WO2019049869A1 - 五環式化合物 - Google Patents
五環式化合物 Download PDFInfo
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- WO2019049869A1 WO2019049869A1 PCT/JP2018/032797 JP2018032797W WO2019049869A1 WO 2019049869 A1 WO2019049869 A1 WO 2019049869A1 JP 2018032797 W JP2018032797 W JP 2018032797W WO 2019049869 A1 WO2019049869 A1 WO 2019049869A1
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- Prior art keywords
- pharmaceutically acceptable
- thieno
- acceptable salt
- dione
- diazepine
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- FXPGUOIKUKRLJQ-CMPLNLGQSA-N CN(CC1)Cc2c1c(C(N([C@H](CCC1)[C@H]1C(N(C)C1)=O)C1=N1)=O)c1[s]2 Chemical compound CN(CC1)Cc2c1c(C(N([C@H](CCC1)[C@H]1C(N(C)C1)=O)C1=N1)=O)c1[s]2 FXPGUOIKUKRLJQ-CMPLNLGQSA-N 0.000 description 2
- IXSSKGUUDABJCD-HCYNLOQUSA-N CC(C)(C)OC(CN(C)C([C@H](CCC1)[C@@H]1NC(OC(C)(C)C)=O)O)=O Chemical compound CC(C)(C)OC(CN(C)C([C@H](CCC1)[C@@H]1NC(OC(C)(C)C)=O)O)=O IXSSKGUUDABJCD-HCYNLOQUSA-N 0.000 description 1
- BUEPEVBYNBQNED-HTQZYQBOSA-N CC(C)(C)OC(N[C@H](CCC1)[C@@H]1C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1)[C@@H]1C(O)=O)=O BUEPEVBYNBQNED-HTQZYQBOSA-N 0.000 description 1
- BLLSMPCWRPCBDL-UHFFFAOYSA-N CCOC(c1c(N)[s]c2c1CCN(C)C2)=O Chemical compound CCOC(c1c(N)[s]c2c1CCN(C)C2)=O BLLSMPCWRPCBDL-UHFFFAOYSA-N 0.000 description 1
- LCMIAOHIRGAPDE-RNFRBKRXSA-N CN(CC(N[C@H]1[C@H]2CCC1)=O)C2=O Chemical compound CN(CC(N[C@H]1[C@H]2CCC1)=O)C2=O LCMIAOHIRGAPDE-RNFRBKRXSA-N 0.000 description 1
- GMFLMEHAXIVZLO-UHFFFAOYSA-N CN(CC(Nc1c2[s]cc1)=O)C2=O Chemical compound CN(CC(Nc1c2[s]cc1)=O)C2=O GMFLMEHAXIVZLO-UHFFFAOYSA-N 0.000 description 1
- YKFDFHUUDLXYIJ-UHFFFAOYSA-N CN(CC1)Cc2c1c(C(N(c1c(C(N(C)C3)=O)[s]cc1)C3=N1)=O)c1[s]2 Chemical compound CN(CC1)Cc2c1c(C(N(c1c(C(N(C)C3)=O)[s]cc1)C3=N1)=O)c1[s]2 YKFDFHUUDLXYIJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
Definitions
- the present invention relates to a pentacyclic compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof, which have cholinergic nerve cell stimulating and / or neuroprotective actions.
- the present invention also relates to a pharmaceutical composition containing the compound as an active ingredient.
- Non-patent Document 1 Cholinergic neurons that release acetylcholine as a transmitter project widely from the Vietnamese nucleus or septal nucleus in the basal forebrain to the hippocampus, the amygdala, and the cerebral cortex in the forebrain for memory, learning and cognition, It is responsible for adjusting attention.
- Non-patent Document 1 Cholinergic neurons in the peduncle and tegmental nucleus of the brainstem project to the striatum, nucleus accumbens, substantia nigra, and the thalamus, and are thought to be involved in the regulation of motivation and wakefulness. (Non-patent documents 2-4).
- Non-patent documents 5-7 Non-patent documents 5-7
- cholinesterase inhibitors increase the amount of acetylcholine and cause cholinergic neurons to It has been shown that cognitive function is improved by raising the function (non-patent documents 8 to 12).
- NGF Nerve Growth Factor
- AD Alzheimer type dementia
- shedding of cholinergic neurons is seen from the early stage of onset and is one of the pathological features of AD.
- senile plaque accumulation due to deposition of amyloid ⁇ and neurofibrillary tangles due to aggregation of tau are also pathological features, and neurofibrillary tangles in particular increase with the progress of pathological conditions and cause neuronal cell death. It is done.
- Neurofibrillary tangles are observed in the basal ganglia of the Meinert and in the entorhinal cortex from the early onset of AD.
- Non-patent documents 16-17 cholinergic neurons present in the basal ganglia of the Golt are shed by accumulation of tau from the early stage, and their shedding and cognitive function It is reported that the decrease in score is correlated (Non-patent documents 16-17).
- genetically modified mice Human tau P301S transgenic mice
- P301S mutation which was found from familial frontotemporal lobe dementia
- hyperphosphorylation and abnormal accumulation of tau are similar to AD. Get up.
- neurofibrillary tangles which are pathological features of AD, occur (Non-patent Document 18) and cause cognitive dysfunction due to synapse disorder, neurodegeneration and neuronal loss.
- Human tau P301S transgenic mice are widely used as AD-like model animals (Non-patent documents 19-22), and by suppressing AD-like pathological changes in Human tau P301S transgenic mice. Can be expected to improve cognitive decline and to suppress the progression of Alzheimer's disease.
- axonal transport disorder has been suggested as one of the causes of loss of cholinergic neurons from analysis using a plurality of genetically modified mice and animal models for injury (Non-Patent Document 23-25).
- the hippocampal craniolar arch dissection model impairs the axons of cholinergic neurons that project from the septal area to the hippocampus, and causes cell shedding by impeding retrograde transport of molecules involved in survival and function ( Non Patent Literature 26-28).
- This impairment in retrograde transport is also seen in genetically modified mice (Non-patent Documents 23 and 24), and the cholinergic neuronal loss due to hippocampal bursal arch reflects one aspect of the pathological condition. Therefore, by suppressing or improving the shedding of cholinergic neurons in this disorder model, it is possible to expect an improvement in cognitive function deterioration of Alzheimer's disease and an effect of suppressing the progression of a pathological condition.
- Dementia with Lewy bodies (DLB; Dementia with Lewy bodies), Parkinson's disease (PD); Parkinson's disease (PD; Parkinson's disease)
- the abnormal inclusion body (Levy body) which has alpha-synuclein as a main component appears in the nerve cell, It is a progressive neurodegenerative disease that causes degeneration and shedding.
- Levy body A large distribution of Lewy bodies in the cerebral cortex causes cognitive dysfunction etc., and a large distribution in the brainstem causes parkinsonism.
- mental symptoms such as hallucinations, hallucinations, delusions, and depressive symptoms, sleep disorders, and autonomic nervous symptoms are observed.
- Parkinson's disease accompanied by dementia is diagnosed as dementia with Lewy bodies if it develops before or within one year of the onset of Parkinsonism, but if Parkinsonism has been present for more than one year before the onset of dementia Diagnosed with (PDD; Parkinson disease with dementia).
- PDD Lewy body disease
- Lewy body dementia, Parkinson's disease with dementia, and Parkinson's disease become different diagnostic names: Considered identical, they are collectively referred to as Lewy body disease (LBD).
- Non-patent Documents 29-31 Dementia with Lewy bodies and Parkinson's disease with dementia, as with Alzheimer's disease, neurons in the basal ganglia of Meinert, which is the origin of acetylcholinergic nerves, are degenerated and dropped, and severe choline in hippocampus and cortex It has been reported that agonistic neuronal damage is seen (Non-patent Documents 29-31). In addition, the progression of cholinergic neuron injury is correlated with the cognitive decline (Non-patent Document 29), and it has been shown that the cholinesterase inhibitor improves the cognitive function.
- cognitive function is improved by improving the function of cholinergic neurons, and suppressing / ameliorating the shedding of cholinergic neurons in multiple impairment models is associated with Alzheimer's disease.
- Lewy-Body Dementia improvement in cognitive decline of Parkinson's disease accompanied by dementia, and the effect of suppressing the progression of the disease can be expected.
- Huntington's chorea Down's syndrome, muscle atrophy lateral sclerosis (ALS), major depressive disorder as a disease in which the association between cognitive dysfunction and cholinergic nerve cell dysfunction is reported besides the above-mentioned diseases Disorders, schizophrenia etc. may be mentioned.
- ALS muscle atrophy lateral sclerosis
- Lapchak PA et al. “Effect of recombinant human nerve growth factor on presynaptic cholinergic function in rat hippocampal slices following partial septohippocampal lesions: measures of [3H] acetylcholine synthetase, -49.
- Gilmor ML et al. “Coordinate expression of the vesicular acetylcholine transporter and choline acetyltransferase following septohippocampal pathway lesions” J. Neurochem. 71 (1998) 2411-20. Gu H et al.
- the subject of the present invention is a compound or compound having cholinergic nerve cell activation and / or neuroprotective activity and having potential as a therapeutic agent for Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease accompanied by dementia. It is providing the pharmaceutically acceptable salt.
- a pentacyclic compound having cholinergic nerve cell activating activity and / or neuroprotective activity or pharmaceutically acceptable thereof is Found salt.
- ⁇ 1> A compound selected from the following group or a pharmaceutically acceptable salt thereof: 3-fluoro-6,11-dimethyl-6,7,10,11,12,13-hexahydrobenzo [f] pyrido [4 ′ ′, 3 ′ ′: 4 ′, 5 ′] thieno [2 ′, 3 ': 4,5' Pyrimido [1,2-a] [1,4] diazepine-5,14-dione: 5,10-Dimethyl-5,6,9,10,11,12-hexahydropyrido [4 '', 3 '': 4 ', 5'] thieno [2 ', 3': 4,5] pyrimido [1,2-a] thieno [2,3-f] [1,4] diazepine-4,13-dione: 5,10-Dimethyl-5,6,9,10,11,12,13-hexahydrobenzo [f] pyrido [4
- ⁇ 9-1> The pharmaceutical composition according to ⁇ 8>, which is a cholinergic nerve cell activator.
- ⁇ 9-2> The pharmaceutical composition according to ⁇ 8>, which is a cholinergic neuroprotective agent.
- ⁇ 10> The pharmaceutical composition according to ⁇ 8> for the treatment of cognitive impairment.
- ⁇ 11> A therapeutic agent for cognitive impairment, comprising the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof.
- ⁇ 12> A method for treating cognitive impairment, which comprises administering the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof to a patient.
- ⁇ 13> The compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof, which is used for the treatment of cognitive impairment.
- ⁇ 14> Use of the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for cognitive impairment.
- a therapeutic agent for Alzheimer's disease which comprises the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof.
- a method for treating Alzheimer's disease which comprises administering the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof to a patient.
- ⁇ 17> The compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof, which is used for the treatment of Alzheimer's disease.
- ⁇ 18> Use of the compound of any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for Alzheimer's disease.
- a therapeutic agent for Lewy body type dementia comprising the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof.
- a method for treating dementia with Lewy bodies comprising administering to a patient a compound according to any one of ⁇ 20> ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof.
- ⁇ 21> The compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof, which is used for the treatment of Lewy-Body Dementia.
- ⁇ 22> Use of the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for dementia with Lewy bodies.
- a therapeutic agent for Parkinson's disease with dementia comprising the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof.
- a method for treating Parkinson's disease with dementia which comprises administering the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof to a patient.
- ⁇ 25> The compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof, which is used for the treatment of Parkinson's disease accompanied by dementia.
- ⁇ 26> Use of the compound according to any one of ⁇ 1> to ⁇ 7> or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for Parkinson's disease associated with dementia.
- the pentacyclic compounds represented by the formulas (I) to (VI) according to the present invention (hereinafter referred to as compounds (I) to (VI)) or pharmaceutically acceptable salts thereof can be subjected to the following pharmacological tests As shown in the activity data in the example, it has nerve cell activation and / or neuroprotection.
- the compounds (I) to (VI) of the present invention lead to the improvement of cognitive function through nerve cell activation action and / or neuroprotection action, thereby treating Alzheimer's disease, Lewy body dementia and Parkinson's disease accompanied by dementia. It has availability as an agent.
- the structural formula of a compound may represent a certain isomer for convenience
- the present invention may include rotamers or tautomers and mixtures thereof which occur in the structure of the compound, for convenience.
- the present invention is not limited to the description of the formula, and any one isomer or a mixture containing each isomer in any ratio may be used.
- the present invention is not limited thereto either, and may be a single substance or a mixture of any of the crystal forms, and in the present invention, it is amorphous.
- the body is also included, and the compounds according to the present invention include anhydrides and solvates (especially hydrates).
- the present invention also includes isotopically labeled compounds of Compounds (I) to (VI).
- Isotopically labeled compounds are compounds (I) to (I), except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Same as VI).
- the isotopes which can be incorporated into the compounds of the invention are, for example, the isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, iodine and chlorine, and 2 H, 3 H, 11 C, 14 C , 15 N, 18 O, 18 F, 32 P, 35 S, 123 I, and 125 I and the like.
- the isotopically labeled compounds described above are useful in drug and / or substrate tissue distribution assays.
- 3 H and 14 C are considered useful because of their ease of preparation and detection.
- the isotopes 11 C and 18 F are considered useful for PET (positron emission tomography), and the isotope 125 I is considered useful for SPECT (single photon emission computed tomography), all useful for brain imaging It is.
- Substitution with heavier isotopes, such as 2 H results in certain therapeutic benefits, such as increased in vivo half life or decreased required dose due to higher metabolic stability, and therefore, under certain circumstances It is considered useful.
- the isotopically labeled compounds are uniformly prepared by performing the procedures disclosed in the following examples, using readily available isotopically labeled reagents in place of non-isotopically labeled reagents. Can.
- the “pharmaceutically acceptable salt” in the present specification is not particularly limited as long as it can form a salt with the compound according to the present invention, and specifically, for example, inorganic acid salts, organic acid salts Or acid addition salts such as acidic amino acid salts.
- “pharmaceutically acceptable salt” means, unless otherwise specified, forming a salt in an appropriate ratio, in the formed salt, an acid per molecule of the compound.
- the number of molecules is not particularly limited, but preferably about 0.5 to about 2 molecules of acid per molecule of the compound, more preferably about 0.5, about 0.5 of acid per molecule of the compound. 1 or about 2 molecules.
- Preferred examples of the inorganic acid salt include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like
- preferred examples of the organic acid salt include, for example, acetate, succinate And fumarates, maleates, tartrates, citrates, lactates, stearates, benzoates, methanesulfonates, p-toluenesulfonates, benzenesulfonates and the like.
- Preferred examples of the acidic amino acid salt include, for example, aspartate, glutamate and the like.
- the salts which may be formed by the aforementioned compounds (I) to (VI) or the hydrates thereof may be prepared according to a conventional method. It can be converted.
- the compounds (I) to (VI) according to the present invention are obtained as salts of the compounds (I) to (VI) or hydrates of the compounds (I) to (VI), the compounds (I) to (VI) are It can be converted to the free form of) according to a conventional method.
- various isomers for example, optical isomers, rotational isomers, stereoisomers, etc.
- various isomers obtained for the compounds (I) to (VI) according to the present invention can be obtained by conventional separation means, for example, recrystallization, diastereomers It can be purified and isolated by using a mer salt method, an enzyme resolution method, various chromatography (eg, thin layer chromatography, column chromatography, gas chromatography, etc.).
- the pharmaceutical composition according to the present invention is produced by mixing a pharmaceutically acceptable additive with a compound selected from the compound groups (I) to (VI) or a pharmaceutically acceptable salt thereof.
- a pharmaceutically acceptable additive selected from the compound groups (I) to (VI) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition according to the present invention can be produced, for example, according to a known method such as the method described in General Formulas of Formulations of the 17th Amended Japanese Pharmacopoeia.
- composition according to the present invention can be suitably administered to a patient depending on its dosage form.
- the dose may vary depending on the age, but usually about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, more preferably 100 ⁇ g to 1 g orally administered per day for adults, and about 30 ⁇ g to 1 g preferably 100 ⁇ g 500 mg, more preferably 100 ⁇ g to 300 mg, is administered in one or more divided doses, respectively.
- the compound of the present invention can be a chemical probe for capturing a target protein of a physiologically active low molecular weight compound. That is, the compound of the present invention is different from the structural part essential for expression of the activity of the compound in a part different from J. Mass Spectrum. Soc. Jpn. Vol. 51, No.
- a labeling group, a linker or the like according to the method described in 5 2003, p 492-498 or WO 2007/139149, etc., it can be converted into an affinity chromatography probe, a photoaffinity probe or the like.
- Examples of the labeling group, linker and the like used for the chemical probe include groups shown in the group consisting of the following (1) to (5).
- Photoaffinity labeling group eg, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group, nitro group, etc.
- chemical affinity group eg, alpha carbon atom is halogen
- a protein labeling group such as an atom-substituted ketone group, carbamoyl group, ester group, alkylthio group, Michael acceptor such as ⁇ , ⁇ -unsaturated ketone, ester, and oxirane group
- cleavable linkers such as -SS-, -O-Si-O-, monosaccharides (such as glucose group and galactose group) or disaccharides (such as lactose), and oligopeptides cleavable by enzymatic reaction Linker
- Radioactive labeling groups such as 125 I, 32 P, 3 H, 14 C, etc .; fluorescein, rhodamine, dansyl, umbelliferone, 7-nitrofrazanyl, 3- (4,4-difluoro-5,7-dimethyl-4H -3a, 4a-Diaza-4-bora-s-indacen-3-yl) fluorescent labeling group such as propionyl group; chemiluminescent group such as luciferin and luminol; heavy metal ion such as lanthanoid metal ion and radium ion etc Markers, or (5) groups to be bound to a solid support such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, nylon beds and the like.
- a probe prepared by introducing a labeling group or the like selected from the group consisting of the above (1) to (5) into the compound of the present invention according to the method described in the above literature, etc. is a novel drug target. It can be used as a chemical probe for identification of a labeled protein useful for searching etc.
- room temperature in the following Examples and Preparation Examples usually indicates about 10 ° C to about 35 ° C. % Indicates weight percent unless otherwise stated.
- silica gel may be either Merck Gelica Silica gel 60 (70-230 mesh or 230-400 mesh ASTM) or Fuji Silysia Chemical PSQ60B, or pre-packed column ⁇ column: YAMAZEN Hi-Flash TM Column (Silicagel ), size; S (16 ⁇ 60mm), M (20 ⁇ 75mm), L (26 ⁇ 100mm), 2L (26 ⁇ 150mm), 3L (46 ⁇ 130mm) either, or Biotage Inc. Biotage TM SNAP Ultra of Silica Cartridge, size: 10 g, 25 g, or 50 g was used ⁇ .
- the residue was sodium bicarbonate (0.911 g, 10.8 mmol), methanol (24 mL), NMM (0.099 mL, 0.90 mmol), and DMT-MM (12.3% H 2 O, 1.80 g, 5. 70 mmol) were sequentially added at room temperature and stirred for 20 hours.
- the reaction mixture was concentrated under reduced pressure and the residue was washed with DCM.
- the washings were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 5-20% methanol / ethyl acetate) to give the title compound (745 mg).
- the reaction mixture was concentrated under reduced pressure.
- the residue was sodium bicarbonate (0.877 g, 10.4 mmol), methanol (24 mL), NMM (0.096 mL, 0.87 mmol), and DMT-MM (12.3% H 2 O, 1.73 g, 5. 48 mmol) were sequentially added at room temperature and stirred for 3 hours.
- the reaction mixture was concentrated under reduced pressure and the residue was washed with DCM.
- the washings were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 0-20% methanol / ethyl acetate) to give the title compound (753 mg).
- the reaction mixture was stirred at 80 ° C. for 20 hours.
- Sodium ethoxide (20% ethanol solution, 80 mL, 207 mmol) was added to the reaction mixture under ice-cooling and stirring.
- the reaction mixture was stirred at room temperature for 20 minutes.
- saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture.
- the organic layer was separated.
- the aqueous layer was extracted with ethyl acetate.
- the combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure.
- the reaction mixture was stirred at 70 ° C. for 2 hours and then at 90 ° C. for 5 hours.
- sodium ethoxide (20% solution in ethanol, 2.60 mL, 6.73 mmol) was added.
- the reaction mixture was stirred at room temperature for 40 minutes.
- Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
- the residue was purified by column chromatography (silica gel, 50% methanol / ethyl acetate) to give the title compound (90.0 mg).
- reaction mixture was stirred at room temperature for 5 minutes and at 90 ° C. for 2 hours.
- sodium ethoxide (20% ethanol solution, 21.7 mL, 56.1 mmol) was added over 5 minutes.
- the reaction mixture was stirred at room temperature for 1.5 hours.
- Ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water were sequentially added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% -50% methanol / ethyl acetate).
- Example 4 (3aS, 14aR) -5,10-dimethyl-3,3a, 5,6,9,10,11,12-octahydro-1H-cyclopenta [f] pyrido [4 '', 3 '': 4 ', 5 Synthesis of '] thieno [2 ′, 3 ′: 4,5] pyrimido [1,2-a] [1,4] diazepine-4,13 (2H, 14aH) -dione (5aS, 8aR) -4-methyloctahydrocyclopenta [e] [1,4] diazepine-2,5-dione (3.10 g, 17.0 mmol) obtained in Production Example 5- (2), Production Example Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-3-carboxylate (8.18 g, 34.0 mmol) and DCE (300 mL) obtained in 1.
- the reaction mixture was stirred at 70 ° C. for 2.5 hours, then brought to room temperature, and ethyl acetate (15 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) were added.
- the reaction mixture was stirred at room temperature for 5 days, ethyl acetate was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, 50-70% ethyl acetate / n-heptane).
- the reaction mixture was stirred at 60 ° C. for 3.5 hours and then returned to room temperature.
- ethyl acetate 15 mL
- saturated aqueous sodium hydrogen carbonate solution 30 mL
- the reaction mixture was stirred at room temperature for 5 days, ethyl acetate was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
- the residue was purified by column chromatography (NH silica gel, 40-80% ethyl acetate / n-heptane).
- Rat Primary Neuronal Cell Culture A septal area was isolated from an embryonic 18-day-old Sprague-Dawley (SD) rat (Charles River Japan, Inc.) and subjected to culture. Specifically, the fetus was aseptically isolated from pregnant rats under isoflurane anesthesia. Brains were removed from the fetus and immersed in ice cold L-15 medium (11415-064, Thermo Fisher Scientific). The septal area was collected from the isolated brain under a stereomicroscope. The collected septal area is treated with enzymes for 30 minutes at 37 ° C.
- the medium is Dulbecco's Modified Eagle's Medium (044-29765, WAKO) N2 supplement (17502-048, Thermo Fisher Scientific) and 1 mM Sodium pyruvate (11360-070, Thermo Fisher Scientific) and Penicillin streptomycin (15140-1221) , Thermo Fisher Scientific) was used.
- the cell mass to which the medium was added was redispersed by gentle pipetting operation, and then centrifuged again at 1000 rpm for 3 minutes to remove the supernatant. 10 mL of a culture medium was added to the obtained cell mass, and the cell dispersion was filtered with a 40 ⁇ m nylon mesh (Cell Strainer) to remove the cell mass to obtain a neuronal cell suspension.
- the neuronal cell suspension was diluted in medium and 10% inactivated bovine serum (26140-079, Thermo Fisher Scientific) and 10% inactivated horse serum were added. Thereafter, the cells were seeded at 100 ⁇ L / well in a 96-well incubator (354461, CORNING) previously coated with poly-D-lysine so that the initial culture density was 1.4 ⁇ 10 5 cells / cm 2 .
- the cultured cells were cultured for 2 days in a 37 ° C. incubator under 5% CO 2 -95% air, and then the whole medium was replaced with 120 ⁇ L of fresh medium, followed by 5 days of culture.
- the DMSO solution of the test compound was diluted in the medium to a final concentration of 10 times.
- NGF 450-01, PEPRO TECH, INC.
- the final DMSO concentration was less than 0.1%.
- only DMSO and NGF were added to the control group.
- ChAT choline acetyltransferase
- RNA purification was performed as described in the package insert of the kit. After RNA purification, total RNA concentration was measured by QIAxpert Instrument (QIAGEN).
- cDNA is SuperScript (registered trademark) VILO TM cDNA Synthesis Kit: was prepared using (# 11754 Thermo Fisher Scientific). Preparation of cDNA was carried out by the method described in the package insert of the kit. The prepared cDNA was diluted 4-fold with RNase free water, and the diluted cDNA solution was used as a sample.
- the test compound was orally administered at a dose of 10 mg / kg once a day for 3 days.
- the medium used 0.01 N hydrochloric acid aqueous solution.
- CSF was collected from the cistern into a tube containing an AChE inhibitor under pentobarbital anesthesia.
- the collected CSF was centrifuged at 3500 ⁇ g at 4 ° C. for 10 minutes, and the supernatant was recovered.
- the collected supernatant was frozen with liquid nitrogen and stored at -80.degree.
- ACh was precursor ion m / z 146.050, product ion m / z 87.071 (ACh d9 detected precursor ion m / z 155.088 and product ion m / z 87.000).
- the increase in ACh concentration in CSF of the test compound administration group was calculated as a percentage (% of control) relative to the ACh concentration in CSF of the vehicle administration group. The results are shown in Table 3.
- rat hippocampal craniotomy incision model Preparation of rat hippocampal ridge- arsenal section model
- Sprague-Dawley male rats (Nippon Charles River Co., Ltd.) having a weight of about 250 to 350 g were used.
- the rat was anesthetized with a mixture of midazolam 2 mg / kg subcutaneously, medetomidine hydrochloride 0.15 mg / kg subcutaneously and butorphanol tartrate tartrate 2.5 mg / kg subcutaneously, mixed, and anesthetized, and fixed in a brain stereotaxic apparatus (Narishige Co., Ltd.).
- the skull was exposed, and the right skull was drilled to a width of 5 mm from the midline 2 mm posterior to Bregma.
- a 4 mm wide razor was inserted into Bregma at a depth of 5.5 mm, and the hippocampal fistula-brain arch was cut. After hemostasis, the scalp was sutured, and the rat was returned to the cage after surgery to recover from anesthesia.
- the right skull was drilled to a width of 5 mm from the midline 2 mm posterior to Bregma, and the group without razor insertion was used as a sham operation group.
- test compound was orally administered once a day, 5 days to 9 days (Example 1: 10 mg / kg) or 7 days to 14 days (Example 3: 3 mg / kg).
- vehicle was 0.01 N hydrochloric acid aqueous solution, and the vehicle was orally administered once a day similarly to the compound in the sham operation group.
- Sampling Percent was perfused with ice cold PBS under pentobarbital anesthesia. After perfusion, the forebrain including the medial septal area was collected, immersed in 4% paraformaldehyde overnight, and shaken.
- ChAT Choline acetyltransferase
- DAB staining (DAB PEROXIDASE SUBSTRATE KIT (Vector, SK-4100)) was performed using a VAChT antibody (Merck Millipore, ABN 100). Take a section image including the medial septal area or hippocampus shown in The Rat Brain in stereotaxic coordinates (COMPACT THIRD EDITION, GEORGE PAXINOS & CHARLES WATSON) with an all-in-one fluorescence microscope (Keyence, BZ-X710), and use BZ analysis software (Keyence) The number of ChAT-positive cells in the medial septal area or the optical density (OD) of the hippocampus VAChT was measured according to.
- the result showed the number of ChAT-positive cells in the vehicle administration group and the test compound administration group or the OD of hippocampus VAChT in percentage in the medial septal area ChAT-positive cells in the sham operation group or the OD of the hippocampus VAChT as 100% .
- the results are expressed as mean ⁇ standard error.
- the difference between the vehicle administration group and the test compound group (significantly different: #) was analyzed by unpaired t-test. p ⁇ 0.05 was judged as a statistically significant difference.
- Statistical analysis was performed using GraphPad Prism version 7.02. The results are shown in Tables 5 and 6.
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Abstract
Description
<1>以下の群から選ばれる化合物またはその薬剤学的に許容される塩:
3-フルオロ-6,11-ジメチル-6,7,10,11,12,13-ヘキサヒドロベンゾ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-5,14-ジオン:
(3aS,14aS)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオン:
<2>3-フルオロ-6,11-ジメチル-6,7,10,11,12,13-ヘキサヒドロベンゾ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-5,14-ジオンまたはその薬剤学的に許容される塩:
<3>5,10-ジメチル-5,6,9,10,11,12-ヘキサヒドロピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a]チエノ[2,3-f][1,4]ジアゼピン-4,13-ジオンまたはその薬剤学的に許容される塩:
<4>5,10-ジメチル-5,6,9,10,11,12-ヘキサヒドロピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a]チエノ[3,2-f][1,4]ジアゼピン-4,13-ジオンまたはその薬剤学的に許容される塩:
<5>(3aS,14aR)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオンまたはその薬剤学的に許容される塩:
<6>(3aR,14aR)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオンまたはその薬剤学的に許容される塩:
<7>(3aS,14aS)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオンまたはその薬剤学的に許容される塩:
<8><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩および1以上の薬剤学的に許容される添加剤を含有する医薬組成物。
<9-1>コリン作動性神経細胞賦活剤である<8>記載の医薬組成物。
<9-2>コリン作動性神経細胞保護剤である<8>記載の医薬組成物。
<10>認知機能障害の治療のための<8>記載の医薬組成物。
<11><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、認知機能障害の治療剤。
<12><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を患者に投与する、認知機能障害の治療方法。
<13>認知機能障害の治療に使用される、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
<14>認知機能障害の治療剤を製造するための、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩の使用。
<15><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、アルツハイマー病治療剤。
<16><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を患者に投与する、アルツハイマー病の治療方法。
<17>アルツハイマー病の治療に使用される、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
<18>アルツハイマー病の治療剤を製造するための、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩の使用。
<19><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、レビー小体型認知症治療剤。
<20><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を患者に投与する、レビー小体型認知症の治療方法。
<21>レビー小体型認知症の治療に使用される、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
<22>レビー小体型認知症の治療剤を製造するための、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩の使用。
<23><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、認知症を伴うパーキンソン病治療剤。
<24><1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を患者に投与する、認知症を伴うパーキンソン病の治療方法。
<25>認知症を伴うパーキンソン病の治療に使用される、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
<26>認知症を伴うパーキンソン病の治療剤を製造するための、<1>~<7>のいずれか一項に記載の化合物またはその薬剤学的に許容される塩の使用。
本発明に係る医薬組成物は、薬剤学的に許容される添加物を化合物群(I)~(VI)から選ばれる化合物またはその薬剤学的に許容される塩と混和することにより製造することができる。本発明に係る医薬組成物は、例えば、第十七改正日本薬局方の製剤総則に記載の方法など既知の方法に従って製造することができる。
(1)光親和性標識基(例えば、ベンゾイル基、ベンゾフェノン基、アジド基、カルボニルアジド基、ジアジリジン基、エノン基、ジアゾ基およびニトロ基等)および化学親和性基(例えば、アルファー炭素原子がハロゲン原子で置換されたケトン基、カルバモイル基、エステル基、アルキルチオ基、α、β-不飽和ケトン、エステル等のマイケル受容体、およびオキシラン基等)等のタンパク質標識基、
(2)-S-S-、-O-Si-O-、単糖(グルコース基、ガラクトース基等)または二糖(ラクトース等)等の開裂可能なリンカー、および酵素反応で開裂可能なオリゴペプチドリンカー、
(3)ビオチン、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等のフィッシングタグ基、
(4)125I、32P、3H、14Cなどの放射性標識基;フルオレセイン、ローダミン、ダンシル、ウンベリフェロン、7-ニトロフラザニル、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等の蛍光標識基;ルシフェリン、ルミノール等の化学発光基;ランタノイド金属イオン、ラジウムイオン等の重金属イオン等の検出可能なマーカー、または
(5)ガラスビーズ、ガラスベット、マイクロタイタープレート、アガロースビーズ、アガロースベッド、ポリスチレンビーズ、ポリスチレンベッド、ナイロンビーズ、ナイロンベッド等の固相担体と結合させる基等。
DCE:1,2-ジクロロエタン
DCM:ジクロロメタン
DIPEA:N,N-ジイソプロピルエチルアミン
DMT-MM:4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウム クロリド
DMSO:ジメチルスルホキシド
EDC:1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート
HOBT:1-ヒドロキシベンゾトリアゾール
n-:ノルマル
NMM:N-メチルモルホリン
t-:ターシャリー
TBD:1,3,4,6,7,8-ヘキサヒドロ-2H-ピリミド[1,2-a]ピリミジン
TBME:ターシャリーブチルメチルエーテル
TEA:トリエチルアミン
THF:テトラヒドロフラン
1H-NMR:プロトン核磁気共鳴スペクトルメトリー
MS:マススペクトルメトリー
HPLC:高速液体クロマトグラフィー
エチル 2-アミノ-6-メチル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-3-カルボキシレートの合成
1H-NMR(400MHz,CDCl3)δ(ppm):1.33(t,J=7.0Hz,3H),2.44(s,3H),2.62-2.70(m,2H),2.79-2.88(m,2H),3.37(t,J=2.0Hz,2H),4.26(q,J=7.3Hz,2H),5.97(br.s,2H).
MS(ESI)m/z:241[M+H]+
7-フルオロ-4-メチル-3,4-ジヒドロ-1H-ベンゾ[e][1,4]ジアゼピン-2,5-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):3.30(s,3H),3.90(s,2H),6.97(dd,J=8.8,4.5Hz,1H),7.20(ddd,J=8.6,7.6,2.9Hz,1H),7.67(dd,J=9.0, 3.1Hz,1H),7.99(br.s,1H).
MS(ESI)m/z:209[M+H]+
4-メチル-3,4-ジヒドロ-1H-チエノ[3,2-e][1,4]ジアゼピン-2,5-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):3.24(s,3H),4.00(s,2H),6.72(d,J=5.3Hz,1H),7.52(d,J=5.3Hz,1H),7.96(br.s,1H).
MS(ESI)m/z:197[M+H]+
4-メチル-3,4-ジヒドロ-1H-チエノ[2,3-e][1,4]ジアゼピン-2,5-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):3.23(s,3H),3.99(s,2H),6.90(d,J=5.9Hz,1H),7.29(d,J=5.7Hz,1H),8.39(br.s,1H).
MS(ESI)m/z:197[M+H]+
(5aS,8aR)-4-メチルオクタヒドロシクロペンタ[e][1,4]ジアゼピン-2,5-ジオンの合成
(1S,2R)-2-((t-ブトキシカルボニル)アミノ)シクロペンタン-1-カルボン酸(CAS No.137170-89-9)(14.6g,63.6mmol)、サルコシンメチルエステル塩酸塩(CAS No. 13515-93-0)(10.7g,76.3mmol)およびTHF(150mL)の混合物へ、TEA(22.2mL,159mmol)、HOBT・一水和物(11.7g,76.3mmol)、およびEDC(14.6g,76.3mmol)を氷冷下に順次加えた。反応混合物を室温で15時間撹拌したのち、酢酸エチルと水を加え、有機層を分離した。水層を酢酸エチルで抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で順次洗浄し、無水硫酸ナトリウム上で乾燥し、ろ過し、減圧下に濃縮した。得られた残渣をカラムクロマトグラフィー(シリカゲル、25-30%酢酸エチル/n-ヘプタン)で2回精製して、標記化合物(16.1g)を得た。
MS(ESI)m/z:337[M+Na]+
(2)(5aS,8aR)-4-メチルオクタヒドロシクロペンタ[e][1,4]ジアゼピン-2,5-ジオンの合成
メチル 2-((1S,2R)-2-((t-ブトキシカルボニル)アミノ)-N-メチルシクロペンタンカルボキサミド)アセテート(16.1g,51.3mmol)へ、4N 塩化水素/1,4-ジオキサン溶液(160mL,640mmol)を氷冷下で加えた。反応混合物を同温で30分間撹拌し、ついで室温で45分撹拌した後、減圧下に濃縮した。残渣のメタノール(130ml)溶液へ、水冷下に、TBD(8.57g,61.6mmol)を加えた。反応混合物を水冷下に3時間撹拌したのち、0℃に冷却した。生じた固体をろ取し、氷冷したメタノールで3回洗浄し、減圧下に乾燥して標記化合物(5.22g)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.41-1.59(m,2H),1.78-1.98(m,2H),2.00-2.15(m,1H),2.36-2.53(m,1H),3.08(s,3H),3.18-3.32(m,1H),3.49(dd,J=15.5,1.7Hz,1H),3.91-4.04(m,1H),4.51(d,J=15.4Hz,1H),5.54(br.s,1H).
MS(ESI)m/z:183[M+H]+
(5aR,8aR)-4-メチルオクタヒドロシクロペンタ[e][1,4]ジアゼピン-2,5-ジオンの合成
(1R,2R)-t-ブトキシカルボニル-2-アミノシクロペンタンカルボン酸(CAS No.245115-25-7)(1.00g,4.36mmol)、サルコシンt-ブチルエステル塩酸塩(CAS No.136088-69-2)(872mg,4.80mmol)およびDCM(10mL)の混合物へ、DIPEA(1.81mL,10.5mmol)およびHATU(1.99g,5.23mmol)を室温で順次加えた。反応混合物を室温で1時間撹拌した後、直接カラムクロマトグラフィー(シリカゲル、30-50%酢酸エチル/n-ヘプタン)で精製して、標記化合物(1.61g)を得た。
MS(ESI)m/z:357[M+H]+
(2)(5aR,8aR)-4-メチルオクタヒドロシクロペンタ[e][1,4]ジアゼピン-2,5-ジオンの合成
t-ブチル 2-((1R,2R)-2-((t-ブトキシカルボニル)アミノ)-N-メチルシクロペンタンカルボキサミド)アセテート(1.61g,4.52mmol)へ4N 塩化水素/1,4-ジオキサン溶液(16mL,64mmol)を室温で加え、20時間撹拌した。反応混合物を減圧下濃縮した。残渣に炭酸水素ナトリウム(0.911g,10.8mmol)、メタノール(24mL)、NMM(0.099mL,0.90mmol)、およびDMT-MM(12.3%H2O,1.80g,5.70mmol)を室温で順次加え、20時間撹拌した。反応混合物を減圧下濃縮し、残渣をDCMで洗浄した。洗浄液を減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、5-20%メタノール/酢酸エチル)で精製して、標記化合物(745mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.56-1.88(m,3H),1.91-2.02(m,1H),2.13-2.23(m,1H),2.26-2.39(m,1H),3.07(s,3H),3.08-3.16(m,1H),3.51-3.62(m,1H),3.79(d,J=18.0Hz,1H),4.58(d,J=18.0Hz,1H),6.76(br.s,1H).
MS(ESI)m/z:183[M+H]+
(5aS,8aS)-4-メチルオクタヒドロシクロペンタ[e][1,4]ジアゼピン-2,5-ジオンの合成
(1S,2S)-t-ブトキシカルボニル-2-アミノシクロペンタンカルボン酸(CAS No.143679-80-5)(1.00g,4.36mmol)、サルコシンt-ブチルエステル塩酸塩(872mg,4.80mmol)、DIPEA(1.81mL,10.5mmol)およびDCM(10mL)の混合物へ、HATU(1.99g,5.23mmol)を室温で加えた。反応混合物を室温にて終夜撹拌した後、直接カラムクロマトグラフィー(シリカゲル、30-50%酢酸エチル/n-ヘプタン)で精製して、標記化合物(1.55g)を得た。
MS(ESI)m/z:357[M+H]+
(2)(5aS,8aS)-4-メチルオクタヒドロシクロペンタ[e][1,4]ジアゼピン-2,5-ジオンの合成
t-ブチル 2-((1S,2S)-2-((t-ブトキシカルボニル)アミノ)-N-メチルシクロペンタンカルボキサミド)アセテート(1.55g,4.35mmol)へ4N 塩化水素/1,4-ジオキサン溶液(16mL,64mmol)を室温で加え、16時間撹拌した。反応混合物を減圧下濃縮した。残渣に炭酸水素ナトリウム(0.877g,10.4mmol)、メタノール(24mL)、NMM(0.096mL,0.87mmol)、およびDMT-MM(12.3%H2O,1.73g,5.48mmol)を室温で順次加え、3時間撹拌した。反応混合物を減圧下濃縮し、残渣をDCMで洗浄した。洗浄液を減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、0-20%メタノール/酢酸エチル)で精製して、標記化合物(753mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.55-1.88(m,3H),1.91-2.02(m,1H),2.11-2.22(m,1H),2.25-2.40(m,1H),3.07(s,3H),3.07-3.16(m,1H),3.51-3.62(m,1H),3.78(d,J=18.0Hz,1H),4.57(d,J=18.0Hz,1H),6.54(br.s,1H).
MS(ESI)m/z:183[M+H]+
3-フルオロ-6,11-ジメチル-6,7,10,11,12,13-ヘキサヒドロベンゾ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-5,14-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):2.51(s,3H),2.66-2.76(m,1H),2.77-2.88(m,1H),3.04-3.18 (m,2H),3.25(s,3H),3.57-3.75(m,2H),4.09 (d,J=15.2Hz,1H),4.47(d,J=14.8Hz,1H),7.25-7.31(m,1H),7.60-7.64(m,1H),7.67(dd,J=9.0,4.7Hz,1H).
MS(ESI)m/z:385[M+H]+
5,10-ジメチル-5,6,9,10,11,12-ヘキサヒドロピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a]チエノ[2,3-f][1,4]ジアゼピン-4,13-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):2.51(s,3H),2.66-2.87(m,2H),3.07-3.20(m,2H),3.26(s,3H),3.56-3.74(m,2H),4.21(d,J=15.0Hz,1H),4.56(d,J=15.0Hz,1H),7.54(d,J=5.3Hz,1H),7.59(d,J=5.3Hz,1H).
MS(ESI)m/z:373[M+H]+
5,10-ジメチル-5,6,9,10,11,12-ヘキサヒドロピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a]チエノ[3,2-f][1,4]ジアゼピン-4,13-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):2.52(s,3H),2.71-2.87(m,2H),3.05-3.30(m,5H),3.59-3.75(m,2H),4.23(d,J=14.8Hz,1H),4.57(d,J=14.8Hz,1H),7.35(d,J=6.2Hz,1H),7.39(d,J=5.9Hz,1H).
MS(ESI)m/z:373[M+H]+
(3aS,14aR)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):1.51-1.73(m,2H),1.94-2.18(m,2H),2.30-2.41(m,1H),2.44-2.59(m,4H),2.71-2.82(m,2H),3.04-3.19(m,5H),3.42-3.54(m,1H),3.64(s,2H),4.17(d,J=15.6Hz,1H),4.75(d,J=15.6Hz,1H),5.69-5.82(m,1H).
MS(ESI)m/z:359[M+H]+
比旋光度:[α] D 20 -146.0(c 0.50,CHCl3)
HPLCによる分析;
(分析条件)カラム:CHIRALPAK IB(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:エタノール/ヘキサン=20/80(v/v),流速:1ml/min.,検出:UV(254nm)
(分析結果)標記化合物を上記分析条件で分析したところ、保持時間は10.38分であり、光学純度は>98%ee、旋光性は(-)であった。エナンチオマーの保持時間は、ラセミ体の出発原料を用いて同様に合成して確認した。
(3aR,14aR)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):1.29-1.49(m,1H),1.68-1.83(m,1H),1.82-2.21(m,3H),2.50(s,3H),2.76(t,J=5.7Hz,2H),2.98-3.23(m,6H),3.40-3.54(m,1H),3.57-3.68(m,2H),4.17-4.34(m,2H),5.30(d,J=17.4Hz,1H).
MS(ESI)m/z:359[M+H]+
HPLCによる分析;
(分析条件)カラム:CHIRALPAK IC(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:エタノール,流速:1mL/min.,検出:UV(254nm)
(分析結果)標記化合物の保持時間は6.64分であり、光学純度は>99%ee、旋光性は(-)であった。
(3aS,14aS)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオンの合成
1H-NMR(400MHz,CDCl3)δ(ppm):1.31-1.50(m,1H),1.69-1.83(m,1H),1.84-1.97(m,1H),1.97-2.20(m,2H),2.50(s,3H),2.73-2.80(m,2H),3.02-3.23(m,6H),3.41-3.55(m,1H),3.57-3.69(m,2H),4.19-4.34(m,2H),5.30(d,J=17.2Hz,1H).
MS(ESI)m/z:359[M+H]+
(分析条件)カラム:CHIRALPAK IC(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:エタノール,流速:1mL/min.,検出:UV(254nm)
(分析結果)標記化合物の保持時間は8.34分であり、光学純度は>99%ee、旋光性は(+)であった。
実施例1-6の化合物を用いて、以下の薬理試験を行った。
(1)ラット初代神経細胞培養
胎生18日齢のSprague-Dawley系(SD)ラット(日本チャールズリバー社)より中隔野を単離し培養に供した。具体的には、イソフルラン麻酔下、妊娠ラットより無菌的に胎仔を摘出した。胎仔より脳を摘出し、氷冷L-15 medium(11415-064、Thermo Fisher Scientific)に浸した。その摘出脳から、実体顕微鏡下で中隔野を採取した。採取した中隔野を、0.25% trypsin(15050-065、Thermo Fisher Scientific)および0.01% DNase(D5025-150KU,Sigma)を含有した酵素溶液中、37℃下30分間の酵素処理することにより、細胞を分散させた。この際、酵素反応は非働化済みウマ血清(26050-088、Thermo Fisher Scientific)を加えることで停止させた。この酵素処理溶液を1000rpmにて3分間遠心分離し、上清を除いた。得られた細胞塊に培地を10mL加えた。培地にはDulbecco‘s Modified Eagle’s Medium(044-29765、WAKO)にN2サプリメント(17502-048、Thermo Fisher Scientific)と1mM Sodium pyruvate(11360-070、Thermo Fisher Scientific)およびPenicilin streptmycin(15140-1221、Thermo Fisher Scientific)を用いた。培地が加えられた細胞塊を、緩やかなピペッティング操作により細胞を再分散後、再度1000rpmにて3分間遠心分離し、上清を除いた。得られた細胞塊に培地を10mL加え、この細胞分散液を40μmナイロンメッシュ(Cell Strainer)でろ過し、細胞塊を除くことにより神経細胞懸濁液を得た。この神経細胞懸濁液を培地にて希釈し、10%非働化済みウシ血清(26140-079、Thermo Fisher Scientific)と10%非働化済みウマ血清を加えた。その後、予めpoly-D-lysineにてコーティングされた96well培養器(354461、CORNING)に初期培養密度が1.4×105cells/cm2になるように100μL/wellにて播種した。播種した細胞は5%CO2-95%air下、37℃インキュベータ中にて二日培養した後、培地全量を新鮮な培地120μLと交換し、引き続き5日間培養した。
(2)化合物添加
培養7日目に薬物添加を以下の通りに行った。試験化合物のDMSO液を培地にて最終濃度の10倍になるように希釈した。NGF(450-01、PEPRO TECH,INC.)を0.3ng/mLに調製した。これらの2つの溶液をそれぞれ15μL/well添加し、よく混和した。最終DMSO濃度は0.1%以下とした。また、対照群にはDMSO及びNGFのみを添加した。
(3)ACh放出量測定
薬物添加1日後に、以下の方法でHPLCにてACh放出量を測定した。培地回収後のwellに温めたバッファーを100μL/well加え、直ぐにバッファーを除いた。その後、10μM choline、10μM physostigmineと6mM KClを加えたバッファーを120μL/well加えた。バッファーは、125mM NaCl、25mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、1.2mM KH2PO4、1.2mM MgSO4、2.2mM CaCl2(2H2O)、10mM Glucoseに滅菌水にて調製し、溶液の最終pHを7.4にした。バッファーを加えた96well培養器を5%CO2-95%air下、37℃インキュベータ中にて40分間インキュベートした後、80μLを回収した。回収したバッファーに内部標準液IPHC(5×10-7M)を6μL加え、HPLC測定用チューブにバッファーを移し、HPLC測定に供した。結果は、対照群のバッファー中ACh濃度に対する百分率(% of control)にて化合物の作用を示し、対照群のバッファー中ACh濃度に対して20%の上昇を示した化合物濃度を以下の表1に示す。
(1)化合物投与
本試験では体重約250-350gのSD雄性ラット(日本チャールズリバー社)を使用した。試験化合物は0.01規定塩酸に溶解し、経口投与した。
(2)サンプリング
試験化合物投与24時間目に、ペントバルビタール麻酔下で脳組織を摘出した。氷冷下で中隔野を分画し、液体窒素で凍結後-80℃にて保管した。
(3)ChAT mRNA発現量の測定
RNA精製にはRNeasy(登録商標) Plus Mini Kit(#74136:QIAGEN社)を使用した。RNA精製はキットの添付文書に記載の方法にて実施した。RNA精製後、total RNA濃度はQIAxpert Instrument(QIAGEN社)で測定した。cDNAはSuperScript(登録商標) VILOTM cDNA Synthesis Kit(#11754:Thermo Fisher Scientific)を使用して調製した。cDNAの調製はキットの添付文書に記載の方法で実施した。調製したcDNAをRNase free waterで4倍希釈し、希釈したcDNA溶液をサンプルとした。Taqman(登録商標) Universal PCR Master Mix(#4304437:Thermo Fisher Scientific)、Taqman(登録商標) Gene Expression Assays,INVENTORIED(#4331182:Thermo Fisher Scientific)、RNase free waterおよびcDNA溶液をそれぞれ10μL、1μL、4μLおよび5μlずつ混和し、測定サンプル溶液とした。Quantitative polymerase chain reaction(qPCR)はABI PRISM(登録商標) 7900HT(Thermo Fisher Scientific)を使用し、蛍光プローブ法で実施した。解析はSDS2.4(Thermo Fisher Scientific)で実施した。結果は媒体投与群のChAT mRNA発現量に対しての試験化合物投与群のChAT mRNA発現量の増加量を百分率で算出した。結果を以下の表2に示す。
(1)背景
脳内とCerebrospinal fluid(CSF)中の神経伝達物質の増減は相関することが齧歯類の研究から明らかとなり、その相関はヒトにおいても同様に捉えられることが明らかとなっている(Lowe S et al. Psychopharmacology 219 (2012) 959-70.)。そこで、試験化合物による脳内のアセチルコリン量変化を検出するために、CSF中アセチルコリン量変化を評価した。
(2)化合物投与
本試験では体重約150-250gのFischer344系雄性ラット(日本チャールズリバー社)を使用した。試験化合物は1日1回、3日間、10mg/kg経口投与した。媒体は0.01規定塩酸水溶液を使用した。
(3)サンプリング
媒体および試験化合物の最終投与24時間後に、ペントバルビタール麻酔下で大槽からAChE阻害剤入りのチューブにCSFを採取した。採取したCSFを3500xg、4℃で10分間遠心し、上清を回収した。回収した上清を液体窒素で凍結後、-80℃にて保管した。
(4)LCMSを用いたACh測定
内標準物質としてCSF 10μLに最終濃度0.34nmol/L acetylcholine-d9 chloride(ACh-d9)を50μL加えた。ピペッティングにて混和後、1200xg、4℃で10分間遠心した。上清を回収し,LC/MS法(NexeraX2(MS)、TSQ Altis(HPLC))により、AChはprecursor ion m/z 146.050、product ion m/z 87.071を(内標のACh-d9はprecursor ion m/z 155.088、product ion m/z 87.000)を検出した。結果は、媒体投与群のCSF中ACh濃度に対しての試験化合物投与群のCSF中ACh濃度増加を百分率(% of control)で算出した。結果を表3に示す。
(1)化合物投与
本試験では4ヶ月齢から7ヶ月齢までの約3ヶ月間、Human tau P301S transgenicマウスに1日1回,試験化合物を経口投与した。媒体は0.01規定塩酸水溶液を使用した。
(2)サンプリング
投与開始日に投与開始時群(4ヶ月齢)、最終投与翌日に媒体投与群及び試験化合物投与群にペントバルビタール(50mg/kg,ip)で麻酔後,PBSで経心的に灌流した。灌流後,内側中隔野を含む前脳を採取し,4%パラホルムアルデヒドで固定した。
(3)脳冠状凍結切片作製
採取した内側中隔野を含む前脳を4%パラホルムアルデヒドで一晩浸漬、振とうした後、7.5%スクロース溶液に置換した。翌日に7.5%スクロース溶液に置換し一晩浸漬、振とう後、15%スクロース溶液に置換しさらに一晩浸漬、振とうした。浸漬液を30%スクロース溶液に置換し一晩浸漬、振とう後、内側中隔野を含む前脳のサンプルから滑走式ミクロトーム(Leica,SM2000R)を用いて30μmの厚さの脳冠状凍結切片を作製した。
(4)Choline acetyltransferase(ChAT)陽性細胞数の免疫組織学的定量
作製した脳冠状凍結切片を用いて,一次抗体としてChAT抗体(SantaCruz,SC-20672)を使用し,DAB染色(DAB PEROXIDASE SUBSTRATE KIT(Vector,SK-4100))を行った。オールインワン蛍光顕微鏡(キーエンス,BZ-X710)でThe mouse Brain in stereotaxic coordinates(COMPACT THIRD EDITION, Keith B.J. Franklin & Geroge Paxinos)に示される内側中隔野を含む切片画像を撮影し、BZ解析ソフト(キーエンス)によりその内側中隔野の主軸沿いに存在するChAT陽性細胞数の計測を行った。結果は投与開始時群(4ヶ月齢)のChAT陽性細胞数を100%としたときの媒体投与群と試験化合物投与群のChAT陽性細胞数を百分率で示した。結果は平均値±標準誤差で表した。投与開始時群と媒体投与群間の差(有意差あり:*)及び媒体投与群と試験化合物群の差(有意差あり:#)はそれぞれ対応のないt検定で解析した。p<0.05を統計学的有意差として判断した。統計解析はGraphPad Prism version 7.02を用いて行った。結果を表4に示す。
(1)ラット海馬采-脳弓切断モデルの作製
本試験では体重約250-350gのSprague-Dawley系雄性ラット(日本チャールズリバー社)を使用した。ラットをミダゾラム2mg/kg皮下投与、塩酸メデトミジン0.15mg/kg皮下投与、酒石酸ブトルファノール2.5mg/kg皮下投与の三種を混合して麻酔し、脳定位固定装置(株式会社ナリシゲ)に固定した。頭蓋を露出し、Bregmaより2mm後方の正中線から右側頭蓋骨を横幅5mmにドリルで穴をあけた。4mm幅のカミソリをBregmaより深さ5.5mmに刺入し、海馬采-脳弓を切断した。止血後、頭皮を縫合し、手術後ラットをケージにもどし麻酔から回復させた。Bregmaより2mm後方の正中線から右側頭蓋骨を横幅5mmにドリルで穴をあけ、カミソリを刺入しない群を偽手術群とした。
(2)化合物投与
手術5日後から9日間(実施例1:10mg/kg)、または7日後から14日間(実施例3:3mg/kg)、1日1回、試験化合物を経口投与した。媒体は0.01規定塩酸水溶液を使用し、偽手術群も化合物同様に1日1回、媒体を経口投与した。
(3)サンプリング
ペントバルビタール麻酔下で氷冷PBSで経心的に灌流した。灌流後,内側中隔野を含む前脳を採取し,4%パラホルムアルデヒドに一晩浸漬、振とうした。翌日に7.5%スクロース溶液に置換し一晩浸漬、振とう後、15%スクロース溶液に置換しさらに一晩浸漬、振とうした。浸漬液を30%スクロース溶液に置換し一晩浸漬、振とう後、内側中隔野を含む前脳のサンプルから滑走式ミクロトーム(Leica,SM2000R)を用いて30μmの厚さの脳冠状凍結切片を作製した。
(4)Choline acetyltransferase(ChAT)陽性細胞数およびvesicular acetylcholine transporter〈VAChT〉の免疫組織学的定量
作製した脳冠状凍結切片を用いて,一次抗体としてChAT抗体(SantaCruz,SC-20672)またはVAChT抗体(Merck Millipore,ABN100)を使用し,DAB染色(DAB PEROXIDASE SUBSTRATE KIT(Vector,SK-4100))を行った。オールインワン蛍光顕微鏡(キーエンス,BZ-X710)でThe Rat Brain in stereotaxic coordinates (COMPACT THIRD EDITION, GEORGE PAXINOS & CHARLES WATSON)に示される内側中隔野または海馬を含む切片画像を撮影し、BZ解析ソフト(キーエンス)により内側中隔野のChAT陽性細胞数または海馬VAChTの光学密度(Optical density,OD)の計測を行った。結果は、偽手術群の内側中隔野ChAT陽性細胞数または海馬VAChTのODを100%としたときの媒体投与群と試験化合物投与群のChAT陽性細胞数または海馬VAChTのODを百分率で示した。結果は平均値±標準誤差で表した。媒体投与群と試験化合物群の差(有意差あり:#)はそれぞれ対応のないt検定で解析した。p<0.05を統計学的有意差として判断した。統計解析はGraphPad Prism version 7.02を用いて行った。結果を表5、表6に示す。
Claims (17)
- 以下の群から選ばれる化合物またはその薬剤学的に許容される塩:
3-フルオロ-6,11-ジメチル-6,7,10,11,12,13-ヘキサヒドロベンゾ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-5,14-ジオン:
(3aS,14aS)-5,10-ジメチル-3,3a,5,6,9,10,11,12-オクタヒドロ-1H-シクロペンタ[f]ピリド[4’’,3’’:4’,5’]チエノ[2’,3’:4,5]ピリミド[1,2-a][1,4]ジアゼピン-4,13(2H,14aH)-ジオン:
- 請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩および1以上の薬剤学的に許容される添加剤を含有する医薬組成物。
- 請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、アルツハイマー病治療剤。
- 請求項1記載の化合物またはその薬剤学的に許容される塩を患者に投与する、アルツハイマー病の治療方法。
- アルツハイマー病の治療に使用される、請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
- 請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、レビー小体型認知症治療剤。
- 請求項1記載の化合物またはその薬剤学的に許容される塩を患者に投与する、レビー小体型認知症の治療方法。
- レビー小体型認知症の治療に使用される、請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
- 請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩を含有する、認知症を伴うパーキンソン病治療剤。
- 請求項1記載の化合物またはその薬剤学的に許容される塩を患者に投与する、認知症を伴うパーキンソン病の治療方法。
- 認知症を伴うパーキンソン病の治療に使用される、請求項1~7のいずれか一項に記載の化合物またはその薬剤学的に許容される塩。
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AU2018330578A AU2018330578B2 (en) | 2017-09-07 | 2018-09-05 | Pentacyclic compound |
RS20220015A RS62796B1 (sr) | 2017-09-07 | 2018-09-05 | Pentaciklično jedinjenje |
BR112020003197-6A BR112020003197A2 (pt) | 2017-09-07 | 2018-09-05 | composto pentacíclico |
KR1020207004232A KR102307738B1 (ko) | 2017-09-07 | 2018-09-05 | 펜타시클릭 화합물 |
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IL272652A IL272652B (en) | 2017-09-07 | 2018-09-05 | A pentacyclic compound, the pharmaceutical compounds that make it up and their use for the treatment of Alzheimer's disease |
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MDE20200725T MD3680243T2 (ro) | 2017-09-07 | 2018-09-05 | Compus pentaciclic |
ES18853415T ES2903172T3 (es) | 2017-09-07 | 2018-09-05 | Compuesto pentacíclico |
MA50093A MA50093B1 (fr) | 2017-09-07 | 2018-09-05 | Composé pentacyclique |
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JOP/2020/0030A JOP20200030A1 (ar) | 2017-09-07 | 2018-09-05 | مركب خماسي الحلقة |
MX2020001786A MX2020001786A (es) | 2017-09-07 | 2018-09-05 | Compuesto pentaciclico. |
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CA3072740A CA3072740A1 (en) | 2017-09-07 | 2018-09-05 | Pentacyclic compound |
CONC2020/0001471A CO2020001471A2 (es) | 2017-09-07 | 2020-02-11 | Compuesto pentacíclico |
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PH12020500341A PH12020500341A1 (en) | 2017-09-07 | 2020-02-14 | Pentacyclic compound |
CY20221100025T CY1125355T1 (el) | 2017-09-07 | 2022-01-10 | Πεντακυκλικη ενωση |
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WO2020179781A1 (ja) * | 2019-03-05 | 2020-09-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 五環式化合物の塩およびそれらの結晶 |
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CN109467538A (zh) | 2017-09-07 | 2019-03-15 | 和记黄埔医药(上海)有限公司 | 环烯烃取代的杂芳环类化合物及其用途 |
JP2020533317A (ja) | 2017-09-07 | 2020-11-19 | オーガスタ ユニバーシティ リサーチ インスティテュート,インコーポレーテッド | 特異的akt3活性化剤およびその使用 |
EP4069369A4 (en) * | 2019-12-06 | 2024-02-14 | Schrödinger, Inc. | CYCLIC COMPOUNDS AND METHODS OF USE THEREOF |
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