of Formula 1 in an amount of 0.01 to 95%, preferably 1 to 80%, based on the total weight of the composition. In addition, for the purpose of preventing and/or improving the above diseases, it can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, beverages, and the like.
또한, 본 발명은 NADPH 산화효소(Nox) 관련 질환의 치료용 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 용도를 제공하고자 한다. In addition, the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of NADPH oxidase (Nox)-related diseases.
또한, 본 발명은 퇴행성 뇌질환의 치료용 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 용도를 제공하고자 한다. In addition, the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of degenerative brain diseases.
또한, 본 발명은 암의 치료용 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염의 용도를 제공하고자 한다. In addition, the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of cancer.
약제의 제조를 위한 상기 화학식 1의 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. The compound of Formula 1 for the preparation of a drug may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
또한, 본 발명에서는 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 인지기능 증진용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for enhancing cognitive function comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명은 또한 하기 실시양태를 포함한다:The present invention also includes the following embodiments:
약제로서 사용하기 위한, 본원에 기술된 임의의 실시양태에 정의된 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염;a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, for use as a medicament;
본원에 논의된 상기 질환의 예방 또는 치료에 사용하기 위한, 본원에 기술된 임의의 실시양태에 정의된 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염;a compound represented by Formula 1 as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of any of the above diseases discussed herein;
본원에 기술된 임의의 실시양태에 정의된 치료학적으로 유효한 양의 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는 상기 언급된 질환의 치료 방법;Treatment of the above-mentioned diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as defined in any embodiment described herein. method;
상기 언급된 질환의 치료를 위한 약제의 제조를 위한, 본원에 기술된 임의의 실시양태에 정의된 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염;a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein, for the manufacture of a medicament for the treatment of the above-mentioned diseases;
본원에 기술된 임의의 실시양태에 정의된 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 Nox 억제제;Nox inhibitors comprising a compound represented by Formula 1 as defined in any of the embodiments described herein or a pharmaceutically acceptable salt thereof;
본원에 기술된 임의의 실시양태에 정의된 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 항산화제;an antioxidant comprising a compound represented by Formula 1 as defined in any of the embodiments described herein or a pharmaceutically acceptable salt thereof;
본원에 기술된 임의의 실시양태에 정의된 치료학적으로 유효한 양의 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염; 및 제2항암제를 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는 암의 치료 방법.A therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as defined in any of the embodiments described herein; and administering a second anti-cancer agent to a subject in need thereof.
모든 예, 이의 이성질체 또는 이의 약학적으로 허용가능한 염은 개별적으로, 또는 본원에 기술된 각각의 모든 실시양태의 임의의 개수와의 임의의 조합으로 함께 그룹으로 청구될 수 있다. All examples, isomers thereof, or pharmaceutically acceptable salts thereof may be claimed as a group, either individually or together in any combination with any number of each and every embodiment described herein.
본 발명에서 사용되는 용어 "예방"은 조성물의 투여로 상기 질환의 형성을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. The term "prevention" used in the present invention refers to any action that inhibits the formation of the disease or delays the onset of the disease by administration of the composition.
본 발명에 있어서, "치료"란 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, "treatment" refers to all activities that improve or beneficially change the symptoms of the disease by administration of the composition.
본 발명의 용어 "대상체"란 상기 질환이 발병하였거나 발병할 수 있는 모든 동물을 의미하며, 전형적으로 본 발명의 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염을 이용한 치료로 유익한 효과를 나타낼 수 있는 동물일 수 있으나, 상기 질환의 증상을 갖거나 이러한 증상을 가질 가능성이 있는 개체이면 제한없이 포함한다. 전술한 바와 같이, 본 발명의 약학 조성물을 개체에게 투여함으로써 상기 전술된 질환을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학 조성물은 개별 치료제로 투여하거나, 기존의 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다.The term "subject" of the present invention means any animal that has or may develop the disease, and typically has a beneficial effect by treatment with the compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof. It may be an animal that can show, but includes without limitation any individual that has symptoms of the disease or is likely to have these symptoms. As described above, the aforementioned diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent, administered in combination with existing therapeutic agents, or sequentially or simultaneously with conventional therapeutic agents.
본 발명의 조성물, 용도, 치료방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the composition, use, and treatment method of the present invention are equally applied unless contradictory to each other.
본 발명에 따른 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염은 우수한 Nox 억제 효과를 나타낸다. 특히, 퇴행성 뇌질환, 암 등을 포함하여 NADPH 산화효소(Nox) 관련 질환 치료에 우수한 효과를 나타낸다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent Nox inhibitory effect. In particular, it exhibits excellent effects in the treatment of NADPH oxidase (Nox)-related diseases, including degenerative brain diseases and cancer.
도 1a는 본 발명에 따른 화합물 E7240-13 및 E7240-17-24의 Nox 억제 효과를 확인하기 위한 IC50 값 측정 결과를 나타낸 것이다.Figure 1a shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds E7240-13 and E7240-17-24 according to the present invention.
도 1b는 본 발명에 따른 화합물 E7240-17-27 및 LMT-1894의 Nox 억제 효과를 확인하기 위한 IC50 값 측정 결과를 나타낸 것이다.Figure 1b shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds E7240-17-27 and LMT-1894 according to the present invention.
도 1c는 본 발명에 따른 화합물 LMT-2132 및 LMT-1895의 Nox 억제 효과를 확인하기 위한 IC50 값 측정 결과를 나타낸 것이다.Figure 1c shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds LMT-2132 and LMT-1895 according to the present invention.
도 1d는 본 발명에 따른 화합물 LMT-1896 및 LMT-2144의 Nox 억제 효과를 확인하기 위한 IC50 값 측정 결과를 나타낸 것이다.Figure 1d shows the IC 50 value measurement results for confirming the Nox inhibitory effect of the compounds LMT-1896 and LMT-2144 according to the present invention.
도 1e는 본 발명에 따른 화합물 LMT-2154 및 LMT-2156의 Nox 억제 효과를 확인하기 위한 IC50 값 측정 결과를 나타낸 것이다.Figure 1e shows the results of measuring IC 50 values for confirming the Nox inhibitory effect of the compounds LMT-2154 and LMT-2156 according to the present invention.
이하, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본 발명의 실시예에 대하여 상세히 설명한다. 그러나 본 발명은 여러 가지 상위한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다. Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention can be implemented in various different forms and is not limited to the embodiments described herein.
이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma-Aldrich, TCI로부터 구입한 것이다. Reagents and solvents mentioned below were purchased from Sigma-Aldrich, TCI unless otherwise specified.
모든 화합물의 1H-, 13C-NMR은 Bruker AV-500으로 측정하였으며, CDCl3 (dH = 7.26 ppm and dC = 77.0 ppm)를 내부 표준으로 사용하였다. NMR 데이터는 MNova 10.0 processing software (Mestrelab Research)사용하여 이루어졌다. 1 H-, 13 C-NMR of all compounds were measured with a Bruker AV-500, and CDCl 3 (d H = 7.26 ppm and d C = 77.0 ppm) was used as an internal standard. NMR data were obtained using MNova 10.0 processing software (Mestrelab Research).
고분해능 질량분석은 전기적 이온화를 기반으로 한 Joel JMS-700 mass spectrometer을 사용하여 이루어졌다.High-resolution mass spectrometry was performed using a Joel JMS-700 mass spectrometer based on electrical ionization.
실시예 1. (Example 1. (
EE
)-3-사이클로헥실-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성Synthesis of )-3-cyclohexyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one
(E7240-13)(E7240-13)
(1) 3-시클로헥실-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성(1) Synthesis of 3-cyclohexyl-1-methyl-2-thioxoimidazolidin-4-one
(8.51 g, 80% 수율, 백색 고체): (8.51 g, 80% yield, white solid):
무수 에탄올 (50 mL) 내 사르코신 (4.45 g, 50.0 mmol)의 교반된 용액에 시클로헥실 이소티오시아네이트 (7.77 g, 55.0 mmol)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 3-시클로헥실-1-메틸-2-티오옥소이미다졸리딘-4-온을 수득하였다. To a stirred solution of sarcosine (4.45 g, 50.0 mmol) in absolute ethanol (50 mL) was added cyclohexyl isothiocyanate (7.77 g, 55.0 mmol). The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give 3-cyclohexyl-1-methyl-2-thiooxoimidazolidin-4-one.
1H NMR (500 MHz, CDCl3): δH 4.52 (tt, J = 12.4, 3.9 Hz, 1H), 3.95 (s, 2H), 3.33 (s, 3H), 2.22 (qd, J = 12.6, 3.7 Hz, 2H), 1.85 (dt, J = 13.5, 3.3 Hz, 2H), 1.76 - 1.63 (m, 3H), 1.37 (qt, J = 13.2, 3.5 Hz, 2H), 1.24 (qt, J = 13.0, 3.4 Hz, 1H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 4.52 (tt, J = 12.4, 3.9 Hz, 1H), 3.95 (s, 2H), 3.33 (s, 3H), 2.22 (qd, J = 12.6, 3.7 Hz, 2H), 1.85 (dt, J = 13.5, 3.3 Hz, 2H), 1.76 - 1.63 (m, 3H), 1.37 (qt, J = 13.2, 3.5 Hz, 2H), 1.24 (qt, J = 13.0, 3.4 Hz, 1H) ppm.
(2) ((2) (
EE
)-3-시클로헥실-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성 (110 mg, 66% 수율, 빨간색 고체): Synthesis of )-3-cyclohexyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one (110 mg, 66% Yield, red solid):
1,4-디옥세인(3 ml) 내 3-시클로헥실-1-메틸-2-티오옥소이미다졸리딘-4-온 (92 mg, 0.43 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (100 mg, 0.52 mmol), 피페리딘 (0.06 ml, 0.65 mmol)의 교반된 용액에 AlCl3 (6 mg, 0.04 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 최종 생성물을 수득하였다. 3-cyclohexyl-1-methyl-2-thioxoimidazolidin-4-one (92 mg, 0.43 mmol) in 1,4-dioxane (3 ml), 4-(diethylamino)-2- To a stirred solution of hydroxybenzaldehyde (100 mg, 0.52 mmol) and piperidine (0.06 ml, 0.65 mmol) was added AlCl 3 (6 mg, 0.04 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the final product.
1H NMR (500 MHz, CDCl3): δH 9.20 (s, 1H), 6.64 (s, 1H), 6.35 (d, J = 8.9 Hz, 1H), 6.31 (s, 1H), 4.77 (t, J = 12.3 Hz, 1H), 3.65 (s, 3H), 3.49 (s, 1H), 3.40 (q, J = 7.0 Hz, 4H), 2.32 (dd, J = 22.9, 11.2 Hz, 2H), 2.18 (s, 2H), 1.85 (d, J = 13.1 Hz, 2H), 1.74 (d, J = 11.3 Hz, 2H), 1.70 - 1.59 (m, 2H), 1.37 (dd, J = 26.3, 13.0 Hz, 2H), 1.20 (t, J = 7.1 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): δC 173.24, 164.29, 159.10, 151.91, 137.00, 123.08, 121.26, 110.67, 106.09, 101.95, 56.21, 50.90, 44.62, 31.61, 30.97, 28.58, 25.94, 25.11, 12.72 ppm; HRMS (EI) m/z [M]+ calcd for C21H30N3O2S, 388.2053, found 402.3. 1 H NMR (500 MHz, CDCl 3 ): δ H 9.20 (s, 1H), 6.64 (s, 1H), 6.35 (d, J = 8.9 Hz, 1H), 6.31 (s, 1H), 4.77 (t, J = 12.3 Hz, 1H), 3.65 (s, 3H), 3.49 (s, 1H), 3.40 (q, J = 7.0 Hz, 4H), 2.32 (dd, J = 22.9, 11.2 Hz, 2H), 2.18 ( s, 2H), 1.85 (d, J = 13.1 Hz, 2H), 1.74 (d, J = 11.3 Hz, 2H), 1.70 - 1.59 (m, 2H), 1.37 (dd, J = 26.3, 13.0 Hz, 2H) ), 1.20 (t, J = 7.1 Hz, 6H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 173.24, 164.29, 159.10, 151.91, 137.00, 123.08, 121.26, 110.67, 106.09, 101.95, 56.21, 50.90, 44.6 2, 31.61, 30.97, 28.58, 25.94, 25.11, 12.72 ppm; HRMS (EI) m/z [M] + calcd for C 21 H 30 N 3 O 2 S, 388.2053, found 402.3.
실시예 2. (Example 2. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-3-((4-플루오로페닐)술포닐)-1-메틸-2-티옥소이미다졸리딘-4-온의 합성 (E7240-17-24))-5-(4-(diethylamino)-2-hydroxybenzylidene)-3-((4-fluorophenyl)sulfonyl)-1-methyl-2-thioxoimidazolidine-4- Synthesis of On (E7240-17-24)
사르코신(Sarcosine)(89.1 mg, 1.0 mmol), 4-플루오로벤젠술포닐 이소티오시아네이트 (217.2 mg, 1.0 mmol) 및 에탄올(10 mL)을 테플론 밀봉 유리 용기(20 mL 용량)에 넣고 이 용기를 135℃ 및 3.5-5.0 Bar에서 60W의 마이크로웨이브 캐비티에 6분 동안 넣었다. 이후 반응물을 실온으로 냉각시켰다. 이 용기에 4-(디에틸아미노)-2-히드록시벤즈알데히드(212.5 mg, 1.1 mmol) 및 피페리딘(170.3 mg, 2.0 mmol)을 첨가하고 135℃ 및 3.5-5.0 Bar에서 60W의 마이크로웨이브 캐비티에 다시 12분 동안 넣은 후, 반응물을 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올(5 mL)로 세척하여 (E)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-3-((4-플루오로페닐)술포닐)-1-메틸-2-티옥소이미다졸리딘-4-온 화합물을 수득하였다(102 mg, 22% 수율, 와인 레드 고체). Sarcosine (89.1 mg, 1.0 mmol), 4-fluorobenzenesulfonyl isothiocyanate (217.2 mg, 1.0 mmol) and ethanol (10 mL) were placed in a Teflon-sealed glass container (20 mL volume) and this The vessel was placed in a 60W microwave cavity at 135° C. and 3.5-5.0 Bar for 6 minutes. The reaction was then cooled to room temperature. To this vessel was added 4-(diethylamino)-2-hydroxybenzaldehyde (212.5 mg, 1.1 mmol) and piperidine (170.3 mg, 2.0 mmol) and placed in a microwave cavity at 60 W at 135°C and 3.5-5.0 Bar. After another 12 min, the reaction was cooled to room temperature. The precipitated solid was filtered and washed with ethanol (5 mL) to obtain ( E )-5-(4-(diethylamino)-2-hydroxybenzylidene)-3-((4-fluorophenyl)sulfonyl) Compound -1-methyl-2-thioxoimidazolidin-4-one was obtained (102 mg, 22% yield, wine red solid).
1H NMR (500 MHz, CDCl3): δH 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (s, 2H), 7.22 (t, J = 8.5 Hz, 2H), 6.83 (s, 1H), 6.38 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 3.77 (s, 3H), 3.43 (q, J = 6.9 Hz, 4H), 1.23 (t, J = 7.0 Hz, 6H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 1 H NMR (500 MHz, CDCl 3 ) δ 8.56 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (s, 2H), 7.22 (t, J = 8.5 Hz, 2H), 6.83 (s, 1H), 6.38 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 3.77 (s, 3H), 3.43 (q, J = 6.9 Hz, 4H), 1.23 (t, J = 7.0 Hz, 6H) ppm.
실시예 3. (Example 3. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-1-메틸-2-티옥소-3-토실이미다졸리딘-4-온의 합성 (E7240-17-27)Synthesis of )-5-(4-(diethylamino)-2-hydroxybenzylidene)-1-methyl-2-thioxo-3-tosylimidazolidin-4-one (E7240-17-27)
사르코신(Sarcosine)(89.1 mg, 1.0 mmol), 토실 이소티오시아네이트(237.2 mg, 1.0 mmol) 및 에탄올(10 mL)을 테플론 밀봉 유리 용기(20 mL 용량)에 넣고 이 용기를 135℃ 및 3.5-5.0 Bar에서 60W의 마이크로웨이브 캐비티에 6분 동안 넣었다. 이후 반응물을 실온으로 냉각시켰다. 이 용기에 4-(디에틸아미노)-2-히드록시벤즈알데히드(212.5 mg, 1.1 mmol) 및 피페리딘(170.3 mg, 2.0 mmol)을 첨가하고 135℃ 및 3.5-5.0 Bar에서 60W의 마이크로웨이브 캐비티에 다시 12분 동안 넣은 후, 반응물을 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올(5 mL)로 세척하여 (E)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-1-메틸-2-티옥소-3-토실이미다졸리딘-4-온 화합물을 수득하였다(118 mg, 26% 수율, 와인 레드 고체).Sarcosine (89.1 mg, 1.0 mmol), tosyl isothiocyanate (237.2 mg, 1.0 mmol) and ethanol (10 mL) were placed in a Teflon-sealed glass container (20 mL volume) and the container was heated at 135 °C and 3.5 °C. It was placed in a 60W microwave cavity at -5.0 Bar for 6 minutes. The reaction was then cooled to room temperature. To this vessel was added 4-(diethylamino)-2-hydroxybenzaldehyde (212.5 mg, 1.1 mmol) and piperidine (170.3 mg, 2.0 mmol) and placed in a microwave cavity at 60 W at 135°C and 3.5-5.0 Bar. After another 12 min, the reaction was cooled to room temperature. The precipitated solid was filtered and washed with ethanol (5 mL) to obtain ( E )-5-(4-(diethylamino)-2-hydroxybenzylidene)-1-methyl-2-thioxo-3-tosylimida A zolidin-4-one compound was obtained (118 mg, 26% yield, wine red solid).
1H NMR (500 MHz, CDCl3): δH 8.83 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 6.79 (s, 1H), 6.37 (t, J = 10.8 Hz, 1H), 6.30 (s, 1H), 3.77 (s, 3H), 3.42 (q, J = 6.8 Hz, 4H), 2.44 (s, 3H), 1.23 (t, J = 7.0 Hz, 6H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 8.83 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 6.79 (s, 1H), 6.37 (t, J = 10.8 Hz, 1H), 6.30 (s, 1H), 3.77 (s, 3H), 3.42 (q, J = 6.8 Hz, 4H) , 2.44 (s, 3H), 1.23 (t, J = 7.0 Hz, 6H) ppm.
실시예 4. (Example 4. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-페닐-2-티오옥소이미다졸리딘-4-온의 합성(LMT-1894)Synthesis of )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenyl-2-thioxoimidazolidin-4-one (LMT-1894)
(1) 1-메틸-3-페닐-2-티오옥소이미다졸리딘-4-온의 합성(1) Synthesis of 1-methyl-3-phenyl-2-thioxoimidazolidin-4-one
(8.97 g, 87% 수율, 분홍색 고체): (8.97 g, 87% yield, pink solid):
무수 에탄올 (50 mL) 내 사르코신 (4.45 g, 50.0 mmol)의 교반된 용액에 페닐 이소티오시아네이트 (7.44 g, 55.0 mmol)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다. To a stirred solution of sarcosine (4.45 g, 50.0 mmol) in absolute ethanol (50 mL) was added phenyl isothiocyanate (7.44 g, 55.0 mmol). The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, DMSO-d6): δH 7.41-7.19 (m, 5H), 4.89 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm. 1 H NMR (500 MHz, DMSO-d 6 ): δ H 7.41-7.19 (m, 5H), 4.89 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm.
(2) ((2) (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-페닐-2-티오옥소이미다졸리딘-4-온의 합성 (42 mg, 45% 수율, 빨간색 고체): Synthesis of )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenyl-2-thioxoimidazolidin-4-one (42 mg, 45% yield , red solid):
1,4-디옥세인(2 ml) 내 1-메틸-3-페닐-2-티오옥소이미다졸리딘-4-온 (50 mg, 0.24 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (56 mg, 0.29 mmol), 피페리딘 (0.04 ml, 0.4 mmol)의 교반된 용액에 AlCl3 (3 mg, 0.02 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 최종 생성물을 수득하였다. 1-Methyl-3-phenyl-2-thioxoimidazolidin-4-one (50 mg, 0.24 mmol), 4-(diethylamino)-2-hydride in 1,4-dioxane (2 ml) To a stirred solution of oxybenzaldehyde (56 mg, 0.29 mmol) and piperidine (0.04 ml, 0.4 mmol) was added AlCl 3 (3 mg, 0.02 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the final product.
1H NMR (500 MHz, CDCl3): δH 1H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 7.51 (dd, J = 24.9, 17.7 Hz, 3H), 7.38 (s, 2H), 7.26 (s, 1H), 6.79 (s, 1H), 6.35 (d, J = 6.0 Hz, 1H), 6.26 (s, 1H), 3.74 (s, 3H), 3.46 - 3.28 (m, 4H), 1.19 (d, J = 6.9 Hz, 7H) ppm; 13C NMR (125 MHz, CDCl3): δC 159.10, 152.14, 136.98, 133.33, 129.21, 129.09, 128.45, 122.05, 106.13, 101.48, 44.65, 31.33, 12.73 ppm; HRMS (EI) m/z [M]+ calcd for C21H24N3O2S, 382.1584, found 402.3. 1H NMR (500 MHz, CDCl 3 ): δ H 1H NMR (500 MHz, CDCl 3 ) δ 8.70 (s, 1H), 7.51 (dd, J = 24.9, 17.7 Hz, 3H), 7.38 (s, 2H) , 7.26 (s, 1H), 6.79 (s, 1H), 6.35 (d, J = 6.0 Hz, 1H), 6.26 (s, 1H), 3.74 (s, 3H), 3.46 - 3.28 (m, 4H), 1.19 (d, J = 6.9 Hz, 7H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 159.10, 152.14, 136.98, 133.33, 129.21, 129.09, 128.45, 122.05, 106.13, 101.48, 44.65, 31.33, 12.7 3 ppm; HRMS (EI) m/z [M] + calcd for C 21 H 24 N 3 O 2 S, 382.1584, found 402.3.
실시예 5. (Example 5. (
EE
)-3-(1-벤질피페리딘-4-닐)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성(LMT-2132))-3-(1-benzylpiperidin-4-yl)-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidine-4 Synthesis of -ones (LMT-2132)
(1) 1-벤질-4-이소티오시아나토피페리딘의 합성(1) Synthesis of 1-benzyl-4-isothiocyanatopiperidine
(670 mg, 94% 수율, 흰색 고체): (670 mg, 94% yield, white solid):
디엠에프 (5 mL) 내 4-아미노-1-벤질피페리딘 (0.6 mL, 3.06 mmol)에 1,1'-티오카르보닐디이미다졸 (600 mg, 3.37 mmol)을 -15℃에서 첨가하였다. 실온에서 14시간 동안 반응시킨 뒤 혼합물을 메틸렌 클로라이드 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득한 뒤 다음 반응에 이용하였다,To 4-amino-1-benzylpiperidine (0.6 mL, 3.06 mmol) in DMF (5 mL) was added 1,1'-thiocarbonyldiimidazole (600 mg, 3.37 mmol) at -15 °C. . After reacting at room temperature for 14 hours, the mixture was extracted with methylene chloride (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to obtain a product which was used in the next reaction.
(2) 3-(1-벤질피페리딘-4-닐)-1-메틸-2-티옥소이미다졸리딘-4-온의 합성(2) Synthesis of 3-(1-benzylpiperidin-4-yl)-1-methyl-2-thioxoimidazolidin-4-one
(800 mg, 88% 수율, 주황색 고체): (800 mg, 88% yield, orange solid):
무수 에탄올 (20 mL) 내 사르코신 (268 mg, 3.01 mmol)의 교반된 용액에 1-벤질-4-이소티오시아나토피페리딘 (700 ml, 3.01 mmol)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다. To a stirred solution of sarcosine (268 mg, 3.01 mmol) in absolute ethanol (20 mL) was added 1-benzyl-4-isothiocyanatopiperidine (700 ml, 3.01 mmol). The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, CDCl3): δH 7.32 (dt, J = 15.1, 7.5 Hz, 4H), 7.25 (dd, J = 11.7, 4.5 Hz, 1H), 4.59 - 4.44 (m, 1H), 3.93 (s, 2H), 3.53 (s, 2H), 3.31 (s, 3H), 2.96 (d, J = 11.6 Hz, 2H), 2.56 (tt, J = 12.3, 6.1 Hz, 2H), 2.07 (t, J = 13.0 Hz, 2H), 1.62 (dd, J = 11.8, 0.9 Hz, 2H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 7.32 (dt, J = 15.1, 7.5 Hz, 4H), 7.25 (dd, J = 11.7, 4.5 Hz, 1H), 4.59 - 4.44 (m, 1H), 3.93 (s, 2H), 3.53 (s, 2H), 3.31 (s, 3H), 2.96 (d, J = 11.6 Hz, 2H), 2.56 (tt, J = 12.3, 6.1 Hz, 2H), 2.07 (t , J = 13.0 Hz, 2H), 1.62 (dd, J = 11.8, 0.9 Hz, 2H) ppm.
(3) ((3) (
EE
)-3-(1-벤질피페리딘-4-닐)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성 (120 mg, 63% 수율, 빨간색 고체): )-3-(1-benzylpiperidin-4-yl)-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidine-4 Synthesis of -one (120 mg, 63% yield, red solid):
1,4-디옥세인(5 ml) 내 3-(1-벤질피페리딘-4-닐)-1-메틸-2-티옥소이미다졸리딘-4-온 (120 mg, 0.40 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (91 mg, 0.47 mmol), 피페리딘 (0.06 mL, 0.59 mmol)의 교반된 용액에 AlCl3 (6 mg, 0.04 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80 ℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다. 3-(1-benzylpiperidin-4-yl)-1-methyl-2-thioxoimidazolidin-4-one (120 mg, 0.40 mmol) in 1,4-dioxane (5 ml), To a stirred solution of 4-(diethylamino)-2-hydroxybenzaldehyde (91 mg, 0.47 mmol) and piperidine (0.06 mL, 0.59 mmol) was added AlCl 3 (6 mg, 0.04 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
1H NMR (500 MHz, CDCl3): δH 7.34 (dt, J = 14.9, 8.5 Hz, 5H), 7.24 (d, J = 7.2 Hz, 1H), 6.66 (s, 1H), 6.35 (dd, J = 9.0, 2.4 Hz, 1H), 6.29 (d, J = 2.2 Hz,1H), 4.84 - 4.74 (m, 1H), 3.64 (s, 3H), 3.55 (s, 2H), 3.39 (q, J = 7.0 Hz, 4H), 2.99 (d, J = 11.5 Hz, 2H), 2.70 (q, J = 12.0 Hz, 2H), 2.12 (t, J = 11.4 Hz,2H), 1.66 (d, J = 10.3 Hz, 2H), 1.20 (t, J = 7.1 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): δC 173.04, 164.13, 159.24, 151.98, 138.53, 137.02, 129.01, 128.17, 126.94, 122.85, 121.51, 110.67, 106.07, 101.91, 62.58, 54.61, 53.02, 52.69, 44.63, 31.63, 28.87, 27.71, 12.74 ppm; HRMS (EI) m/z [M]+ calcd for C27H35N4OS, 463.2526, found 402.3. 1 H NMR (500 MHz, CDCl 3 ): δ H 7.34 (dt, J = 14.9, 8.5 Hz, 5H), 7.24 (d, J = 7.2 Hz, 1H), 6.66 (s, 1H), 6.35 (dd, J = 9.0, 2.4 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 4.84 - 4.74 (m, 1H), 3.64 (s, 3H), 3.55 (s, 2H), 3.39 (q, J = 7.0 Hz, 4H), 2.99 (d, J = 11.5 Hz, 2H), 2.70 (q, J = 12.0 Hz, 2H), 2.12 (t, J = 11.4 Hz, 2H), 1.66 (d, J = 10.3 Hz, 2H), 1.20 (t, J = 7.1 Hz, 6H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 173.04, 164.13, 159.24, 151.98, 138.53, 137.02, 129.01, 128.17, 126.94, 122.85, 121.51, 110.67, 10 6.07, 101.91, 62.58, 54.61, 53.02, 52.69, 44.63 , 31.63, 28.87, 27.71, 12.74 ppm; HRMS (EI) m/z [M] + calcd for C27H35N4OS, 463.2526, found 402.3.
실시예 6. (Example 6. (
EE
)-3-벤질-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성(LMT-1895)Synthesis of )-3-benzyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thiooxoimidazolidin-4-one (LMT-1895)
(1) 3-벤질-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성 (2.40 g, 97% 수율, 주황색 고체): (1) Synthesis of 3-benzyl-1-methyl-2-thioxoimidazolidin-4-one (2.40 g, 97% yield, orange solid):
무수 에탄올 (30 mL) 내 사르코신 (1.0 g, 11.2 mmol)의 교반된 용액에 벤질 이소티오시아네이트 (1.5 ml, 11.2 mmol)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다. To a stirred solution of sarcosine (1.0 g, 11.2 mmol) in absolute ethanol (30 mL) was added benzyl isothiocyanate (1.5 ml, 11.2 mmol). The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, CDCl3): δH 7.45 (d, J = 7.2 Hz, 2H), 7.25 (m, 3H), 4.96 (s, 2H), 3.91 (s, 2H), 3.24 (s, 3H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 7.45 (d, J = 7.2 Hz, 2H), 7.25 (m, 3H), 4.96 (s, 2H), 3.91 (s, 2H), 3.24 (s, 3H) ppm.
(2) ((2) (
EE
)-3-벤질-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온의 합성 (57 mg, 63% 수율, 빨간색 고체): Synthesis of )-3-benzyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one (57 mg, 63% yield) , red solid):
1,4-디옥세인(2 ml) 내 3-벤질-1-메틸-2-티오옥소이미다졸리딘-4-온 (50 mg, 0.23 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (53 mg, 0.27 mmol), 피페리딘 (0.03 ml, 0.34 mmol)의 교반된 용액에 AlCl3 (3 mg, 0.02 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다. 3-Benzyl-1-methyl-2-thioxoimidazolidin-4-one (50 mg, 0.23 mmol), 4-(diethylamino)-2-hydride in 1,4-dioxane (2 ml) To a stirred solution of oxybenzaldehyde (53 mg, 0.27 mmol) and piperidine (0.03 ml, 0.34 mmol) was added AlCl 3 (3 mg, 0.02 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
1H NMR (500 MHz, CDCl3): δH 9.04 (s, 1H), 7.53 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.36 - 7.16 (m, 3H), 6.65 (s, 1H), 6.34 (dd, J = 8.9, 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.20 (s, 2H), 3.64 (s, 3H), 3.39 (q, J = 7.1 Hz, 4H), 1.20 (t, J = 7.0 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): δC 172.68, 163.85, 159.07, 152.06, 137.05, 135.78, 128.98, 128.44, 127.84, 121.87, 110.58, 106.13, 101.76, 45.45, 44.65, 31.16, 12.73 ppm; HRMS (EI) m/z [M]+ calcd for C22H26N3O2S, 396.1740, found 402.3. 1 H NMR (500 MHz, CDCl 3 ): δ H 9.04 (s, 1H), 7.53 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.36 - 7.16 (m, 3H), 6.65 (s, 1H), 6.34 (dd, J = 8.9, 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.20 (s, 2H), 3.64 (s, 3H), 3.39 (q, J = 7.1 Hz, 4H), 1.20 (t, J = 7.0 Hz, 6H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 172.68, 163.85, 159.07, 152.06, 137.05, 135.78, 128.98, 128.44, 127.84, 121.87, 110.58, 106.13, 10 1.76, 45.45, 44.65, 31.16, 12.73 ppm; HRMS (EI) m/z [M] + calcd for C 22 H 26 N 3 O 2 S, 396.1740, found 402.3.
실시예 7. (Example 7. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-펜에틸-2-티오옥소이미다졸리딘-4-온의 합성(LMT-1896)Synthesis of )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenethyl-2-thioxoimidazolidin-4-one (LMT-1896)
(1) 1-메틸-3-펜에틸-2-티오옥소이미다졸리딘-4-온의 합성(1) Synthesis of 1-methyl-3-phenethyl-2-thioxoimidazolidin-4-one
(940 mg, 71% 수율, 주황색 고체): (940 mg, 71% yield, orange solid):
무수 에탄올 (20 mL) 내 사르코신 (500 mg, 5.7 mmol)의 교반된 용액에 2-펜에틸 이소티오시아네이트 (0.8 ml, 5.7 mmol)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다. To a stirred solution of sarcosine (500 mg, 5.7 mmol) in absolute ethanol (20 mL) was added 2-phenethyl isothiocyanate (0.8 ml, 5.7 mmol). The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, DMSO-d6): δH 7.36 - 7.26 (m, 2H), 7.26 - 7.16 (m, 3H), 4.24 (s, 2H), 3.92 - 3.75 (m, 2H), 3.22 (s, 3H), 2.95 - 2.77 (m, 2H) ppm. 1 H NMR (500 MHz, DMSO-d 6 ): δ H 7.36 - 7.26 (m, 2H), 7.26 - 7.16 (m, 3H), 4.24 (s, 2H), 3.92 - 3.75 (m, 2H), 3.22 (s, 3H), 2.95 - 2.77 (m, 2H) ppm.
(2) ((2) (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-펜에틸-2-티오옥소이미다졸리딘-4-온의 합성 (105 mg, 60% 수율, 빨간색 고체): Synthesis of )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenethyl-2-thioxoimidazolidin-4-one (105 mg, 60% Yield, red solid):
1,4-디옥세인(5 ml) 내 1-메틸-3-펜에틸-2-티오옥소이미다졸리딘-4-온 (100 mg, 0.43 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (82.6 mg, 0.43 mmol), 피페리딘 (54.6 mg, 0.64 mmol)의 교반된 용액에 AlCl3 (6 mg, 0.04 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다. 1-Methyl-3-phenethyl-2-thioxoimidazolidin-4-one (100 mg, 0.43 mmol) in 1,4-dioxane (5 ml), 4-(diethylamino)-2- To a stirred solution of hydroxybenzaldehyde (82.6 mg, 0.43 mmol) and piperidine (54.6 mg, 0.64 mmol) was added AlCl 3 (6 mg, 0.04 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
1H NMR (500 MHz, CDCl3): δH 9.03 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 4.5 Hz, 3H), 7.25 - 7.16 (m, 1H), 6.67 (s, 1H), 6.36 (dd, J = 8.9, 2.4 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.25 - 4.12 (m, 2H), 3.66 (s, 3H), 3.40 (q, J = 7.0 Hz, 4H), 3.09 - 2.91 (m, 2H), 1.59 (s, 1H), 1.21 (t, J = 7.1 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): δC 172.54, 163.72, 159.12, 152.05, 137.98, 137.08, 128.97, 128.54, 126.61, 122.49, 121.79, 110.55, 106.11, 101.79, 44.65, 43.44, 33.89, 31.00, 12.74, 12.57 ppm; HRMS (EI) m/z [M]+ calcd for C22H26N3O2S, 396.1740, found 402.3. 1 H NMR (500 MHz, CDCl 3 ): δ H 9.03 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 4.5 Hz, 3H), 7.25 - 7.16 (m, 1H), 6.67 (s, 1H), 6.36 (dd, J = 8.9, 2.4 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.25 - 4.12 (m, 2H), 3.66 (s, 3H) ), 3.40 (q, J = 7.0 Hz, 4H), 3.09 - 2.91 (m, 2H), 1.59 (s, 1H), 1.21 (t, J = 7.1 Hz, 6H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 172.54, 163.72, 159.12, 152.05, 137.98, 137.08, 128.97, 128.54, 126.61, 122.49, 121.79, 110.55, 10 6.11, 101.79, 44.65, 43.44, 33.89, 31.00, 12.74 , 12.57 ppm; HRMS (EI) m/z [M] + calcd for C 22 H 26 N 3 O 2 S, 396.1740, found 402.3.
실시예 8. (Example 8. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메틸)벤질)이미다졸리딘-4-온의 합성(LMT-2144))-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethyl)benzyl)imidazolidine-4- Synthesis of On (LMT-2144)
(1) 1-(이소티오사이아나토메틸)-4-(트리플루오로메틸)벤젠의 합성(1) Synthesis of 1-(isothiocyanatomethyl)-4-(trifluoromethyl)benzene
디엠에프 (5 mL) 내 4-(트리플루오로메틸)아닐린 (0.24 mL, 1.71 mmol)에 1,1'-티오카르보닐디이미다졸 (336 mg, 1.88 mmol)을 -15℃에서 첨가하였다. 실온에서 14시간 동안 반응시킨 뒤 혼합물을 메틸렌 클로라이드 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득한 반응에 이용하였다.To 4-(trifluoromethyl)aniline (0.24 mL, 1.71 mmol) in DMF (5 mL) was added 1,1'-thiocarbonyldiimidazole (336 mg, 1.88 mmol) at -15 °C. After reacting at room temperature for 14 hours, the mixture was extracted with methylene chloride (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography and used in the reaction to give the product.
(2) 1-메틸2-티옥소-3-(4-(트리플루오로메틸)벤질)이미다졸리딘-4-온의 합성(2) Synthesis of 1-methyl2-thioxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-4-one
(420 mg, 주황색 고체): (420 mg, orange solid):
무수 에탄올 (20 mL) 내 사르코신 (152 mg, 1.71 mmol)의 교반된 용액에 (1) 단계에서 수득한 1-(이소티오사이아나토메틸)-4-(트리플루오로메틸)벤젠 (Crude)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다. 1-(isothiocyanatomethyl)-4-(trifluoromethyl)benzene (Crude ) was added. The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, CDCl3): δH 7.61 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 5.05 (s, 2H), 4.06 (s, 2H), 3.34 (s, 3H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 7.61 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 5.05 (s, 2H), 4.06 (s, 2H) , 3.34 (s, 3H) ppm.
(3) ((3) (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메틸)벤질)이미다졸리딘-4-온의 합성 (56 mg, 35% 수율, 빨간색 고체): )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethyl)benzyl)imidazolidine-4- Synthesis of On (56 mg, 35% yield, red solid):
1,4-디옥세인(5 ml) 내 1-메틸2-티옥소-3-(4-(트리플루오로메틸)벤질)이미다졸리딘-4-온 (100 mg, 0.35 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (81 mg, 0.42 mmol), 피페리딘 (0.05 mL, 0.52 mmol)의 교반된 용액에 AlCl3 (6 mg, 0.04 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다. 1-methyl2-thioxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-4-one (100 mg, 0.35 mmol) in 1,4-dioxane (5 ml), 4- To a stirred solution of (diethylamino)-2-hydroxybenzaldehyde (81 mg, 0.42 mmol) and piperidine (0.05 mL, 0.52 mmol) was added AlCl 3 (6 mg, 0.04 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
1H NMR (500 MHz, CDCl3): δH 7.64 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 6.35 (dd, J = 9.0, 2.2 Hz, 1H), 6.27 (d, J = 2.1 Hz, 1H), 5.24 (s, 2H), 3.65 (s, 3H), 3.40 (q, J = 7.0 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): δC 172.29, 163.59, 159.07, 152.22, 137.00, 129.20, 125.42, 122.24, 110.39, 106.19, 101.48, 44.90, 44.68, 31.23, 12.71 ppm; HRMS (EI) m/z [M]+ calcd for C23H25F3N3O2S, 464.1614, found 402.3. 1 H NMR (500 MHz, CDCl 3 ): δ H 7.64 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 6.35 (dd, J = 9.0, 2.2 Hz, 1H), 6.27 (d, J = 2.1 Hz, 1H), 5.24 (s, 2H), 3.65 (s, 3H), 3.40 (q, J = 7.0 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 172.29, 163.59, 159.07, 152.22, 137.00, 129.20, 125.42, 122.24, 110.39, 106.19, 101.48, 44.90, 44. 68, 31.23, 12.71 ppm; HRMS (EI) m/z [M] + calcd for C 23 H 25 F 3 N 3 O 2 S, 464.1614, found 402.3.
실시예 9. (Example 9. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(3-(트리플루오로메틸)벤질)이미다졸리딘-4-온의 합성(LMT-2154))-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(3-(trifluoromethyl)benzyl)imidazolidine-4- Synthesis of On (LMT-2154)
(1) 1-(이소티오사이아나토메틸)-3-(트리플루오로메틸)벤젠의 합성(1) Synthesis of 1-(isothiocyanatomethyl)-3-(trifluoromethyl)benzene
디엠에프 (5 mL) 내 3-(트리플루오로메틸)아닐린 (0.24 mL, 1.71 mmol)에 1,1'-티오카르보닐디이미다졸 (336 mg, 1.88 mmol)을 -15℃에서 첨가하였다. 실온에서 14시간 동안 반응시킨 뒤 혼합물을 메틸렌 클로라이드 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다.To 3-(trifluoromethyl)aniline (0.24 mL, 1.71 mmol) in DMF (5 mL) was added 1,1′-thiocarbonyldiimidazole (336 mg, 1.88 mmol) at -15°C. After reacting at room temperature for 14 hours, the mixture was extracted with methylene chloride (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
(2) 1-메틸2-티옥소-3-(3-(트리플루오로메틸)벤질)이미다졸리딘-4-온의 합성(2) Synthesis of 1-methyl2-thioxo-3-(3-(trifluoromethyl)benzyl)imidazolidin-4-one
(400 mg, 주황색 고체): (400 mg, orange solid):
무수 에탄올 (20 mL) 내 사르코신 (152 mg, 1.71 mmol)의 교반된 용액에 (1) 단계에서 수득한 1-(이소티오사이아나토메틸)-4-(트리플루오로메틸)벤젠 (Crude)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다. 1-(isothiocyanatomethyl)-4-(trifluoromethyl)benzene (Crude ) was added. The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, CDCl3): δH 7.75 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 5.04 (s, 2H), 4.05 (s, 2H), 3.33 (s, 3H) ppm. 1 H NMR (500 MHz, CDCl 3 ): δ H 7.75 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 5.04 (s, 2H), 4.05 (s, 2H), 3.33 (s, 3H) ppm.
(3) ((3) (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(3-(트리플루오로메틸)벤질)이미다졸리딘-4-온의 합성 (67 mg, 41% 수율, 빨간색 고체): )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(3-(trifluoromethyl)benzyl)imidazolidine-4- Synthesis of On (67 mg, 41% yield, red solid):
1,4-디옥세인(5 ml) 내 1-메틸2-티옥소-3-(3-(트리플루오로메틸)벤질)이미다졸리딘-4-온 (100 mg, 0.35 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (81 mg, 0.42 mmol), 피페리딘 (0.05 mL, 0.52 mmol)의 교반된 용액에 AlCl3 (6 mg, 0.04 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다. 1-methyl2-thioxo-3-(3-(trifluoromethyl)benzyl)imidazolidin-4-one (100 mg, 0.35 mmol) in 1,4-dioxane (5 ml), 4- To a stirred solution of (diethylamino)-2-hydroxybenzaldehyde (81 mg, 0.42 mmol) and piperidine (0.05 mL, 0.52 mmol) was added AlCl 3 (6 mg, 0.04 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
1H NMR (500 MHz, DMSO-d6): δH 10.13 (s, 1H), 8.70 (d, J = 9.2 Hz, 1H), 7.73 (s, 1H), 7.60 (dt, J = 32.3, 7.7 Hz, 3H), 7.11 (s, 1H), 6.25 (d, J = 9.1 Hz, 1H), 6.18 (s, 1H), 5.13 (s, 2H), 3.57 (s, 3H), 3.36 (s, 4H), 1.11 (t, J = 6.9 Hz, 6H) ppm; 13C NMR (125 MHz, DMSO-d6): δC 172.34, 161.35, 159.91, 151.87, 138.50, 132.61, 132.15, 130.03, 122.70, 119.45, 107.93, 104.04, 96.75, 44.43, 31.18, 13.06 ppm; HRMS (EI) m/z [M]+ calcd for C23H25F3N3O2S, 464.1614, found 402.3. 1 H NMR (500 MHz, DMSO-d 6 ): δ H 10.13 (s, 1H), 8.70 (d, J = 9.2 Hz, 1H), 7.73 (s, 1H), 7.60 (dt, J = 32.3, 7.7 Hz, 3H), 7.11 (s, 1H), 6.25 (d, J = 9.1 Hz, 1H), 6.18 (s, 1H), 5.13 (s, 2H), 3.57 (s, 3H), 3.36 (s, 4H) ), 1.11 (t, J = 6.9 Hz, 6H) ppm; 13 C NMR (125 MHz, DMSO-d 6 ): δ C 172.34, 161.35, 159.91, 151.87, 138.50, 132.61, 132.15, 130.03, 122.70, 119.45, 107.93, 104.04, 96.75, 44.43, 31.18, 13.06 ppm; HRMS (EI) m/z [M] + calcd for C 23 H 25 F 3 N 3 O 2 S, 464.1614, found 402.3.
실시예 10. (Example 10. (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메톡시)벤질)이미다졸리딘-4-온의 합성(LMT-2156))-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethoxy)benzyl)imidazolidine-4- Synthesis of On (LMT-2156)
(1) 1-(이소티오사이아나토메틸)-4-(트리플루오로메톡시)벤젠의 합성(1) Synthesis of 1-(isothiocyanatomethyl)-4-(trifluoromethoxy)benzene
디엠에프 (5 mL) 내 4-(트리플루오로메톡시)아닐린 (0.24 mL, 1.57 mmol)에 1,1'-티오카르보닐디이미다졸 (308 mg, 1.73 mmol)을 -15℃에서 첨가하였다. 실온에서 14시간 동안 반응시킨 뒤 혼합물을 메틸렌 클로라이드 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다.To 4-(trifluoromethoxy)aniline (0.24 mL, 1.57 mmol) in DMF (5 mL) was added 1,1'-thiocarbonyldiimidazole (308 mg, 1.73 mmol) at -15 °C. After reacting at room temperature for 14 hours, the mixture was extracted with methylene chloride (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
(2) 1-메틸2-티옥소-3-(4-(트리플루오로메톡시)벤질)이미다졸리딘-4-온의 합성 (270mg, 주황색 액체): (2) Synthesis of 1-methyl2-thioxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-4-one (270 mg, orange liquid):
무수 에탄올 (20 mL) 내 사르코신 (140 mg, 1.57 mmol)의 교반된 용액에 (1) 단계에서 수득한 1-(이소티오사이아나토메틸)-4-(트리플루오로메톡시)벤젠 (Crude)를 첨가하였다. 반응 혼합물을 6 시간 동안 환류시킨 후 실온으로 냉각시켰다. 침전된 고체를 여과하였고 에탄올 (10 mL)로 세척하고 건조하여 상응하는 티오히단토인을 수득하였다.
1-(isothiocyanatomethyl)-4-(trifluoromethoxy)benzene (Crude ) was added. The reaction mixture was refluxed for 6 hours and then cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to give the corresponding thiohydantoin.
1H NMR (500 MHz, DMSO-d6): δH 7.46 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.91 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm. 1 H NMR (500 MHz, DMSO-d 6 ): δ H 7.46 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.91 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm.
(3) ((3) (
EE
)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메톡시)벤질)이미다졸리딘-4-온의 합성 (80 mg, 51% 수율, 빨간색 고체): )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethoxy)benzyl)imidazolidine-4- Synthesis of On (80 mg, 51% yield, red solid):
1,4-디옥세인(5 ml) 내 1-메틸2-티옥소-3-(4-(트리플루오로메톡시)벤질)이미다졸리딘-4-온 (100 mg, 0.33 mmol), 4-(다이에틸아미노)-2-하이드록시벤잘데히드 (77 mg, 0.40 mmol), 피페리딘 (0.05 mL, 0.49 mmol)의 교반된 용액에 AlCl3 (4 mg, 0.03 mmol)을 첨가하였다. 반응이 완료될 때까지 교반된 반응 혼합물을 68-80℃로 가열하였다. 이어서, 혼합물을 에틸 아세테이트 (10 mL) (x3)로 추출하였다. 합한 유기층을 무수 MgSO4상에서 건조시키고, 여과하고 진공에서 농축시켰다. 잔류물을 여과 및 실리카 크로마토그래피로 정제하여 생성물을 수득하였다. 1-Methyl2-thioxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-4-one (100 mg, 0.33 mmol) in 1,4-dioxane (5 ml), 4- To a stirred solution of (diethylamino)-2-hydroxybenzaldehyde (77 mg, 0.40 mmol) and piperidine (0.05 mL, 0.49 mmol) was added AlCl 3 (4 mg, 0.03 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by filtration and silica chromatography to give the product.
1H NMR (500 MHz, CDCl3): δH 8.56 (d, J = 8.80 Hz, 1H), 6.96 (s, 1H), 6.46-6.36 (m, 1H), 6.20 (d, J = 2.45 Hz, 1H), 4.77-4.66 (m, 1H), ), 3.92-3.83 (m, 5H), 3.67-3.52 (m, 5H), 3.13-3.02 (m, 3H), 2.43-2.26 (m, 2H), 1.83 (d, J = 12.72 Hz, 2H), 1.55-1.77 (m, 6H), 1.36 (q, J = 13.21 Hz, 2H), 1.25 (t, J = 12.96 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δC 172.35, 161.30, 159.92, 151.85, 136.54, 132.62, 130.03, 122.73, 121.50, 119.35, 107.94, 104.00, 96.76, 44.43, 44.08, 31.14, 13.07 ppm; HRMS (EI) m/z [M]+ calcd for C23H25F3N3O3S, 480.1563, found 402.3. 1 H NMR (500 MHz, CDCl 3 ): δ H 8.56 (d, J = 8.80 Hz, 1H), 6.96 (s, 1H), 6.46-6.36 (m, 1H), 6.20 (d, J = 2.45 Hz, 1H), 4.77-4.66 (m, 1H), ), 3.92-3.83 (m, 5H), 3.67-3.52 (m, 5H), 3.13-3.02 (m, 3H), 2.43-2.26 (m, 2H), 1.83 (d, J = 12.72 Hz, 2H), 1.55–1.77 (m, 6H), 1.36 (q, J = 13.21 Hz, 2H), 1.25 (t, J = 12.96 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ): δ C 172.35, 161.30, 159.92, 151.85, 136.54, 132.62, 130.03, 122.73, 121.50, 119.35, 107.94, 104.00, 96 .76, 44.43, 44.08, 31.14, 13.07 ppm; HRMS (EI) m/z [M] + calcd for C 23 H 25 F 3 N 3 O 3 S, 480.1563, found 402.3.
실험예 1. 루시게닌 화학발광 분석 실험Experimental Example 1. Lucigenin chemiluminescence assay
실험방법Experiment method
인간 Nox 이소자임을 daughterless (Da)-GAL4 프로모터에서 인간 Nox 이소자임을 발현하는 형질 전환 파리로부터 제공하였다. 각 파리 라인의 유전자형은 하기에 나타내었다.Human Nox isozymes were provided from transgenic flies expressing human Nox isozymes under the daughterless (Da)-GAL4 promoter. The genotype of each fly line is shown below.
- 인간 Nox2 : UAS-hNox2/UAS-dDuox-RNAi; Da-GAL4/+- Human Nox2: UAS-hNox2/UAS-dDuox-RNAi; Da-GAL4/+
- 인간 Nox4 : UAS-hNox4/UAS-dDuox-RNAi; Da-GAL4/+- Human Nox4: UAS-hNox4/UAS-dDuox-RNAi; Da-GAL4/+
형질전환 파리를 프로테아제 억제제 (아프로티닌, 류펩틴)를 함유하는 PBS로 균질화하여 각각의 Nox 이소자임의 초파리 막을 수득하였다. 막을 진탕기에서 10분 동안 화합물(100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0 μM)과 함께 배양하였다. 그 후 1X HEPES (4-(2-히드록시에틸)-1-피페라진에탄술폰산) 버퍼 내 500 μM NADPH (b-니코틴아미드 아데닌 디뉴클레오티드 2'- 포스페이트 환원 테트라나트륨염 수화물; Sigma-Aldrich) 및 400μM 루시게닌 (N,N'-디메틸-9,9'-비아크리디늄 디니트레이트; Sigma-Aldrich)의 혼합물을 막에 첨가하였다. 루시게닌 화학 발광은 다중 모드 마이크로 플레이트 리더 (SpectraMax iD3, Molecular Devices)를 사용하여 10분 동안 1분 간격으로 검출하였다. IC50 값은 Graph-Pad Prism 5 (GraphPad Software)로 계산하였다. Transgenic flies were homogenized with PBS containing protease inhibitors (Aprotinin, Leupeptin) to obtain Drosophila membranes of each Nox isozyme. Membranes were incubated with compounds (100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0 μM) for 10 min on a shaker. Then 500 μM NADPH (b-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate; Sigma-Aldrich) in 1X HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer and A mixture of 400 μM lucigenin (N,N′-dimethyl-9,9′-biacridinium dinitrate; Sigma-Aldrich) was added to the membrane. Lucigenin chemiluminescence was detected at 1-minute intervals for 10 minutes using a multimode microplate reader (SpectraMax iD3, Molecular Devices). IC 50 values were calculated with Graph-Pad Prism 5 (GraphPad Software).
루시게닌 화학 발광 분석을 hNox1, hNox2 및 hNox4를 발현하는 초파리 막으로 수행하였다. 분석을 3회 반복하고 IC50 값의 평균을 확인하였다. Lucigenin chemiluminescence assays were performed with Drosophila membranes expressing hNox1, hNox2 and hNox4. The assay was repeated three times and the average of the IC 50 values was determined.
하기 표 1 및 도 1a 내지 도 1e는 본 발명에 따른 실시예 1 내지 10의 Nox2 및 Nox4 억제 효과를 확인한 결과를 나타낸다. Table 1 and FIGS. 1a to 1e show the results of confirming the Nox2 and Nox4 inhibitory effects of Examples 1 to 10 according to the present invention.
ICIC 5050 (μM)(μM) | Nox2Nox2 | Nox4Nox4 |
실시예 1 (E7240-13)Example 1 (E7240-13) | 1.6551.655 | 2.3502.350 |
실시예 2 (E7240-17-24)Example 2 (E7240-17-24) | 0.2220.222 | 0.5500.550 |
실시예 3 (E7240-17-27)Example 3 (E7240-17-27) | 0.8290.829 | 0.7990.799 |
실시예 4 (LMT-1894)Example 4 (LMT-1894) | 0.9060.906 | 1.0991.099 |
실시예 5 (LMT-2132)Example 5 (LMT-2132) | 1.4011.401 | 1.7571.757 |
실시예 6 (LMT-1895)Example 6 (LMT-1895) | 0.7870.787 | 0.7170.717 |
실시예 7 (LMT-1896)Example 7 (LMT-1896) | 0.8520.852 | 0.8390.839 |
실시예 8 (LMT-2144)Example 8 (LMT-2144) | 1.0231.023 | 0.8400.840 |
실시예 9 (LMT-2154)Example 9 (LMT-2154) | 1.0831.083 | 0.9500.950 |
실시예 10 (LMT-2156)Example 10 (LMT-2156) | 1.3791.379 | 0.7790.779 |
실험예 2. PAMPA (Parallel artificial membrane permeability assay) 및 Metabolic stability 분석 실험Experimental Example 2. PAMPA (Parallel artificial membrane permeability assay) and metabolic stability analysis experiment
PAMPA 분석PAMPA assay
본 발명의 히탄토인 유도체 화합물의 BBB (Brain Barrier Blood) 투과성을 확인하기 위하여 PAMPA (parallel artificial membrane permeability assay)를 수행하였으며, 구체적인 실험 조건은 다음과 같다:In order to confirm the BBB (Brain Barrier Blood) permeability of the hytantoin derivative compound of the present invention, PAMPA (parallel artificial membrane permeability assay) was performed, and specific experimental conditions are as follows:
- PAMPA: Double sink (Pion, BBB PAMPA)- PAMPA: Double sink (Pion, BBB PAMPA)
- Assay format: 96-well plate-Assay format: 96-well plate
- Reference compound: Theophylline, Progesterone- Reference compound: Theophylline, Progesterone
- Number of replicates: 3-Number of replicates: 3
- Stock soln of compound: 10mM in DMSO-Stock soln of compound: 10mM in DMSO
- Test pH: 7.4- Test pH: 7.4
- Test concentration Reference (50μM), Test (12.5μM)- Test concentration Reference (50μM), Test (12.5μM)
- Incubation time: 4hr-Incubation time: 4hr
- Analysis method: UV detection- Analysis method: UV detection
구체적으로, Deep well plate에 해당하는 donor buffer를 1.5 ml씩 분주한 후 7.5 μl의 10mM compound stock을 섞어서 혼합물을 준비하였다 (10 mM stock-->final 50 μM). 준비된 혼합물을 deep well plate에 500 μl 씩 3 well로 분주한 후, Blank 측정을 위해 96 well donor buffer를 UV plate에 well당 150 μl씩 분주한 후 software를 이용해 UV값을 측정한다<blank>. Reference 측정을 위해 Deep well plate에 있는 mixture를 well당 150μl 씩 UV plate로 분주한 후 software를 이용해 UV값을 측정하였다<Reference>. PAMPA sandwich의 donor plate에 혼합물을 200μl씩 compound당 3 well로 분주하였다. Acceptor plate를 뒤집고 멤브레인을 5μl의 BBB lipid solution으로 적신 후 Acceptor plate에 acceptor sink buffer를 200 μl씩 각 well에 분주하였다. Acceptor plate와 donor plate를 합치고 25℃에서 4시간 incubation하였다. 4시간 배양 후, acceptor plate와 donor plate를 분리한 후 각 well에서 150 μl씩 UV plate로 transfer하여 software를 이용해 UV값을 측정하였다 <Donor, Acceptor>. 이후, PAMPA explore program을 이용하여 PAMPA permeability를 분석하였다. 물질의 투과도(permeability; Pe, cm/sec)는 UV에 의해 분석되었다.Specifically, after dispensing 1.5 ml of donor buffer corresponding to the deep well plate, 7.5 μl of 10 mM compound stock was mixed to prepare a mixture (10 mM stock-->final 50 μM). After dispensing 500 μl of the prepared mixture into 3 wells on a deep well plate, dispense 150 μl of 96 well donor buffer per well on a UV plate for blank measurement, and measure the UV value using software<blank>. For reference measurement, the mixture in the deep well plate was dispensed to the UV plate by 150 μl per well, and the UV value was measured using software <Reference>. 200 μl of the mixture was dispensed into 3 wells per compound on the donor plate of the PAMPA sandwich. After inverting the acceptor plate and soaking the membrane with 5 μl of BBB lipid solution, 200 μl of acceptor sink buffer was dispensed into each well. The acceptor plate and the donor plate were combined and incubated at 25°C for 4 hours. After culturing for 4 hours, the acceptor plate and the donor plate were separated, and 150 μl from each well was transferred to a UV plate, and UV values were measured using software <Donor, Acceptor>. Then, PAMPA permeability was analyzed using the PAMPA explore program. The permeability (Pe, cm/sec) of the material was analyzed by UV.
Metabolic stability 분석Metabolic stability analysis
약물대사의 주요 장기인 간에서 약물이 대사되는 정도를 Liver microsomes를 이용하여 측정함으로써 in vivo에서의 약물의 안정성을 확인하였다. 구체적인 실험 방법은 다음과 같다:The stability of the drug in vivo was confirmed by measuring the degree of drug metabolism in the liver, a major organ of drug metabolism, using Liver microsomes. The specific test method is as follows:
a) 시료 처리a) Sample processing
Human liver microsomes (0.5 mg/ml)과 0.1 M 인산 완충용액 (pH 7.4), 화합물 LMT-1895, LMT-1896을 1 μM 농도로 첨가하고 37℃에서 5분간 미리 배양한 후, NADPH Regeneration system 용액을 첨가하여 37℃에서 30분간 배양하였다. 이후 반응을 종결시키기 위해 내부표준물질(chlorpropamide)이 포함된 아세토니트릴 용액을 첨가하고, 5분간 원심분리(14,000 rpm, 4℃) 한 후 상층액을 LC-MS/MS 시스템에 주입하여 기질약물을 분석함으로써 2종 화합물에 대한 대사안정성을 평가하였다.Human liver microsomes (0.5 mg/ml), 0.1 M phosphate buffer solution (pH 7.4), and compounds LMT-1895 and LMT-1896 were added at a concentration of 1 μM, incubated at 37°C for 5 minutes, and then the NADPH Regeneration system solution was added. It was added and incubated at 37°C for 30 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, centrifuged for 5 minutes (14,000 rpm, 4 ℃), and the supernatant was injected into the LC-MS/MS system to obtain the substrate drug. The metabolic stability of the two compounds was evaluated by analysis.
b) LC-MS/MS 분석b) LC-MS/MS analysis
상기 반응을 통하여 남아 있는 기질의 양은 Agilent 1290 infinity series pump system (Agilent, USA) 및 Triple Quad 5500 LC-MS/MS system (Applied Biosystems, USA)을 사용하여 분석하였다. HPLC 칼럼은 Acquity UPLC BEH Amide column (2.1 × 100 mm, 1.7μm particle size; Waters, Ireland)을 사용하였다. 이동상은 0.1% formic acid 함유 증류수 (A)와 0.1% formic acid 함유 acetonitrile (B)이였다. 데이터 분석은 Analyst software (version 1.6.3)를 사용하였다.The amount of substrate remaining through the reaction was analyzed using an Agilent 1290 infinity series pump system (Agilent, USA) and a Triple Quad 5500 LC-MS/MS system (Applied Biosystems, USA). As the HPLC column, an Acquity UPLC BEH Amide column (2.1 × 100 mm, 1.7 μm particle size; Waters, Ireland) was used. The mobile phase was distilled water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B). Data analysis was performed using Analyst software (version 1.6.3).
위 방법에 따른 PAMPA 및 Metabolic stability 분석 결과는 하기 표 2와 같다. 30 분간의 반응 실험결과인 % remaining 값에 따른 microsomal stability 평가기준에 따르면 70-90%인 경우 반감기가 1~3시간 정도로 안정한 화합물로 판단한다.The results of PAMPA and metabolic stability analysis according to the above method are shown in Table 2 below. According to the microsomal stability evaluation criteria according to the % remaining value, which is the result of a 30-minute reaction experiment, if it is 70-90%, it is judged as a stable compound with a half-life of 1 to 3 hours.
화합물compound | PAMPAPAMPA | MSMS |
Pe (10-6 cm/sec)Pe (10 -6 cm/sec) |
Human (%)Human (%) | |
LMT-1895LMT-1895 | 15.1815.18 | 8080 |
LMT-1896LMT-1896 | 1.31.3 | 86.786.7 |
표 2를 통해 확인할 수 있는 바와 같이, 본 발명의 히단토인 유도체 화합물은 BBB 통과능이 있는 것을 확인하였다. 또한, 30분간의 반응 실험결과인 % remaining 값에 따른 microsomal stability 평가기준에 따르면 70-90%인 경우 반감기가 1~3시간 정도로 안정한 화합물로 판단하는 바, 본 발명의 히단토인 유도체 화합물은 대사 안정성이 우수한 화합물임을 확인하였다. As can be seen from Table 2, it was confirmed that the hydantoin derivative compound of the present invention has the ability to pass through the BBB. In addition, according to the microsomal stability evaluation criteria according to the % remaining value, which is the result of the reaction experiment for 30 minutes, when the half-life is 70-90%, it is judged to be a stable compound with a half-life of about 1 to 3 hours, and the hydantoin derivative compound of the present invention has metabolic stability. It was confirmed that this excellent compound.
이상과 같이 실시예를 통하여 본 발명을 설명하였다. 본 발명이 속하는 기술분야의 통상의 기술자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로 상술한 실시예들은 모든 면에 예시적인 것이며 한정적인 것이 아닌 것으로서 이해되어야 한다. 본 발명의 범위는 상세한 설명보다는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미 및 범위 그리고 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.As described above, the present invention has been described through examples. Those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing its technical spirit or essential features. Therefore, the above-described embodiments should be understood as illustrative in all respects and not limiting. The scope of the present invention is indicated by the following claims rather than the detailed description, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be construed as being included in the scope of the present invention.
Claims (21)
- 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염:A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:[화학식 1][Formula 1]상기 화학식 1에서,In Formula 1,R1은 수소원자, C1-C6 알킬기 또는 할로겐이고, R 1 is a hydrogen atom, a C 1 -C 6 alkyl group or a halogen;L은 단결합, -O-, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C2-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6알킬렌)-R3, -O-(C1-C6 알킬) 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));R3은 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴임. R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing a substituted or unsubstituted heteroatom selected from oxygen, nitrogen and sulfur.
- 제1항에 있어서, 상기 화학식 1로 표시되는 화합물은 하기 화학식 2로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염:The method of claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 2 below or a pharmaceutically acceptable salt thereof:[화학식 2][Formula 2]상기 화학식 2에서,In Formula 2,L은 단결합, -O-, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -O-, -C 1 -C 6 alkylene or -SO 2 -;R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C2-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, -O-(C1-C6 알킬) 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing heteroatoms selected from substituted or unsubstituted oxygen, nitrogen and sulfur, wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , when C 6 -C 12 aryl or C 2 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)- R 3 , -O-(C 1 -C 6 alkyl) or -O-(C 1 -C 4 haloalkyl));R3은 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C2-C12 헤테로아릴임.R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl, C 2 -C 12 heteroaryl containing a substituted or unsubstituted heteroatom selected from oxygen, nitrogen and sulfur.
- 제1항에 있어서, According to claim 1,상기 화학식 1에서,In Formula 1,R1은 C1-C6 알킬기이고, R 1 is a C 1 -C 6 alkyl group;L은 단결합, -C1-C6 알킬렌 또는 -SO2-이고, L is a single bond, -C 1 -C 6 alkylene or -SO 2 -;R2는 치환 또는 비치환된 C3-C8 시클로알킬, 치환 또는 비치환된 산소, 질소 및 황으로부터 선택되는 헤테로원자를 포함하는 C3-C8 헤테로시클로알킬, 치환 또는 비치환된 C6-C12 아릴이고 (여기서, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬, C6-C12 아릴 또는 C6-C12 헤테로아릴이 치환되는 경우 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, 또는 -O-(C1-C4 할로알킬)로 치환될 수 있음),R 2 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl containing heteroatoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted C 6 -C 12 aryl (wherein, when C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 12 aryl, or C 6 -C 12 heteroaryl is substituted, each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)-R 3 , or -O-(C 1 -C 4 haloalkyl));R3은 치환 또는 비치환된 C6-C12 아릴인, 화합물 또는 이의 약제학적으로 허용가능한 염.R 3 is a substituted or unsubstituted C 6 -C 12 aryl, a compound or a pharmaceutically acceptable salt thereof.
- 제1항에 있어서, R1은 메틸기 또는 에틸기인, 화합물 또는 이의 약제학적으로 허용가능한 염.The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is a methyl group or an ethyl group.
- 제1항에 있어서,R2는 , 또는 이고, 여기서 , 또는 는 비치환 또는 하나 이상의 H가 각각 독립적으로 할로겐, C1-C6 알킬기, C1-C4 할로알킬, -(C1-C6 알킬렌)-R3, 또는 -O-(C1-C4 할로알킬)로 치환될 수 있는 것인, 화합물 또는 이의 약제학적으로 허용가능한 염.According to claim 1, R 2 Is , or and here , or is unsubstituted or one or more H is each independently halogen, C 1 -C 6 alkyl group, C 1 -C 4 haloalkyl, -(C 1 -C 6 alkylene)-R 3 , or -O-(C 1 - A compound or a pharmaceutically acceptable salt thereof, which may be substituted with C 4 haloalkyl).
- 제1항에 있어서, 화학식 1의 화합물은 하기 화합물들로 이루어진 군으로부터 선택된 어느 하나인, 화합물 또는 이의 약제학적으로 허용가능한 염:The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula 1 is any one selected from the group consisting of the following compounds:(E)-3-사이클로헥실-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온;( E )-3-cyclohexyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one;(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-3-((4-플루오로페닐)술포닐)-1-메틸-2-티옥소이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidene)-3-((4-fluorophenyl)sulfonyl)-1-methyl-2-thioxoimidazolidine- 4-one;(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리덴)-1-메틸-2-티옥소-3-토실이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidene)-1-methyl-2-thioxo-3-tosylimidazolidin-4-one;(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-페닐-2-티오옥소이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenyl-2-thioxoimidazolidin-4-one;(E)-3-(1-벤질피페리딘-4-닐)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온;( E )-3-(1-benzylpiperidin-4-yl)-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidine -4-one;(E)-3-벤질-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소이미다졸리딘-4-온;( E )-3-benzyl-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxoimidazolidin-4-one;(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-3-펜에틸-2-티오옥소이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-3-phenethyl-2-thioxoimidazolidin-4-one;(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메틸)벤질)이미다졸리딘-4-온;( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethyl)benzyl)imidazolidine- 4-one;(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(3-(트리플루오로메틸)벤질)이미다졸리딘-4-온; 및( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(3-(trifluoromethyl)benzyl)imidazolidine- 4-one; and(E)-5-(4-(다이에틸아미노)-2-히드록시벤질리딘)-1-메틸-2-티오옥소-3-(4-(트리플루오로메톡시)벤질)이미다졸리딘-4-온.( E )-5-(4-(diethylamino)-2-hydroxybenzylidine)-1-methyl-2-thioxo-3-(4-(trifluoromethoxy)benzyl)imidazolidine- 4-on.
- 제1항 내지 제8항 중 어느 한 항에 따른 화합물 또는 이의 약제학적으로 허용가능한 염을 포함하는 NADPH 산화효소(NOX) 관련 질환 예방 또는 치료용 약학 조성물로서, A pharmaceutical composition for preventing or treating NADPH oxidase (NOX) related diseases comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof,상기 NADPH 산화효소(NOX) 관련 질환은 건선, 류마티스 관절염, 골관절염, 재발협착증, 아테롬성 경화증, 궤양, 간경병증, 사구체신염, 당뇨병성 신장병증, 악성 신경화증, 혈전성 미소혈관증, 기관 이식 거부, 당뇨병, 고혈압, 심장 비대증, 심부전증, 재발협착증, 암, 자가면역질환, 염증성 질환, 퇴행성 뇌질환 및 망막 질환로 이루어진 군으로부터 선택되는 어느 하나인, 약학 조성물.The NADPH oxidase (NOX)-related diseases are psoriasis, rheumatoid arthritis, osteoarthritis, restenosis, atherosclerosis, ulcer, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, diabetes , Hypertension, cardiac hypertrophy, heart failure, restenosis, cancer, autoimmune disease, inflammatory disease, any one selected from the group consisting of degenerative brain disease and retinal disease, a pharmaceutical composition.
- 제9항에 있어서, 상기 퇴행성 뇌질환은 파킨슨 병, 헌팅턴 병, 알츠하이머 병, 경도인지장애, 노인성 치매, 근위축성 측삭경화증 (amyotrophic lateral sclerosis), 척수소뇌성 운동실조증(Spinocer ebellar Atrophy), 뚜렛 증후군(Tourette`s Syndrome), 프리드리히 보행실조(Friedrich`s Ataxia), 마차도-조셉 병(Machado-Joseph`s disease), 루이 소체 치매(Lewy Body Dementia), 근육긴장이상(Dystonia), 진행성 핵상 마비(Progressive Supranuclear Palsy) 및 전두측두엽 치매(Frontotemporal Dementia)로 이루어진 군으로부터 선택되는 어느 하나인, 약학 조성물. The method of claim 9, wherein the degenerative brain disease is Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette's syndrome (Tourette's Syndrome), Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy ( Progressive Supranuclear Palsy) and frontotemporal dementia (Frontotemporal Dementia), any one selected from the group consisting of, a pharmaceutical composition.
- 제9항에 있어서, 상기 암은 뇌암, 신경 내분비 암, 위암, 폐암, 유방암, 난소암, 간암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 부신암, 대장암, 결장암, 자궁경부암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암 및 요관암로 이루어진 군으로부터 선택되는 어느 하나인, 약학 조성물. The method of claim 9, wherein the cancer is brain cancer, neuroendocrine cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, colorectal cancer, colon cancer, cervical cancer, prostate Any one selected from the group consisting of cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer and ureteral cancer, a pharmaceutical composition.
- 제11항에 있어서, 상기 뇌암은 성상세포종(astrocytoma), 교모세포종(glioblastoma), 상의세포종(ependymoma), 핍지교종(oligodendroglioma), 혼합교종(mixed glioma), 뇌간 교종(brain stem glioma), 시신경 교종(optic nerve glioma), 뇌하수체 종양(pituitary adenoma), 두개인두종(craniopharyngioma), 수모세포종(medulloblastoma), 원시신경외배엽종양(primitive neuroectodermal tumors), 송과체 종양(pineal tumors), 수막종(meningioma), 신경초종(schwannoma), 전이성 뇌종양(metastatic brain tumors), 중추신경 임파종(CNS lymphoma), 신경섬유종증(neurofibromatosis), 가성뇌종양(pseudotumor cerebri), 및 결절성 경화증(tuberous sclerosis)로 이루어진 군으로부터 선택되는 어느 하나인, 약학 조성물. The method of claim 11, wherein the brain cancer is astrocytoma, glioblastoma, ependymoma, oligodendroglioma, mixed glioma, brain stem glioma, optic glioma ( optic nerve glioma, pituitary adenoma, craniopharyngioma, medulloblastoma, primitive neuroectodermal tumors, pineal tumors, meningioma, schwannoma , Metastatic brain tumors (metastatic brain tumors), central nerve lymphoma (CNS lymphoma), neurofibromatosis (neurofibromatosis), pseudotumor cerebri, and tuberous sclerosis (tuberous sclerosis) any one selected from the group consisting of, a pharmaceutical composition.
- NADPH 산화효소(NOX) 관련 질환의 치료용 약제의 제조를 위한 제1항 내지 제8항 중 어느 한 항에 따른 화합물 또는 이의 약제학적으로 허용가능한 염의 용도로서,Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of NADPH oxidase (NOX) related diseases,상기 NADPH 산화효소(NOX) 관련 질환은 건선, 류마티스 관절염, 골관절염, 재발협착증, 아테롬성 경화증, 궤양, 간경병증, 사구체신염, 당뇨병성 신장병증, 악성 신경화증, 혈전성 미소혈관증, 기관 이식 거부, 당뇨병, 고혈압, 심장 비대증, 심부전증, 재발협착증, 암, 자가면역질환, 염증성 질환, 퇴행성 뇌질환 및 망막 질환로 이루어진 군으로부터 선택되는 어느 하나인, 용도.The NADPH oxidase (NOX)-related diseases are psoriasis, rheumatoid arthritis, osteoarthritis, restenosis, atherosclerosis, ulcer, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, diabetes , Hypertension, cardiac hypertrophy, heart failure, restenosis, cancer, autoimmune disease, inflammatory disease, degenerative brain disease and any one selected from the group consisting of retinal disease, use.
- 제13항에 있어서, 상기 퇴행성 뇌질환은 파킨슨 병, 헌팅턴 병, 알츠하이머 병, 경도인지장애, 노인성 치매, 근위축성 측삭경화증 (amyotrophic lateral sclerosis), 척수소뇌성 운동실조증(Spinocer ebellar Atrophy), 뚜렛 증후군(Tourette`s Syndrome), 프리드리히 보행실조(Friedrich`s Ataxia), 마차도-조셉 병(Machado-Joseph`s disease), 루이 소체 치매(Lewy Body Dementia), 근육긴장이상(Dystonia), 진행성 핵상 마비(Progressive Supranuclear Palsy) 및 전두측두엽 치매(Frontotemporal Dementia)로 이루어진 군으로부터 선택되는 어느 하나인 용도.The method of claim 13, wherein the degenerative brain disease is Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette syndrome (Tourette's Syndrome), Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy ( Progressive Supranuclear Palsy) and frontotemporal dementia (Frontotemporal Dementia).
- 제13항에 있어서, 상기 암은 뇌암, 신경 내분비 암, 위암, 폐암, 유방암, 난소암, 간암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 부신암, 대장암, 결장암, 자궁경부암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암 및 요관암로 이루어진 군으로부터 선택되는 어느 하나인 용도.The method of claim 13, wherein the cancer is brain cancer, neuroendocrine cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, colorectal cancer, colon cancer, cervical cancer, prostate cancer Use of any one selected from the group consisting of cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer and ureter cancer.
- 제15항에 있어서, 상기 뇌암은 성상세포종(astrocytoma), 교모세포종(glioblastoma), 상의세포종(ependymoma), 핍지교종(oligodendroglioma), 혼합교종(mixed glioma), 뇌간 교종(brain stem glioma), 시신경 교종(optic nerve glioma), 뇌하수체 종양(pituitary adenoma), 두개인두종(craniopharyngioma), 수모세포종(medulloblastoma), 원시신경외배엽종양(primitive neuroectodermal tumors), 송과체 종양(pineal tumors), 수막종(meningioma), 신경초종(schwannoma), 전이성 뇌종양(metastatic brain tumors), 중추신경 임파종(CNS lymphoma), 신경섬유종증(neurofibromatosis), 가성뇌종양(pseudotumor cerebri), 및 결절성 경화증(tuberous sclerosis)로 이루어진 군으로부터 선택되는 어느 하나인 용도. The method of claim 15, wherein the brain cancer is astrocytoma, glioblastoma, ependymoma, oligodendroglioma, mixed glioma, brain stem glioma, optic glioma ( optic nerve glioma, pituitary adenoma, craniopharyngioma, medulloblastoma, primitive neuroectodermal tumors, pineal tumors, meningioma, schwannoma , Metastatic brain tumors (metastatic brain tumors), central nerve lymphoma (CNS lymphoma), neurofibromatosis (neurofibromatosis), pseudotumor cerebri, and tuberous sclerosis (tuberous sclerosis) any one selected from the group consisting of use.
- 치료학적으로 유효한 양의 제1항 내지 제8항 중 어느 한 항에 따른 화합물 또는 이의 약제학적으로 허용가능한 염을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는 NADPH 산화효소(NOX) 관련 질환의 치료 방법으로서, NADPH oxidase (NOX) related disease comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof to a subject in need thereof. As a treatment method,상기 NADPH 산화효소(NOX) 관련 질환은 건선, 류마티스 관절염, 골관절염, 재발협착증, 아테롬성 경화증, 궤양, 간경병증, 사구체신염, 당뇨병성 신장병증, 악성 신경화증, 혈전성 미소혈관증, 기관 이식 거부, 당뇨병, 고혈압, 심장 비대증, 심부전증, 재발협착증, 암, 자가면역질환, 염증성 질환, 퇴행성 뇌질환 및 망막 질환로 이루어진 군으로부터 선택되는 어느 하나인, 치료 방법. The NADPH oxidase (NOX)-related diseases are psoriasis, rheumatoid arthritis, osteoarthritis, restenosis, atherosclerosis, ulcer, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, diabetes , Hypertension, cardiac hypertrophy, heart failure, restenosis, cancer, autoimmune disease, inflammatory disease, any one selected from the group consisting of degenerative brain disease and retinal disease, treatment method.
- 제17항에 있어서, 상기 퇴행성 뇌질환은 파킨슨 병, 헌팅턴 병, 알츠하이머 병, 경도인지장애, 노인성 치매, 근위축성 측삭경화증 (amyotrophic lateral sclerosis), 척수소뇌성 운동실조증(Spinocer ebellar Atrophy), 뚜렛 증후군(Tourette`s Syndrome), 프리드리히 보행실조(Friedrich`s Ataxia), 마차도-조셉 병(Machado-Joseph`s disease), 루이 소체 치매(Lewy Body Dementia), 근육긴장이상(Dystonia), 진행성 핵상 마비(Progressive Supranuclear Palsy) 및 전두측두엽 치매(Frontotemporal Dementia)로 이루어진 군으로부터 선택되는 어느 하나인 치료방법.The method of claim 17, wherein the degenerative brain disease is Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette syndrome (Tourette's Syndrome), Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy ( Progressive supranuclear palsy) and frontotemporal dementia (Frontotemporal Dementia) any one treatment method selected from the group consisting of.
- 제17항에 있어서, 상기 암은 뇌암, 신경 내분비 암, 위암, 폐암, 유방암, 난소암, 간암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 부신암, 대장암, 결장암, 자궁경부암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암 및 요관암로 이루어진 군으로부터 선택되는 어느 하나인 치료방법.The method of claim 17, wherein the cancer is brain cancer, neuroendocrine cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, colorectal cancer, colon cancer, cervical cancer, prostate cancer A method of treating any one selected from the group consisting of cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer and ureteral cancer.
- 제19항에 있어서, 상기 뇌암은 성상세포종(astrocytoma), 교모세포종(glioblastoma), 상의세포종(ependymoma), 핍지교종(oligodendroglioma), 혼합교종(mixed glioma), 뇌간 교종(brain stem glioma), 시신경 교종(optic nerve glioma), 뇌하수체 종양(pituitary adenoma), 두개인두종(craniopharyngioma), 수모세포종(medulloblastoma), 원시신경외배엽종양(primitive neuroectodermal tumors), 송과체 종양(pineal tumors), 수막종(meningioma), 신경초종(schwannoma), 전이성 뇌종양(metastatic brain tumors), 중추신경 임파종(CNS lymphoma), 신경섬유종증(neurofibromatosis), 가성뇌종양(pseudotumor cerebri), 및 결절성 경화증(tuberous sclerosis)로 이루어진 군으로부터 선택되는 어느 하나인 치료방법.The method of claim 19, wherein the brain cancer is astrocytoma, glioblastoma, ependymoma, oligodendroglioma, mixed glioma, brain stem glioma, optic glioma ( optic nerve glioma, pituitary adenoma, craniopharyngioma, medulloblastoma, primitive neuroectodermal tumors, pineal tumors, meningioma, schwannoma , Metastatic brain tumors (metastatic brain tumors), central nerve lymphoma (CNS lymphoma), neurofibromatosis (neurofibromatosis), pseudotumor cerebri, and tuberous sclerosis (tuberous sclerosis) any one selected from the group consisting of a treatment method.
- 제1항 내지 제8항 중 어느 한 항에 따른 화합물 또는 이의 약제학적으로 허용가능한 염; 및 약제학적으로 허용가능한 담체를 포함하는 약학적 조성물.The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
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