WO2016148114A1 - 酸化ストレス誘導神経細胞死抑制化合物 - Google Patents

酸化ストレス誘導神経細胞死抑制化合物 Download PDF

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WO2016148114A1
WO2016148114A1 PCT/JP2016/058048 JP2016058048W WO2016148114A1 WO 2016148114 A1 WO2016148114 A1 WO 2016148114A1 JP 2016058048 W JP2016058048 W JP 2016058048W WO 2016148114 A1 WO2016148114 A1 WO 2016148114A1
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compound
group
halogen
hydrogen
optionally substituted
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PCT/JP2016/058048
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French (fr)
Japanese (ja)
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政弘 堺谷
いづみ 尾瀬
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国立大学法人北海道大学
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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to an oxidative stress-induced cell death inhibitor compound, particularly an oxidative stress-induced neuronal cell death inhibitor compound, and an oxidative stress-induced cell death inhibitor containing the compound, and Parkinson's disease containing the oxidative stress-induced cell death inhibitor , Alzheimer's disease, spinocerebellar degeneration (SCD), Huntington's disease, progressive supranuclear palsy (PSP), cortical basal ganglia degeneration, amyotrophic lateral sclerosis (ALS), cranial nerve damage due to cerebral ischemia ( Ischemic brain disease), stroke, heart failure, diabetes, rheumatoid arthritis, acute ischemic attack, atherosclerosis, inflammatory bowel disease, dry eye, mitochondrial encephalomyopathy, inflammatory bowel disease, coronary atherosclerosis, Crohn's disease, Provided is a pharmaceutical composition for preventing and / or treating oxidative stress-related diseases such as mucositis due to radiation therapy, cerebral ischemia, myo
  • the present invention also provides a method for preventing and / or treating the above-mentioned disease, wherein the pharmaceutical composition comprises administering an effective amount of the oxidative stress-induced cell death inhibitory compound, particularly an oxidative stress-induced neuronal cell death inhibitory compound or a salt thereof.
  • the pharmaceutical composition comprises administering an effective amount of the oxidative stress-induced cell death inhibitory compound, particularly an oxidative stress-induced neuronal cell death inhibitory compound or a salt thereof.
  • the present invention relates to the use of the oxidative stress-induced cell death inhibitory compound, particularly the oxidative stress-induced neuronal cell death inhibitory compound, for the production of a product.
  • Reactive oxygen has beneficial effects such as attacking and sterilizing pathogenic bacteria that have entered the body, but it causes non-specific chemical reactions to various substances and damages cells and tissues.
  • catalase superoxide dismutase, peroxidase, etc.
  • antioxidant enzymes that erase or remove active oxygen in each tissue
  • damage caused to cells and tissues by active oxygen is usually repaired immediately (Non-Patent Document 2).
  • Oxidative stress means that the balance between the damage caused by this active oxygen to cells and organs in the body and the function of the biological system to detoxify the active oxygen species and repair the damage caused is lost. A state in which the obstacle is moving forward.
  • oxidative stress is known to be involved in various diseases. For example, Alzheimer's disease, Parkinson's disease, diabetic complications, rheumatoid arthritis, neurodegeneration due to motor neuron disease, autism spectrum disorder (autism spectrum disorder), Rett syndrome, cancer, hyper astroglia, atherosclerosis, angina It has been reported that oxidative stress contributes to the progression of a wide range of diseases such as myocardial infarction, schizophrenia, bipolar disorder, fragile X syndrome, and chronic fatigue syndrome and promotion of aging.
  • diseases such as myocardial infarction, schizophrenia, bipolar disorder, fragile X syndrome, and chronic fatigue syndrome and promotion of aging.
  • Non-patent Document 3 Oxidation of low density lipoprotein (LDL cholesterol) induces atherogenesis, which results in atherosclerosis and ultimately leads to cardiovascular disease.
  • Parkinson's disease one of the neurodegenerative diseases, is one of geriatric diseases whose incidence increases rapidly after the age of 60, and is expected to continue to increase in the future as an aging society progresses. Parkinson's disease itself does not generally progress and die, and it has been reported that there is almost no difference between patients with Parkinson's disease and overall life expectancy.
  • tremor, muscular rigidity, agitation, peristalsis, and postural reflex disorder which are characteristic of Parkinson's disease, greatly reduce quality of life (Quality of Life, QOL), resulting in long-term inconvenience for patients and caregivers. Will be forced. *
  • Parkinson's disease is thought to be caused by the loss of neuronal cells that produce a neurotransmitter called dopamine. Insufficient dopamine precursors and dopamine degradation inhibitors are used as therapeutic agents. However, treatment using such therapeutic agents is only symptomatic treatment, and the progress of neuronal cell death cannot be stopped even during treatment. Similarly, many neurodegenerative diseases do not even have symptomatic treatment, and development of a drug having an inhibitory effect on neuronal cell death that can be useful for a fundamental treatment is awaited.
  • Non-Patent Document 4 In many of the diseases that are thought to contribute to the above oxidative stress, oxidizing substances such as active oxygen have been detected. Whether these oxidizing substances are the cause of the disease, or It is unclear whether an oxidant is secondarily produced from general tissue damage (Non-Patent Document 4).
  • antioxidants have been reported that suppress or eliminate oxidants. For example, because the brain is very vulnerable to oxidative damage due to its high metabolic rate and high concentration of polyunsaturated fats, antioxidants are widely used as drugs for treating brain damage (Non-patent Document 5). . In addition, since free radicals damage DNA, research has been conducted on the preventive effect of antioxidants against cancer.
  • Non-patent document 6 Non-patent document 6
  • J-1 protein having antioxidative stress function As therapeutic agents for neurodegenerative diseases, the following compounds that bind to DJ-1 protein having antioxidative stress function have been reported as compounds exhibiting oxidative stress-induced neuronal cell death inhibitory activity, and are useful for fundamental therapeutic methods (Non-patent document 6, Patent document 1). It is known that the functional breakdown of DJ-1 protein causes Parkinson's disease, stroke, and the like. These compounds are considered to exert pharmacological action through the antioxidant ability of the DJ-1 protein by maintaining the activity of the DJ-1 protein (Patent Document 1).
  • Patent Documents 2 and 3 SMO receptor binding compounds (Patent Documents 2 and 3) that act as hedgehog signaling cascade inhibitors and compounds for labeling double helical filaments (Patent Document 4) have been reported.
  • the oxidative stress-induced neuronal cell death inhibitory activity of the compound has not been studied at all.
  • the object of the present invention is not symptomatic therapy, but an oxidative stress-induced neuronal death inhibitory compound, particularly an oxidative stress-induced neuronal death inhibitory compound, which enables fundamental treatment of suppressing cell death due to oxidative stress,
  • An oxidative stress-induced neuronal cell death inhibitor comprising a compound, a pharmaceutical composition comprising the oxidative stress-induced neuronal cell death inhibitor, and a method for treating a disease using the compound.
  • DJ-1-dependent cell death inhibitory effect a compound having a specific structure that exerts a neuronal cell death inhibitory effect on the compound 23 described in Patent Document 1 that is independent of only the activity of the DJ-1 protein.
  • a substituent at a specific position causes a cell death inhibitory effect independent of DJ-1 (hereinafter also referred to as a DJ-1-independent cell death inhibitory effect or simply a DJ-1-independent effect).
  • DJ-1-independent cell death inhibitory effect or simply a DJ-1-independent effect.
  • W, Y and Z are each independently C or N;
  • R 1 is hydrogen, halogen, —CN, —NH 2 , —NO 2 , —N 3 , a C 1 -C 6 alkyl group optionally substituted with halogen, C 1 -C 6 alkoxy R 1 is not present when W is N,
  • R 2 is hydrogen, halogen, —CN, —NH 2 , —NO 2 , —N 3 , a C 1 -C 6 alkyl group optionally substituted with halogen, C 1 -C 6 alkoxy Group or carboxyl group and when Y is N, R 2 is absent,
  • R 3 is hydrogen, halogen, —CN, —NH 2 , —NO 2 , —N 3 , a C 1 -C 6 alkyl group optionally substituted with halogen, C
  • compound of formula (I) or oxidative stress-induced cell death suppressing activity ED 50 of a pharmaceutically acceptable salt thereof is less than or equal to 1000 nM, oxidative stress-induced cell death suppressing according to [1] Agent.
  • ED 50 of a pharmaceutically acceptable salt thereof is less than or equal to 1000 nM, oxidative stress-induced cell death suppressing according to [1] Agent.
  • X is the following group The oxidative stress-induced cell death inhibitor according to any one of [1] to [3], selected from: [5] The oxidative stress-induced cell death inhibitor according to any one of [1] to [4], wherein at least one of R 1 to R 5 is halogen. [6] The oxidative stress-induced cell death inhibitor according to [5], wherein at least one of R 1 to R 5 is fluorine.
  • the compound represented by the formula (I) is the following compound:
  • R 2 and R 4 are each independently hydrogen, halogen, —CN, —NH 2 , —N 3 , —CH 3 or —OCH 3 ;
  • R 3 is hydrogen, halogen, —CN, —NH 2 , —N 3 , —CH 3 , —OCH 3 , an optionally substituted heteroaryl, an optionally substituted arylamide, or an optionally substituted
  • R 1 and R 5 are each independently hydrogen or —NO 2 —NH 2 ;
  • X is the following formula In the formula, * indicates a bonding point, R 9 is hydrogen or C 1 - a 6 alkyl group, in a group represented by R 10 is hydrogen or C 1 - a 6 alkyl group, However, 3,4-dimethoxy-N- [4- (8-methylimidazo [1,2-a] pyridin-2-yl) phenyl] benzamide, 3,5-dimethoxy-N-
  • R 2 and R 4 are each independently hydrogen, halogen, —CN, —NH 2 , —N 3 , C 1 -C 6 alkyl group or methoxy group;
  • R 3 is hydrogen, halogen, —CN, —NH 2 , —N 3 , C 1 -C 6 alkyl group, methoxy group, optionally substituted aryl, optionally substituted heteroaryl, substituted An optionally substituted aryl amide or an optionally substituted heteroaryl amide
  • X is the following formula In the formula, * indicates a bonding point, R 9 is hydrogen or C 1 - a 6 alkyl group, in a group represented by R 10 is hydrogen or C 1 - a 6 alkyl group, However, N- [4- (imidazo [1,2-a] pyridin-2-yl) phenyl] -4-pyridinecarboxamide and N- [4- (8-
  • R 2 and R 4 are each independently hydrogen, halogen, —CN, —NH 2 , —N 3 , C 1 -C 6 alkyl group or methoxy group;
  • R 3 is hydrogen, halogen, —CN, —NH 2 , —N 3 , C 1 -C 6 alkyl group, methoxy group, optionally substituted aryl, optionally substituted heteroaryl group, substituted An arylamide group which may be substituted or a heteroarylamide group which may be substituted,
  • X is the following formula In the formula, * indicates a bonding point, R 9 is hydrogen or C 1 - a 6 alkyl group, in a group represented by R 10 is hydrogen or C 1 - a 6 alkyl group, Or a pharmaceutically acceptable salt thereof according to [13].
  • a pharmaceutical composition comprising the compound according to [8] to [14] or a pharmaceutically acceptable salt thereof.
  • An oxidative stress-induced cell death inhibitor comprising the compound according to [8] to [14] or a pharmaceutically acceptable salt thereof.
  • the compound or oxidative stress-induced cell death suppressing activity ED 50 of a pharmaceutically acceptable salt thereof according to is less than 1000 nM, oxidative stress-induced cell death according to [16] Inhibitor.
  • the disease is Parkinson's disease, Alzheimer's disease, stroke, ischemic brain disease, Parkinson's disease, mitochondrial encephalomyopathy, spinocerebellar degeneration (SCD), Huntington's disease, progressive supranuclear palsy (PSP), cerebral cortex
  • SCD spinocerebellar degeneration
  • PSP progressive supranuclear palsy
  • cerebral cortex [19]
  • ALS amyotrophic lateral sclerosis
  • the compound of the present invention since the compound of the present invention has high membrane permeability, it can be absorbed into the living body with high efficiency even by oral administration, and since it has no phenol group, it undergoes glucuronic acid conjugation like a polyphenolic antioxidant for a short time. It is not metabolized by the pharmacological agent and has a high pharmacological effect by oral administration. Further, since it exhibits resistance to metabolism by CYP, which is an oxidative metabolic enzyme, it is considered that it can be taken into circulating blood and stably distributed in the living body. Furthermore, since it is a low molecule, it can efficiently pass through the blood-brain barrier (BBB), can easily reach cerebral nervous system cells, and can suppress neuronal cell death. Therefore, although it is known that the structure of CNS drugs is usually difficult to optimize for oral administration, the compound of the present application can also be expected to be used as an orally administrable CNS drug.
  • BBB blood-brain barrier
  • an orally effective oxidative stress-induced cell death inhibitory compound for example, Parkinson's disease, Alzheimer's disease, spinocerebellar degeneration (SCD), Huntington's disease, progressive supranuclear palsy (PSP), cortical basal ganglia degeneration, amyotrophic lateral sclerosis (ALS), cranial nerve injury (ischemic brain disease) due to cerebral ischemia, stroke, heart failure, diabetes, rheumatoid arthritis, acute ischemic attack, atheroma
  • oxidative stress related diseases such as atherosclerosis, inflammatory bowel disease, dry eye, mitochondrial encephalomyopathy, inflammatory bowel disease, coronary arteriosclerosis, Crohn's disease, mucositis by radiation therapy, cerebral ischemia, myocardial infarction, Especially Parkinson's disease, Alzheimer's disease, stroke, ischemic brain disease, Parkinson's disease, mitochondrial encephalomyopathy, spinocere
  • FIG. 4 is a graph showing the results of a test for suppressing oxidative stress-induced cell death by SH-SY5Y of compound HUP0381.
  • the present invention provides the following formula (I): Where W, Y and Z are each independently C or N; When W is C, R 1 is hydrogen, halogen, —CN, —NH 2 , —NO 2 , —N 3 , a C 1 -C 6 alkyl group optionally substituted with halogen, C 1 -C 6 alkoxy R 1 is not present when W is N, When Y is C, R 2 is hydrogen, halogen, —CN, —NH 2 , —NO 2 , —N 3 , a C 1 -C 6 alkyl group optionally substituted with halogen, C 1 -C 6 alkoxy Group or carboxyl group and when Y is N, R 2 is absent, When Z is C, R 3 is hydrogen, halogen, —CN, —NH 2 , —NO 2 , —N 3 , a C 1 -C 6 alkyl group optionally substituted
  • halogen means an element belonging to Group 17 of the periodic table, or an atom of which is a substituent such as a hydrocarbon, an aromatic carbocycle, an aromatic heterocycle, or the like.
  • substituent such as a hydrocarbon, an aromatic carbocycle, an aromatic heterocycle, or the like.
  • halogen in the present invention include fluorine, chlorine, bromine, iodine and the like.
  • preferred halogens include fluorine, chlorine and bromine.
  • the “C 1 -C 6 alkyl group” is a monovalent group derived by removing one arbitrary hydrogen atom from linear and branched aliphatic hydrocarbons having 1 to 6 carbon atoms. . Specifically, methyl group, ethyl group, isopropyl group, butyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, isopentyl group, 2,3-dimethylpropyl group, hexyl group Etc.
  • the “C 1 -C 6 alkoxy group” is a monovalent group formed by bonding the aforementioned “C 1 -C 6 alkyl group” to an oxygen atom. Specifically, methoxy group, ethoxy group, isopropyloxy group, butoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, pentyloxy group, isopentyloxy group, 2,3-dimethylpropyl An oxy group, a hexyloxy group, etc. are mentioned.
  • Aryl is an aromatic ring group such as a monocyclic ring, a condensed ring, or a polycyclic ring in which a single ring is bonded by a single bond, and examples thereof include a phenyl group, a biphenyl group, and a naphthyl group.
  • Heteroaryl is a monocyclic or condensed aromatic ring group containing at least one element selected from O, N and S, and includes a pyridinyl group, a phenylpyridinyl group, a quinolyl group, and the like. .
  • Arylamide and “heteroarylamide” are those in which the above “aryl” and “heteroaryl” are —C (O) —NH— * or —NH—C (O) — * (* represents a bond with another element. A group having a dot). Examples of the heteroaryl amide include the following groups.
  • optionally substituted means that it may be substituted with any substituent, and examples of the substituent include the substituents shown in R 2 and R 4 above. Specific examples include a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkenyl group, and a halogen. Accordingly, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl and optionally substituted arylamide in R 3 are one or more of aryl or heteroaryl. Of the hydrogen atoms may be independently substituted by the above substituents.
  • W, Y and Z each independently represent C or N. Preferably, all of W, Y and Z are C, or one or two are N.
  • a preferable alkyl group is a C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl group, and particularly preferably a methyl group.
  • a preferred alkoxy group is a C 1 -C 4 alkoxy group, more preferably a C 1 -C 3 alkoxy group, and even more preferably a methoxy group.
  • At least one of R 1 to R 5 is halogen, and fluorine is particularly preferred from the viewpoint of high oxidative stress-induced cell death inhibitory activity and no irreversible inhibition of CYP.
  • R 1 and R 5 are hydrogen.
  • R 2 , R 3 and R 4 are all hydrogen, or at least one is halogen and the remainder is hydrogen.
  • R 2 and R 3 and R 4 are hydrogen
  • R 2 and R 4 are fluorine
  • R 3 is hydrogen
  • R 3 is halogen and R 2 and R 4 are hydrogen
  • R 1 and R 5 are preferably hydrogen.
  • R 1 and R 5 are hydrogen
  • at least one of R 2 , R 3 and R 4 is an alkoxy group.
  • a methoxy group is particularly preferable.
  • X is the following formula (A), (B) or (C) It is group represented by these. From the viewpoint of high oxidative stress-induced cell death inhibitory activity, in the above formulas (A) and (B), when R 6 to R 9 are all simultaneously hydrogen, or only R 9 is a C 1 -C 6 alkyl group It is preferable that R 6 to R 8 are hydrogen.
  • a preferred alkyl group is a C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl group, and particularly preferably a methyl group.
  • a preferred alkoxy group is a C 1 -C 4 alkoxy group, more preferably a C 1 -C 3 alkoxy group, and even more preferably a methoxy group.
  • X is a heterocyclic group represented by the formula (A), R 6 to R 9 are all hydrogen at the same time, and X is the formula (A)
  • R 6 to R 9 are all hydrogen at the same time
  • X is the formula (A)
  • R 8 is hydrogen is exemplified.
  • X is preferably a group selected from the following group.
  • a preferable alkyl group is a C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl group, and particularly preferably a methyl group.
  • R 10 is preferably hydrogen from the viewpoint of high oxidative stress-induced cell death inhibitory activity.
  • X is a heterocyclic group represented by the formula (A)
  • R 1 , R 5 , R 6 , R 7 and R 8 are hydrogen
  • R 2 , R 3 and R When 4 is a methoxy group, R 9 and R 10 are both methyl groups, or R 9 and R 10 are both hydrogen. More preferably, R 9 and R 10 are both methyl groups.
  • the oxidative stress-induced cell death inhibitor of the present invention is represented by the following formula (Iaa): Wherein R 2 to R 4 and R 10 are the same as defined in formula (I), and X represents the following formula Where * indicates the point of attachment, R 9 is hydrogen or C 1 - a 6 alkyl group, R 10 is hydrogen or C 1 - a 6 alkyl group, A heterocyclic group represented by Or a pharmaceutically acceptable salt thereof.
  • R 4 is hydrogen.
  • R 2 and R 3 are each independently hydrogen or halogen, where halogen is preferably fluorine, R 4 is hydrogen; R 9 is hydrogen or C 1 - an alkyl group, preferably a methyl group, R 10 is hydrogen or C 1 - an alkyl group, preferably a methyl group.
  • R 2 and R 3 are each independently hydrogen or halogen, where halogen is preferably fluorine, R 4 is hydrogen; R 9 is C 1 - an alkyl group, preferably a methyl group, R 10 is hydrogen.
  • R 2 is hydrogen or halogen, where halogen is preferably fluorine, R 3 is fluorine, R 4 is hydrogen; R 9 is C 1 - an alkyl group, preferably a methyl group, R 10 is hydrogen.
  • the oxidative stress-induced cell death inhibitor of the present invention preferably contains one or more compounds selected from the following compounds from the viewpoint of particularly high oxidative stress-induced cell death inhibitory activity.
  • the compound represented by the above formula (I) has been newly found as a compound having an effect of suppressing oxidative stress-induced cell death, and among these, in particular, the following formulas (Ia) to (Ie)
  • the compound represented by) includes a novel compound that has not been conventionally known. Accordingly, the present invention in one aspect relates to a novel compound represented by formula (Ia) to formula (Ie).
  • R 2 and R 4 are each independently hydrogen, halogen, —CN, —NH 2 , —N 3 , —CH 3 or —OCH 3 ;
  • R 3 is hydrogen, halogen, -CN, -NH 2, -N 3 , -CH 3, -OCH 3, aryl which may be substituted, an optionally substituted heteroaryl, optionally substituted An arylamide or an optionally substituted heteroarylamide;
  • R 1 and R 5 are each independently hydrogen or —NO 2 —NH 2 ;
  • X is the following formula Where * indicates the point of attachment, R 9 is hydrogen or C 1 - a 6 alkyl group, A group represented by R 10 is hydrogen or C 1 - a 6 alkyl group, Or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is obtained by removing the above-mentioned compound described in the literature from the compound represented by the formula Ia.
  • R 2 , R 3 and R 4 are each independently hydrogen, halogen or methoxy group.
  • R 2 , R 3 and R 4 are each independently hydrogen or halogen, where when R 2 is fluorine, any one of R 3 and R 4 is fluorine; R 9 is C 1 - an alkyl group, preferably a methyl group, R 10 is hydrogen and the halogen is preferably fluorine.
  • R 2 , R 3 and R 4 are each independently a hydrogen, halogen or alkoxy group;
  • R 9 is hydrogen or C 1 - 6 alkyl group, wherein C 1 - 6 alkyl group is preferably a methyl group,
  • R 10 is C 1 - a 6 alkyl group, preferably a methyl group, the halogen is preferably fluorine.
  • X is a heterocyclic group represented by the formula (B1), R 2 , R 3 and R 4 are each independently a hydrogen, halogen or alkoxy group; R 9 is hydrogen or C 1 - 6 alkyl group, wherein C 1 - 6 alkyl group is preferably a methyl group, R 10 is hydrogen and the halogen is preferably fluorine.
  • Examples of preferred compounds of the present invention include the following compounds.
  • HUP2290 is CAS number: 1371052-86-6
  • HUP0373 is CAS number: 1209725-03-0
  • HUP2298 is CAS number: 1170188-20-1
  • HUP2479 is CAS number: 1371267-96- 7
  • HUP2480 is a compound registered as CAS number: 1581030-55-8
  • HUP2490 is registered as CAS number: 1370971-77-9
  • HUP2291 is a compound registered as CAS number: 1293881-32-9.
  • the production method is not described at all, and therefore there is no record of the actual production of the compound.
  • R 2 and R 4 are each independently hydrogen, halogen, —CN, —NH 2 , —N 3 , C 1 -C 6 alkyl group or methoxy group;
  • R 3 is hydrogen, halogen, —CN, —NH 2 , —N 3 , C 1 -C 6 alkyl group, methoxy group, optionally substituted aryl, optionally substituted heteroaryl, substituted An optionally substituted aryl amide or an optionally substituted heteroaryl amide
  • X is the following formula In the formula, * indicates a bonding point, R 9 is hydrogen or C 1 - a 6 alkyl group, in a group represented by R 10 is hydrogen or C 1 - a 6 alkyl group, However, N- [4- (imidazo [1,2-a] pyridin-2-yl) phenyl] -4-pyridinecarboxamide and N- [
  • N- [4- (imidazo [1,2-a] pyridin-2-yl) phenyl] -4-pyridinecarboxamide and the N- [4- (8-methylimidazo [1,2-a] pyridine -2-yl) phenyl] -4-pyridinecarboxamide has the following structure, respectively.
  • Examples of preferred compounds of the present invention include the following compounds.
  • the compounds represented by the above (Ib), (Ic) or (Ie) are preferable, and the following compounds are particularly preferable.
  • the following compounds are particularly preferred because of their high oxidative stress-induced cell death inhibitory activity.
  • the value of the oxidative stress-induced cell death inhibitory activity ED 50 of the compound of the present invention is preferably as small as possible, preferably 1000 nM or less, more preferably 100 nM or less, still more preferably 10 nM or less, particularly preferably 1 nM or less. is there.
  • examples of the salt of the compound represented by the formula (I) include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, methanesulfonate.
  • Sulfonates such as p-toluenesulfonate, carboxylates such as acetate, citrate, malate, tartrate, succinate and salicylate, or alkali metals such as sodium and potassium Salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts.
  • These salts may be produced by bringing the compound into contact with an acid or base that can be used in the production of a pharmaceutical product.
  • the compound represented by the formula (I) or a salt thereof may be an anhydride, or may form a solvate such as a hydrate.
  • “Solvation” as used herein refers to a phenomenon in which a solute molecule or ion strongly attracts a solvent molecule adjacent to it in a solution to form a single molecular group. For example, hydration is performed when the solvent is water.
  • the solvate may be either a hydrate or a non-hydrate.
  • alcohol for example, methanol, ethanol, n-propanol
  • dimethylformamide and the like can be used.
  • the compounds of the present invention and salts thereof can exist in tautomeric forms such as keto and enol forms of amide bonds, and mixtures thereof.
  • Tautomers exist as a mixture of tautomeric sets in solution. In the solid form, one tautomer is usually predominant. Although one tautomer may be described, the present invention includes all tautomers of the compounds of the present invention.
  • the present invention includes all isotopes of the compounds represented by formula (I).
  • the isotope of the compound of the present invention is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons).
  • isotopes contained in the compounds of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom, and the like. 2 H, 3 H, 13 C, respectively. , 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and the like.
  • radioactive isotopes such as 3 H and 14 C that decay by emitting radioactivity are useful in pharmaceutical tissue or compound tissue distribution tests. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity.
  • the isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
  • the compounds of the present invention also include prodrugs of compounds of formula (I).
  • the “prodrug of the compound of the formula (I)” refers to a compound of the formula (I) or a pharmaceutically acceptable salt thereof after administration by enzymatic or non-enzymatic degradation under physiological conditions. Means a derivative of the compound of formula (I) to be converted. Prodrugs may be inactive when administered to a patient, but are present converted to a compound of formula (I) that is active in vivo. Those having ordinary knowledge in the art can immediately understand derivatives that can be used as prodrugs.
  • prodrugs include, but are not limited to, prodrugs that, for example, convert to a desired drug form when a specific pH is reached or by the action of an enzyme.
  • a typical prodrug is a compound that generates a free acid in vivo and has a hydrolyzable ester residue.
  • Such hydrolyzable ester residues include, but are not limited to, for example, free hydrogen (eg, when the amide in formula (I) has an N-carboxyl group, the free hydrogen in the carboxyl group) Is a C 1 -C 4 alkyl group, a C 2 -C 7 alkanoyloxymethyl group, a 1- (alkanoyloxy) ethyl group having 4 to 9 carbon atoms, and a 1-methyl- having 5 to 10 carbon atoms 1- (alkanoyloxy) -ethyl group, alkoxycarbonyloxymethyl group having 3-6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl group having 4-7 carbon atoms, 5-8 carbons 1-methyl-1- (alkoxycarbonyloxy) ethyl group having atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 4 to 1- (N- (alkoxycarbonyl) amino) ethy
  • the compound represented by the formula (I) relating to the present invention can be produced, for example, according to the following method, but the production method of the compound of the present invention is not limited thereto. Further, the order of reaction steps such as introduction of substituents can be changed as necessary. In addition, as a raw material compound used in manufacture, you may use what is marketed, or may manufacture it by a conventional method as needed. In the formulas representing the following reaction steps, R 1 to R 10 are as defined in formula (I). Other abbreviations used in the following reaction formulas have ordinary meanings that can be understood by those skilled in the art. The names of reagents and solvents corresponding to the abbreviations and chemical formulas generally used in the following general synthesis methods and examples are described below.
  • the present invention relates to a method for producing the compound represented by the formula (I), Following formula In the formula, X is an aniline represented by the formula (I), By adding excess sodium hydride to the sodium salt of aniline, Following formula Wherein R 1 to R 5 , W, Y, and Z are as shown in the above formula (I), and Hal is a halogen.
  • Manufacturing method I The compounds of the present invention can be prepared according to the following scheme.
  • Step I-1 This is a step of constructing an imidazopyridine skeleton IIc by condensation of an acetophenone derivative IIa and a 2-aminopyridine derivative IIb. This step can be performed by reacting acetophenone derivative IIa with 2-aminopyridine derivative IIb in the presence of a base.
  • a base For example, Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 22 p. It can be implemented with reference to the method.
  • the reaction is carried out in the presence or absence of a base in a solvent at room temperature to the boiling point of the solvent, and further using a microwave synthesizer under reaction conditions up to 300 degrees. After completion of the reaction, the product was crystallized by pouring the reaction solution into water, the precipitate was collected by filtration, dried and used in the next step.
  • 2-aminopyridine derivatives include 2-aminopyridine, 3-methyl-2-aminopyridine, 4-methyl-2-aminopyridine, 3-fluoro-2-aminopyridine, 4-fluoro-2-aminopyridine, 5- Fluoro-2-aminopyridine and 6-fluoro-2-aminopyridine are used, and 2-aminopyridine or 3-methyl-2-aminopyridine is preferable. More preferred is 3-methyl-2-aminopyridine.
  • the reaction proceeds even in the absence of a base, the use of a base is preferable for improving the yield and reaction rate.
  • the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, calcium hydride, or t-BuOK, t-BuONa, pyridine, TEA, Organic bases such as DIPEA, LDA, LiHMDS, and n-BuLi can be mentioned, and sodium carbonate is preferable.
  • solvent examples include toluene, xylene, n-hexane, cyclohexane, DMF, DMA, EtOAc, DMSO, dichloromethane, carbon tetrachloride, THF, dioxane, acetonitrile and the like, water, methanol, ethanol and the like and mixtures thereof. Acetonitrile is preferred.
  • the reaction temperature can be raised from room temperature to the boiling point of the solvent, and further up to 300 ° C. by using a microwave synthesizer, preferably 150 ° C. and the reaction time is 15 minutes using the microwave synthesizer.
  • the product was crystallized by pouring the reaction solution into water, the precipitate was collected by filtration, washed with a mixed solvent of acetonitrile-water, and then dried under reduced pressure and used in the next step. .
  • Step I-2 This is a catalytic reduction reaction of a nitro group to an amine.
  • the reduction process of a nitro group using palladium carbon in a hydrogen gas atmosphere which is a general process, cannot be adapted because the imidazopyridine skeleton is also reduced along with the reduction of the nitro group. Therefore, it is possible to react by using 1,4-cyclohexadiene as a hydrogen source. For example, see the method described in Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 22 p. 3309-3331; Can be implemented.
  • the reaction is carried out in the presence of palladium on carbon under a reaction condition of room temperature to the boiling point of the solvent, and further up to 300 ° C. using a microwave synthesizer. After completion of the reaction, palladium carbon was removed by filtration, and then the reaction solution was distilled off. The resulting precipitate was collected by filtration, dried and used for the next step.
  • the palladium carbon used in the reaction for example, 5% palladium carbon or 10% palladium carbon can be used, and preferably 10% palladium carbon.
  • An excess amount of 1,4-cyclohexadiene used as a hydrogen source is required, and preferably 10 equivalents.
  • the solvent examples include alcohol solvents such as methanol and ethanol, preferably methanol.
  • the reaction temperature may be from room temperature to the boiling point of the solvent, and further by using a microwave synthesizer, the reaction conditions may be up to 300 degrees, preferably 120 degrees when using the microwave synthesizer, and the reaction time is 10 minutes.
  • the palladium carbon is removed by filtration, and then the reaction solution is distilled off.
  • the resulting precipitate is collected by filtration, crystallized from ethyl acetate-n-hexane, collected by filtration, and collected under reduced pressure. Dry aniline IId was used in the next step.
  • Step I-3 It is an amidation step.
  • This step can be usually synthesized by dehydration condensation reaction of aniline and carboxylic acid.
  • the aniline derivative IId synthesized in Step I-2 is hardly soluble in an organic solvent and precipitates under the reaction conditions of a commonly used dehydration condensation reaction, so that the reaction proceeds slowly and is not completed. It was. Therefore, after the aniline derivative IId synthesized in Step I-2 is dispersed in a THF solvent, an excess amount of sodium hydride is added to form a sodium salt of aniline, so that a solution is obtained instead of a suspension. As a result, an equivalent amount of the carboxylic acid halide IIe was added to the sodium salt of the produced aniline and stirred at room temperature.
  • Step I-4 This is an alkylation step of amide IIf to an amino group.
  • This step can be performed by reacting amide IIf with an alkylating agent in the presence of a base.
  • an alkylating agent include alkyl halides such as MeI, EtI, and i-PrI, and sulfonic acid esters such as dimethyl sulfate, methylmethanesulfonate, methyltosylate, and methyltrifluoromethanesulfonate, and preferably alkyl such as MeI. It is a halide.
  • the base examples include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, calcium hydride, or t-BuOK, t-BuONa, pyridine, TEA, Organic bases such as DIPEA, LDA, LiHMDS, and n-BuLi can be mentioned, and sodium hydride is preferable.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, calcium hydride, or t-BuOK, t-BuONa, pyridine, TEA
  • Organic bases such as DIPEA, LDA, LiHMDS, and n-BuLi can be mentioned, and sodium hydride is preferable.
  • solvent examples include toluene, xylene, n-hexane, cyclohexane, DMF, DMA, EtOAc, DMSO, dichloromethane, carbon tetrachloride, THF, dioxane, acetonitrile and the like, and mixtures thereof, preferably THF. .
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and particularly relates to a pharmaceutical composition for prevention and / or treatment of oxidative stress-related diseases.
  • an oxidative stress-related disease refers to a balance between a disorder caused by active oxygen to cells and organs in a living body and a function of a biological system that detoxifies reactive oxygen species and repairs the resulting disorder.
  • Parkinson's disease Alzheimer's disease, spinocerebellar degeneration Disease (SCD), Huntington's disease
  • the pharmaceutical composition of the present invention includes, as a preferred embodiment, at least one novel compound represented by formulas (Ia) to (Ie).
  • the pharmaceutical composition of the present invention contains at least one compound of the present invention as an active ingredient.
  • other pharmaceutical compounds of the present invention and A known antioxidant may be included.
  • a pharmaceutically acceptable carrier, a surfactant and the like may be used to contain other optional components such as a component for effectively achieving the therapeutic effect of the compound of the present invention and an excipient.
  • the term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid shaped diluents or encapsulating materials suitable for administration to mammals.
  • the term “acceptable” refers to the composition in such a way that under normal conditions of use, reactions that do not substantially reduce the pharmaceutical effectiveness of the composition do not occur with each other. This means that the component in the product and the target compound can be mixed.
  • the pharmaceutically acceptable carrier should of course have a sufficiently high purity and a sufficiently low toxicity so that it is suitable for administration to the animal to be treated, preferably an animal, more preferably a mammal.
  • Examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; Tragacanth gum powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, vegetable oil, cacao oil; propylene glycol, glycerin, sorbitol Polyhydric alcohols such as mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEEN; wetting agents such as lecithin; coloring agents; flavorings; tableting agents; Agents; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer and the like.
  • sugars such as lactose
  • the administration method is oral, rectal, parenteral (intravenous, intramuscular, subcutaneous). ), Intravaginal, intravaginal, intraperitoneal, intravesical, transdermal (such as patches, ointments, gels or creams), transmucosal (oral patches, suppositories, sublingual tablets, etc.) ), Topical (infusion, powder, etc.) administration and inhalation (such as buccal or nasal spray).
  • the compound of the present invention which is an active ingredient of the pharmaceutical composition of the present invention has one feature that it can be administered orally. Therefore, it is preferably administered orally.
  • the dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-filled containers adapted to be subdivided into individual doses. Examples include oral solutions.
  • the dosage form can also be adapted to various modes of administration including controlled release formulations such as subcutaneous implantation.
  • Said formulation is manufactured by a well-known method using additives, such as an excipient
  • excipients include starches such as starch, potato starch, and corn starch, lactose, crystalline cellulose, and calcium hydrogen phosphate.
  • coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.
  • the binder include polyvinyl pyrrolidone, macrogol and the same compound as the excipient.
  • disintegrant examples include the same compounds as the above excipients and chemically modified starch / celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.
  • stabilizer examples include paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; Mention may be made of dehydroacetic acid; and sorbic acid.
  • the flavoring agent include sweeteners, acidulants, and fragrances that are commonly used.
  • ethanol phenol, chlorocresol, purified water, distilled water, or the like can be used as a solvent for producing the liquid agent.
  • the surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol and the like.
  • the invention also provides a method for preventing and / or treating an oxidative stress related disorder in a subject comprising administering an effective amount of one or more compounds of the invention to a subject in need thereof. It also relates to the method of inclusion.
  • the pharmaceutical composition of the present invention is used as a therapeutic or prophylactic agent for a disease induced by oxidative stress
  • the amount of the compound of the present invention or a salt or solvate thereof used depends on symptoms, age, body weight, relative health. It depends on the condition, the presence of other medications, the method of administration, etc.
  • generally effective amounts are preferably per kg body weight per day in the case of oral agents as active ingredients (compounds of the invention represented by formula (I)).
  • the present invention also relates to a method for suppressing oxidative stress-induced cell death using the compound of the present invention. Administering an effective amount of one or more compounds of the invention to a subject in need thereof.
  • Step I-1 Compound HUP0360 8-Methyl-2- (4-nitrophenyl) -imidazo [1,2-a] pyridine 3-methyl-2-aminopyridine (561 ⁇ L, 8.2 mmol), 2-bromo-4′-nitro-acetophenone (1.0 g, 4.1 mmol), sodium carbonate (318 mg, 3.0 mmol) in 20 mL of Biotage
  • acetonitrile (18 mL) was added and suspended at room temperature, and the mixture was heated and stirred at 150 ° C. for 15 minutes using a microwave synthesizer.
  • Step I-2 Compound HUP0361 8-Methyl-2- (4-aminophenyl) -imidazo [1,2-a] pyridine
  • Compound HUP0360 500 mg, 1.97 mmol
  • 1,4-cyclohexadiene (1.84 ml, 19.7 mmol
  • 10% palladium on carbon 50 mg
  • methanol (18 mL) was suspended at room temperature, and the mixture was heated and stirred at 130 ° C. for 10 minutes using a microwave synthesizer. After cooling to room temperature, the reaction suspension was filtered to remove 10% palladium on carbon.
  • Step I-3 Compound HUP0344 3,4,5-trimethoxy-N- [4- (8-methylimidazo [1,2-a] pyridin-2-yl) phenyl] benzamide
  • Compound HUP0361 (85.3 mg, 0.38 mmol) was added to 8 ml of anhydrous THF and stirred, 60% sodium hydride (18.4 mg, 0.46 mmol) was added to the resulting suspension, and stirring was continued for 10 minutes at room temperature. A brownish solution was obtained.
  • 3,4,5-trimethoxybenzoyl chloride (87.6 mg, 0.38 mmol) was added, and the mixture was further stirred at room temperature for 30 minutes.
  • the reaction mixture was added with 4 ml of saturated aqueous ammonium chloride solution to stop the reaction, poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was crystallized from ethyl acetate. The crystals were collected by filtration and dried under reduced pressure to give the title compound as a white powder (130 mg, 81%).
  • the reaction solution was poured into water and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over sodium sulfate.
  • the desiccant was removed by filtration and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (SiO 2 12 g, eluted with 10% methanol / chloroform, then eluted with 50% ethyl acetate / hexane).
  • the compound was obtained as a yellow powder (15.1 mg, 2.4%).
  • HUP2479 60 mg, 0.16 mmol
  • 1,4-cyclohexadiene 150 ⁇ l, 1.6 mmol
  • 10% palladium on carbon 6 mg
  • methanol 2 mL
  • HUP2480 (152 mg, 0.44 mmol), picolinic acid (137 mg, 0.82 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (157.2 mg, 0.82 mmol), 1-hydroxy Benzotriazole (125.5 mg, 0.82 mmol) and N, N-diisopropylethylamine (289 ⁇ l, 1.7 mmol) were added to 5 ml of anhydrous DMF and stirring was continued for 4 hours at room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was washed with water and methanol, and dried under reduced pressure to give the title compound HUP2492 as a pale blue powder (124.6 mg, 63%).
  • Step I-4 Compound HUP0352 3,4,5-trimethoxy-N-methyl [4- (8-methylimidazo [1,2-a] pyridin-2-yl) phenyl] benzamide
  • Compound HUP0344 (43.6 mg, 0.10 mmol) was added to 2 ml of anhydrous DMF and stirred, and the resulting suspension was mixed with 60% sodium hydride (5.0 mg, 0.12 mmol) and MeI (7.8 ⁇ L, 0.12 mmol). And stirring was continued for 1 hour at room temperature.
  • DJ-1 Binding Compound Cell Death Inhibitory Effect on Hydrogen Peroxide Concentration in Cultured Cells (1) Preparation of DJ-1 Knockout Neuron Contribution of DJ-1 Protein Expression to Oxidative Stress-Induced Cell Death Inhibitory Effect
  • the human dopaminergic neuron SH-SY5Y that highly expresses the DJ-1 protein was used to create a DJ-1-gene knocked-out cell, DJ-1-KO SH-SY5Y, using the CRISPR-Cas9 system. used.
  • the disappearance of the expression of DJ-1 protein from the prepared cells was confirmed by Western blotting using disrupted cells (FIG. 1).
  • Patent Document 1 a 3,4,5-trimethoxy derivative (CAS No: 724737-74-0) which is a compound that binds to DJ-1 and exhibits oxidative stress-induced cell death inhibitory activity and has the same mother nucleus as that of the present invention It has been reported (Patent Document 1).
  • this compound was synthesized as compound number HUP0344 in the present invention and the oxidative stress-induced cell death inhibitory activity was examined as a positive compound, it showed ED 50 at a concentration of 5 ⁇ M which was almost the same as the activity described in Patent Document 1. It did not have an ED 90 value.
  • the 4-fluorine derivative (HUP0381) of the present invention reached ED 50 which is an oxidative stress-induced cell death inhibitory activity at a concentration of 1 nM or less, and further reached ED 90 at a concentration of 10 nM or less. It was proved that the activity was about 1000 times higher than that of the trimethoxy derivative.
  • ADMET evaluation Evaluation of drug-likeness (ADMET evaluation) Derivatives with strong activity were evaluated by ADMET (Bleicher NATURE REVIEWS 2003) in order to select compounds that proceed to drug efficacy and safety assessment in cell lines and animal models.
  • Analytical system for each assay is HPLC system: High Performance Liquid Chromatograph LC-20A Series (Shimadzu Corporation) Mass spectrometer: API 4000 (AB Sciex Pte. Ltd.) Plate Reader: Molecular Devices SpectraMax 190 was used.
  • Metabolic Stability Test Method A 1 mmol / L DMSO solution of the compound was diluted to 10 ⁇ mol / L with acetonitrile, and then further diluted to 200 nmol / L with a 6.5 mmol / L ⁇ -NADPH solution. 50 ⁇ L of 0.2 mg protein / mL liver microsome solution was added to 50 ⁇ L of this solution, followed by incubation at 37 ° C. for 35 minutes with shaking. After the incubation, 400 ⁇ L of methanol was added to stop the reaction. The solution was allowed to stand at -20 degrees for about 30 minutes and then centrifuged at 3,000 rpm for about 10 minutes at 4 degrees. Thereafter, the supernatant was measured by LC / MS / MS, and the residual ratio of the compound was calculated.
  • CYP1A2 ⁇ -naphthoflavone CYP2C8 quercetin dihydrate CYP2C9 sulfaphenazole CYP2C19 (S)-(+)-N-3-benzylnylanol CYP2D6 quinidine anhydride CYP3A4 ketoconazole was used as an inhibitor of each CYP.
  • CYP1A2 furaphyrin CYP2C9 suprofen CYP2B6 / 2C19 ticlopidine hydrochloride CYP2D6 paroxetine maleate CYP3A4 erythromycin was used as an inhibitor for MBI measurement.
  • the reaction solution was composed of a microsome-buffer mixed solution.
  • Liquid volume 0.5 mol / L potassium phosphate buffer (pH 7.4) 12 mL 165 mmol / L magnesium chloride aqueous solution 1.2 mL 34.65 mL water 20 mg protein / mL human liver microsome 150 ⁇ L (Final concentration in reaction solution 0.05 mg protein / mL)
  • CYP Inhibition Test Method Compound, DMSO (control), and inhibitor mixture were serially diluted with DMSO 1x, 5x, 25x, and 125x, and then mixed with 5 ⁇ L of each solution and 295 ⁇ L of the microsome-buffer mixture. . 30 ⁇ L of the solution and 50 ⁇ L of the microsome-buffer mixture were mixed, and 10 ⁇ L of 13 mM ⁇ -NADPH aqueous solution was added. If pre-incubation was required, it was incubated at 37 ° C for 30 minutes before addition. After incubation, 50 ⁇ L of methanol was added to stop the reaction. After dilution, the mixture was centrifuged at 3000 rpm, 4 degrees for 10 minutes, and the supernatant was collected and used as an injection sample for LC / MS / MS.
  • Residual activity rate calculation and MBI determination The residual activity rate was calculated from the metabolite-area ratio in each well and the metabolite-area ratio in the control group, and the IC 50 value was calculated from the concentration plot.
  • MBI (+ When the change in IC 50 value by preincubation was more than twice, it was determined as MBI (+). In addition, when the change in IC 50 value by preincubation was 2 times or less, it was determined as MBI (+/ ⁇ ).
  • MBI concentration concentration 100 times higher than the concentration at which the drug effect was observed.
  • CYP1A2 was judged as MBI. In the case of a compound having MBI, accumulative CYP inhibition appears by the administration of the compound, and as a result, toxicity may occur due to an increase in the concentration of a concomitant drug.
  • Example 62 PAMPA test As an artificial membrane, GIT-0 Lipid (GIT: Gastrointestinal tract) manufactured by pION Inc. was used. As the buffer, ASB-7.4 Acceptor Sink Buffer or ASB-5.0 Acceptor Sink Buffer manufactured by pION Inc. was used. Artificial Membrane Permeability Test Method The diluted compound was added to the Donor side, incubated for 4 hours at room temperature, and then the Acceptor and Donor spectra were measured. From the results, the membrane permeation coefficient (Pe value) was calculated using PAMPA analysis software. HUP2495 could not be evaluated due to insufficient solubility, but all other compounds evaluated showed good membrane permeability under both pH 5.0 and pH 7.4 conditions.
  • Example 63 Water-soluble solution precipitation method (DMSO method) Artificial fasting artificial intestinal fluid (FaSSIF) was obtained from Celeste. Test Method A compound solution diluted 100-fold was dispensed into a 96-well plate at 15 ⁇ L each in 4 wells, then placed in a centrifugal evaporator and evaporated to dryness at 40 degrees for 90 minutes. After confirming dryness, 3 ⁇ L of DMSO was added, redissolved, 300 ⁇ L of FaSSIF was added, shaken for 90 minutes with a constant temperature shaker at 25 ° C., and allowed to stand at the same temperature for 16 hours or more.
  • DMSO method Water-soluble solution precipitation method
  • FaSSIF Artificial fasting artificial intestinal fluid
  • Example 64 Evaluation of in vivo neuronal cell death inhibitory activity and safety using MPTP-induced Parkinson's disease mouse model MPTP (methy-phenyl-tetrahydopyridine) -induced Parkinson's disease model mice were used to evaluate the efficacy of many drugs for treating Parkinson's disease. in use. Using this model mouse, it is possible to evaluate the drug efficacy dose, and the safety at the time of 10-fold, 30-fold, preferably 100-fold dose administration. Evaluation of in vivo drug efficacy and safety such as weight loss, behavioral abnormalities, hematologic toxicity, and intestinal bleeding can be performed simultaneously. In this study, the effect of HUP0381 on experimental parkinsonism was evaluated using a mouse MPTP * -induced Parkinson model.

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US11673891B2 (en) 2017-11-14 2023-06-13 Dana-Farber Cancer Institute, Inc. Imidazopyrimidine compounds and uses thereof
US11730810B2 (en) 2017-11-14 2023-08-22 Children's Medical Center Corporation Composition comprising an antigen and a substituted imidazo[1,2-a]pyrimidine for enhancing human immune response
US11845753B2 (en) 2018-12-31 2023-12-19 Biomea Fusion, Inc. Inhibitors of menin-mll interaction
US12018032B2 (en) 2021-08-20 2024-06-25 Biomea Fusion, Inc. Crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(r)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as an irreversible inhibitor of menin-MLL interaction
KR102726437B1 (ko) 2018-12-31 2024-11-05 바이오메아 퓨전, 인크. 메닌-mll 상호작용의 비가역적 억제제

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