JP7314259B2 - ペプチドボロン酸エステル類化合物の合成及び使用 - Google Patents
ペプチドボロン酸エステル類化合物の合成及び使用 Download PDFInfo
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- JP7314259B2 JP7314259B2 JP2021517089A JP2021517089A JP7314259B2 JP 7314259 B2 JP7314259 B2 JP 7314259B2 JP 2021517089 A JP2021517089 A JP 2021517089A JP 2021517089 A JP2021517089 A JP 2021517089A JP 7314259 B2 JP7314259 B2 JP 7314259B2
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
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- VDPIZIZDKPFXLI-UHFFFAOYSA-N 1-iodo-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(I)=CC(C(F)(F)F)=C1 VDPIZIZDKPFXLI-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- HWXBTNAVRSUOJR-UHFFFAOYSA-N 2-hydroxyglutaric acid Chemical compound OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 description 1
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- BNMPIJWVMVNSRD-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NO1 BNMPIJWVMVNSRD-UHFFFAOYSA-N 0.000 description 1
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- KRGKCYHAKAXSKM-UHFFFAOYSA-N B(O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O Chemical compound B(O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRGKCYHAKAXSKM-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102100025566 Chymotrypsin-like protease CTRL-1 Human genes 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 101000856199 Homo sapiens Chymotrypsin-like protease CTRL-1 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- 230000003698 anagen phase Effects 0.000 description 1
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- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
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- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- RUOCNJROFJABJC-UHFFFAOYSA-N boric acid;2,3-dihydroxybutanedioic acid Chemical compound OB(O)O.OC(=O)C(O)C(O)C(O)=O RUOCNJROFJABJC-UHFFFAOYSA-N 0.000 description 1
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- 239000013592 cell lysate Substances 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- NSHIYIMHYBAIEY-UHFFFAOYSA-N ethyl hypochlorite Chemical group CCOCl NSHIYIMHYBAIEY-UHFFFAOYSA-N 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000003677 hemocyte Anatomy 0.000 description 1
- 229940000351 hemocyte Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000006301 indolyl methyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- VVPPFDYWMFZCDG-HNNXBMFYSA-N methyl (2S)-2-(1,3-dioxoisoindol-2-yl)-3-[4-(trifluoromethyl)phenyl]propanoate Chemical compound C1(C=2C(C(N1[C@H](C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F)=O)=CC=CC=2)=O VVPPFDYWMFZCDG-HNNXBMFYSA-N 0.000 description 1
- HHFROSANQBEFJL-HNNXBMFYSA-N methyl (2S)-2-[(2,5-dichlorobenzoyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoate Chemical compound COC([C@@H](NC(C1=C(C=CC(=C1)Cl)Cl)=O)CC1=CC=C(C=C1)C(F)(F)F)=O HHFROSANQBEFJL-HNNXBMFYSA-N 0.000 description 1
- OJXILQSWGOESHA-NSHDSACASA-N methyl (2s)-2-[(2-methoxyacetyl)amino]-3-phenylpropanoate Chemical compound COCC(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 OJXILQSWGOESHA-NSHDSACASA-N 0.000 description 1
- 229940078547 methylserine Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- LJPYJRMMPVFEKR-UHFFFAOYSA-N prop-2-ynylurea Chemical compound NC(=O)NCC#C LJPYJRMMPVFEKR-UHFFFAOYSA-N 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000004906 unfolded protein response Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
R1は、C1~10アルキル、C1~10アルコキシ、C1~10アルコキシC1~10アルキル、C3~6シクロアルキル、フェニル、ナフチル、テトラリニル、2,5-ジクロロフェニル又は複素環基から選択される、或いは、C1~4アルキル、C1~4アルコキシ、C1~4シクロアルキル、ハロゲン又はハロC1~4アルキルで任意に置換され、R1としては、好ましくはC1~10アルキル、C1~10アルコキシ、C1~10アルコキシメチル、C1~10アルコキシエチル、C3~6シクロアルキル、フェニル、2,5-ジクロロフェニル、ピラジニル、ピリジル、ナフチル、テトラリニル、オキサゾリル又はイソキサゾリルである、或いは、C1~4アルキル、C1~4アルコキシ、ハロゲン又はハロC1~4アルキルで任意に置換される。
本発明の化合物の調製は以下の過程により実施することができる。
フタルイミドをDMFに溶解し、トリエチルアミンを添加し、0℃で反応系にクロロ酢酸エチルを滴下し、ゆっくりと室温まで上昇させた後、2時間反応させ、反応液を氷水に注ぎ、濾過し、濾過ケーキを氷水で洗浄し、真空乾燥して純粋な(式II-1)の化合物を得た。
化合物II-1及びL-アラニンをH2Oに溶解し、Na2CO3を添加して2時間反応させ、1NのHClを添加してpHを2に調節し、濾過し、真空乾燥して純粋な(式II-2)の化合物を得た。
化合物II-2をCH2Cl2に溶解し、SOCl2を添加して6時間凝縮還流させ、溶媒を減圧留去した。8-アミノキノリン及びDIPEAをCH2Cl2に溶解し、-20℃でCH2Cl2に溶解した酸クロリドを滴下し、ゆっくりと室温まで上昇させ、一晩反応させた。溶媒を減圧留去し、カラムクロマトグラフィーにより分離して化合物II-3を得た。
化合物II-3をt-ブチルアルコールに溶解し、酢酸パラジウム、テトラフルオロホウ酸銀及びヨウ化アルキルを添加し、24時間凝縮還流させ、室温に戻した後、CH2Cl2で希釈し、トリエチルアミンを添加して3時間反応させ、珪藻土を通過させ、溶媒を減圧留去し、カラムクロマトグラフィーにより分離して化合物II-4を得た。
厚肉耐圧フラスコに、化合物II-4をMeOHに溶解し、三フッ化ホウ素エーテラート溶液を滴下し、100℃で一晩反応させ、トリエチルアミンを添加して撹拌し、溶媒を減圧留去し、CH2Cl2に溶解した後、それぞれ酸洗浄(10%塩酸)、アルカリ洗浄(5%炭酸水素ナトリウム)及び飽和食塩水洗浄を行い、乾燥剤(無水硫酸ナトリウム及び無水硫酸マグネシウム)で乾燥させた。乾燥剤を濾過除去し、溶媒を減圧下で蒸発乾燥し、カラムクロマトグラフィーにより分離して化合物II-5を得た。
化合物II-5をMeOHに溶解し、エチレンジアミンを添加し、70℃で5時間凝縮還流させて反応させ、濾過し、濾液から溶媒を減圧下で蒸発乾燥し、カラムクロマトグラフィーにより分離して化合物IIを得た。
R1-COOHをCH2Cl2に溶解し、1-ヒドロキシベンゾトリアゾール(HOBt)を添加し、-5℃で10分間反応させた後、ペプチド縮合剤(EDC・HCl)を添加し、20分間反応させ、化合物II又はIIIを添加し、10分間後、N,N-ジイソプロピルエチルアミン(DIPEA)を添加し、30分間反応させた後、室温で一晩撹拌した。反応液に対してそれぞれ酸洗浄(10%塩酸)、アルカリ洗浄(5%炭酸水素ナトリウム)及び飽和食塩水洗浄を行い、乾燥剤(無水硫酸ナトリウム及び無水硫酸マグネシウム)で乾燥させた。乾燥剤を濾過除去し、溶媒を減圧下で蒸発乾燥し、カラムクロマトグラフィーにより分離して化合物I-1を得た。
化合物I-1をMeOHに溶解し、LiOH・H2O及びH2Oを添加し、3時間反応させた後、MeOHを減圧留去し、1NのHClを添加してpHを2に調節し、酢酸エチルで抽出して分液し、溶媒を減圧下で蒸発乾燥し、化合物I-2を得た。
化合物I-2をCH2Cl2に溶解し、1-ヒドロキシベンゾトリアゾール(HOBt)を添加し、-5℃で10分間反応させた後、ペプチド縮合剤(EDC・HCl)を添加し、20分間反応させ、ボレートの塩酸塩又はトリフルオロ酢酸塩を添加し、10分間後、N,N-ジイソプロピルエチルアミン(DIPEA)を添加し、30分間反応させた後、室温で一晩撹拌した。反応液に対してそれぞれ酸洗浄(10%塩酸)、アルカリ洗浄(5%炭酸水素ナトリウム)及び飽和食塩水洗浄を行い、乾燥剤(無水硫酸ナトリウム及び無水硫酸マグネシウム)で乾燥させた。乾燥剤を濾過除去し、溶媒を減圧下で蒸発乾燥し、カラムクロマトグラフィーにより分離して化合物I-3を得た。
化合物I-3をMeOHに溶解し、イソブチルボロン酸、n-ヘキサン及び1NのHClを添加し、一晩反応させた。分液し、MeOHでn-ヘキサン相を2回抽出し、更にn-ヘキサンでメタノール相を1回洗浄し、メタノールを減圧留去し、CH2Cl2で水相を2回抽出し、水相が中性になるまで飽和食塩水で有機相を洗浄した。溶媒を減圧下で蒸発乾燥し、カラムクロマトグラフィーにより分離して化合物IVを得た。
74℃でグリコールを含むアミン又は酸を酢酸エチルに溶解し、化合物IVを添加し、60℃まで降下させ、3時間反応させ、更に25℃まで降下させて一晩反応させた。濾過し、真空乾燥して純粋な(式I)化合物を得た。
フタルイミド(7.36g、50mmol)をDMF(25mL)に溶解し、トリエチルアミン(9mL、65mmol)を添加し、0℃で反応系にクロロ酢酸エチル(5.7mL、60mmol)を滴下し、ゆっくりと室温まで上昇させた後、TLCで反応を確認し、2h後に反応が終了した後、反応液を氷水に注ぎ、濾過し、濾過ケーキを氷水で洗浄し、真空乾燥して純粋なN-フタルイミドエチルアセテート8.67gを得た。収率79.1%, mp 81.4~83.6℃。1H NMR (400 MHz, CDCl3) δ 1.44 (-CH3, t, J = 7.1 Hz, 3H), 4.48 (-CH2, q, J = 7.1 Hz, 2H), 7.80 - 7.85 (-Ph, m, 2H), 7.93 - 7.99 (-Ph, m, 2H)。MS (ESI): m/z 220.1 [M+H]+。
化合物II-1(21.9g、100mmol)及びL-アラニン(8.9g、10mmol)をH2O(100mL)に溶解し、Na2CO3(10.6g、100mmol)を添加し、TLCで反応を確認し、2h後に反応が終了した後、1NのHClを添加してpHを2に調節し、濾過し、真空乾燥して純粋な(式II-2)化合物17.4gを得た。収率79.3%, mp 145.8~146.6℃。1H NMR(400 MHz, CDCl3) δ 1.71 (-CH3, d, J = 7.4 Hz, 3H), 5.02 (-CH, q, J = 7.4 Hz, 1H), 7.69 - 7.75 (-Ph, m, 2H), 7.82 - 7.88 (-Ph, m, 2H)。MS (ESI): m/z218.2 [M-H]-。
化合物II-2(17.37g、79.25mmol)をCH2Cl2(80mL)に溶解し、SOCl2(29mL、396.25mmol)を添加して6時間凝縮還流させ、溶媒を減圧留去した。8-アミノキノリン(11.4g、79.25mmol)及びDIPEA(20.5g、158.5mmol)をCH2Cl2(103mL)に溶解し、-20℃でCH2Cl2(31mL)に溶解した酸クロリドを滴下し、滴下終了後、ゆっくりと室温まで上昇させ、一晩反応させた。TLCで反応を確認し、溶媒を減圧留去し、カラムクロマトグラフィーにより分離してII-3化合物21.2gを得た。収率77.42%, mp 180.0~181.9℃。1H NMR (400 MHz, CDCl3) δ 1.98 (-CH3, d, J = 7.3 Hz, 3H), 5.27 (-CH, q, J = 7.5 Hz, 1H), 7.42 (-Ph, dd, J1 = 4.2 Hz, J2 = 8.3 Hz, 1H), 7.51 (-Ph, s, 1H), 7.53 (-Py, d, J = 9.0 Hz, 1H), 7.65 - 7.85 (-Ph, m, 2H), 7.90 (-Ph, dt, J1 = 3.6 Hz, J2 = 7.1 Hz, 2H), 8.15 (-Py, d, J = 8.3 Hz, 1H), 8.69 (-Ph, d, J = 4.2 Hz, 1H), 8.73 (-Py, dd, J1 = 4.7 Hz, J2 = 8.9 Hz, 1H), 10.33 (-CONH, s, 1H)。MS(ESI): m/z346.0 [M+H]+。
(1)(S)-2-(フタルイミド)-N-(8-キノリル)-3-(4-(トリフルオロメチル)フェニル)プロピオンアミド(II-4a)の調製
BOC-L-セリンメチルエステル(5g、22.8mmol)をアセトン(110mL)に溶解し、ヨウ化メチル(32mL、524mmol)及び酸化銀(8.2g、35.4mmol)を添加し、59℃で暗所で一晩凝縮還流させた。TLCで反応を確認し、濾過し、溶媒を減圧留去し、カラムクロマトグラフィーにより分離して油状の目的化合物1.8gを得た。収率34.5%。1H NMR (400 MHz, CDCl3) δ 1.43 (-CH3, s, 9H), 3.32 (-CH3, s, 3H), 3.57 (-CH2, dd, J1 = 3.4 Hz, J2 = 9.4 Hz, 1H), 3.74 (-CH3, d, J = 6.3 Hz, 3H), 3.78 (-CH2, dd, J1 = 3.1 Hz, J2 = 9.4 Hz, 1H), 4.35 - 4.44 (-CH, m, 1H), 5.28 - 5.44 (-CONH, m, 1H)。MS (ESI): m/z 234.2 [M+H]+。
化合物IIIe-1(496mg、2.1mmol)を酢酸エチル(2.5mL)に溶解し、氷浴にてHClの酢酸エチル溶液(5.2mL、21.2mmol)を滴下し、室温で反応させ、TLCで反応を確認し、2h後に反応が終了した後、濾過し、濾過ケーキを真空乾燥して純粋な生成物351mgを得た。収率97.5%。1H NMR (400 MHz, CDCl3) δ 3.41 (-CH3, s, 3H), 3.83 (-CH3, s, 3H), 3.95 (-CH2, dd, J1 = 3.6 Hz, J2 = 10.4 Hz, 1H), 4.03 (-CH2, dd, J1 = 2.6 Hz, J2 = 10.3 Hz, 1H), 4.45 (-CH, s, 1H), 8.70 (-NH3 +, s, 3H)。
L-システイン塩酸塩一水和物(3.1g、17.5mmol)をMeOH(45mL)に溶解し、氷浴にて30%のナトリウムメトキシドのメタノール溶液(11.2g、62mmol)を滴下し、1h反応させた後、ヨウ化メチル(0.9mL、13mmol)を滴下し、室温まで上昇させて反応させ、TLCで反応を確認し、2h後に反応が終了した後、10NのHClでpHを5に調節し、40mLのエチルエーテルを添加して10min撹拌し、濾過し、濾過ケーキを60mLのエチルエーテルで洗浄し、真空乾燥し、粗製品4.715gを得た。
S-メチル-L-システイン(4.715g、34.9mmol)をMeOH(25mL)に溶解し、氷塩浴にて-10℃まで冷却し、撹拌しながらゆっくりとSOCl2(25mL、348.8mmol)を滴下し、滴下終了後、10min反応させ、氷塩浴を取り除き、室温で一晩反応させ、TLCで反応を確認し、濾過し、濾過ケーキをCH2Cl2で洗浄し、真空乾燥して純粋なS-メチル-L-システインメチルエステル塩酸塩3.1gを得た。収率95.4%。1H NMR(400 MHz, D2O) δ 4.44(-CH, dd, J =7.7, 4.6 Hz, 1H), 3.90 (-CH3, s, 3H), 3.23 (-CH2, dd, J = 15.1 Hz, 4.6 Hz, 1H), 3.14 - 3.07 (-CH2, m, 1H), 2.18 (-CH3, s, 3H)。
化合物I-3a(317mg、0.49mmol)を3mLのMeOHに溶解し、イソブチルボロン酸(247mg、2.43mmol)、n-ヘキサン(3mL)及び1NのHCl(1.2mL、1.2mmol)を順次添加し、一晩反応させて撹拌した。TLCで反応を確認し、n-ヘキサン相をMeOH(2×3mL)で2回抽出し、n-ヘキサン(3mL)でメタノール相を1回洗浄し、メタノールを減圧留去し、CH2Cl2(2×2mL)で水相を2回抽出し、水相が中性になるまで飽和食塩水(3×5mL)で有機相を洗浄した。溶媒を減圧留去し、カラムクロマトグラフィーにより分離して純粋な生成物193mgを得た。収率76.5%。1H NMR(400MHz, CDCl3) δ 1.18 (-CH3, s, 3H), 1.25 (-CH3, s, 3H), 2.13 - 2.41 (-CH2, m, 2H), 2.45 - 2.61 (-CH, m, 1H), 3.20 - 3.58 (-CH2, m, 2H), 3.58 - 3.71 (-CH, m, 1H), 5.21 - 5.62 (-CH, m, 1H), 7.62 - 7.75 (-Ph, m, 4H), 7.84 (-Ph, t, J = 13.5 Hz, 3H)。 13C NMR (CDCl3, 100MHz) δ 22.67, 27.21, 31.90, 35.60, 51.28, 54.80, 125.37, 125.55, 128.92, 129.05, 129.47, 129.76, 129.85, 131.34, 131.60, 133.12, 133.17, 139.92, 165.18, 170.98。MS (ESI): m/z 517.1 [M-H]-, calcd: 518.1。 HRMS(ESI): C22H24BCl2F3N2NaO4 [M+Na]+ 計算値 541.1054, 実験値 541.1118.
本発明の他のボロン酸類化合物は、上記方法により合成することができる。
プロテアソーム阻害活性
本発明は、蛍光ポリペプチド基質Suc-Leu-Leu-Val-Tyr-AMC(Suc-LLVY-AMCと略称し、Sueはスクシニルを表し、AMCは7-アミド-4-メチルクマリンを表す)によりプロテアソームのキモトリプシン様酵素活性を測定した。
薬物を量り、DMSOを添加して濃度が10-2Mになるまで溶解した。ピペットで2μLを吸い取り、濃度が2×10-4Mになるように98μLのDMSOに添加し、続いて濃度が2×10-4Mである薬物から8μLを吸い取り、濃度が8×10-6Mになるように198μLのH2Oに添加した。同じ方法により濃度が2×10-6M、5×10-7M、1.25×10-7M、3.12×10-8M、7.8×10-9M、1.95×10-9Mである薬物を得、最後の濃度が0Mであり、薬物を添加しなかったものである。
25mgの蛍光ペプチド基質を654μLのDMSOに溶解し、50mMの貯蔵液を得、-20℃で貯蔵し、使用時に500倍希釈し、各サンプルに8μLずつを添加し、反応系における最終基質濃度を50μMにした。
緩衝溶液で20Sプロテアソーム(2ng/μL)を溶液の濃度が8ng/μLになるまで希釈し、384ウェルの蛍光マイクロプレートに添加し、各ウェルに4μLずつを添加し、更に各ウェルに試験サンプルを4μLずつ添加した。市販の薬物であるベルケイドを陽性対照薬とし、37℃で15min反応させた。反応終了後、各ウェルに蛍光基質を8μLずつ添加し、37℃で暗所で1時間反応させた。360nm/460nmの蛍光マイクロプレートリーダー(BMG LABTECH POLARstar OPTIMA Microplate Reader)により蛍光値を測定した。
背景値を除去した後濃度の異なる薬物で得られた生成物の蛍光値を算出し、GraphPad Prismソフトウェアによりプロテアソーム阻害に対する薬物のIC50濃度を算出した。
本発明に用いられる検出液はPromega社製の単一溶液細胞増殖検出キットであった。用いられる細胞はU266、RPMI8226、ARH77であった。実験系は110μLであり、そのうち細胞懸濁液90μL、検出液10μL、薬物(阻害剤)10μLが含まれ、その最終濃度が4.54×10-8M~1.77×10-9Mであり、最後の濃度が0Mであり、実際の配合濃度が5×10-7M~1.95×10-8Mであり、最後の濃度が0Mであった。具体的な実験過程は以下のとおりである。
薬物を正確に量り、DMSOを添加して濃度が10-2Mになるまで溶解した。ピペットで1μLを吸い取り、濃度が5×10-5Mになるように199μLのDMSOに添加し、続いて濃度が5×10-5Mである薬物から3.3μLを吸い取り、濃度が5×10-7Mになるように326.7μLの無血清RPMI1640培地を添加し、1.5倍の勾配で希釈し、濃度が3.3×10-7M、2.2×10-7M、1.48×10-7M、9.87×10-8M、6.58×10-8M、4.38×10-8M、2.92×10-8M、1.95×10-8Mである薬物を得、最後の濃度が0Mであり、薬物を添加しなかったものである。
細胞をそれぞれカウントした後、U266を希釈して1×104個/ウェルとなるように接種し、RPMI8226とARH77をともに1×104個/ウェルとなるように播種した。
96ウェル蛍光マイクロプレートの各ウェルに細胞懸濁液を90μLずつ添加し、24hインキュベートし、続いて各ウェルに試験サンプルを10μLずつ添加し、市販の薬物であるベルケイドを陽性対照薬とし、24hインキュベートし、反応終了後、各ウェルに検出液を10μLずつ添加し、2~3hインキュベートし、490nmの蛍光マイクロプレートリーダー(BMG LABTECH POLARstar OPTIMA Microplate Reader)により吸光度を検出した。
基質を除去した後濃度の異なる薬物で得られた生成物の吸光度を算出し、GraphPad Prismソフトウェアにより細胞毒性に対する薬物のIC50濃度を算出した。
体重220±20gの12匹のSD雄ラットを四つの群にランダムに分けた。
ヒト多発性骨髄腫細胞系ARH-77を用い、Balb/cnudeマウスに腫瘍を皮下移植し、移植腫瘍モデルを構築した。具体的な実験過程は以下のとおりである。
本発明で設計された化合物は、血液系の悪性腫瘍を治療するために用いることができるため、単回投与後の血中プロテアソーム活性を検出することにより化合物の薬力を評価し、異なる時点で採血して検出することによりインビボ薬力学的研究を行うことができる。
1、上海必凱実験動物有限公司から試験に用いられた8週齢の雌ICRマウスを購入し、バリアシステムに移して一週間環境に適応させて飼育した。
Claims (6)
- 薬学的に許容される担体及び請求項1に記載の化合物を含む、薬物組成物。
- 請求項1に記載の化合物のプロテアソーム阻害剤の調製における使用。
- 請求項1に記載の化合物の疾患の治療用薬物の調製における使用であって、前記疾患は固形腫瘍及び血腫から選択されることを特徴とする使用。
- 請求項1に記載の化合物の疾患の治療用薬物の調製における使用であって、前記疾患は、非小細胞肺癌、小細胞肺癌、肺腺癌、肺扁平上皮細胞癌、膵臓癌、乳癌、前立腺癌、肝臓癌、皮膚癌、上皮細胞癌、消化管間質腫瘍又は鼻咽頭癌から選択されることを特徴とする使用。
- 請求項1に記載の化合物の疾患の治療用薬物の調製における使用であって、前記疾患は、白血病、多発性骨髄腫、マントル細胞リンパ腫又は組織球性リンパ腫から選択されることを特徴とする使用。
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CN110540547A (zh) | 2018-05-28 | 2019-12-06 | 秦艳茹 | 一种肽硼酸酯类化合物的合成与用途 |
DK3826723T3 (da) * | 2018-07-26 | 2024-01-15 | Merck Patent Gmbh | Boronsyrederivater |
CN112007160A (zh) * | 2020-08-17 | 2020-12-01 | 暨南大学 | 蛋白酶体抑制剂在抗癌药物中的应用 |
CN113105486B (zh) * | 2021-02-24 | 2023-08-15 | 南京师范大学 | 一种硼酸酯类化合物及其药学上可接受的盐、其制备方法及其用途 |
WO2023078437A1 (zh) * | 2021-11-08 | 2023-05-11 | 江苏正大丰海制药有限公司 | 一种肽硼酸类化合物新晶型及其制备方法 |
WO2023107470A1 (en) * | 2021-12-06 | 2023-06-15 | Pretzel Therapeutics, Inc. | Lonp1 inhibitors, uses and methods |
CN114671900A (zh) * | 2022-04-26 | 2022-06-28 | 广州医科大学 | 硼酸类化合物及其应用 |
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CN112384519A (zh) | 2021-02-19 |
CA3101824A1 (en) | 2019-12-05 |
US20210214377A1 (en) | 2021-07-15 |
CN112384519B (zh) | 2022-11-25 |
EP3805237A4 (en) | 2021-08-18 |
JP2021526159A (ja) | 2021-09-30 |
AU2019277933B2 (en) | 2021-12-16 |
CN115785137A (zh) | 2023-03-14 |
KR20210010579A (ko) | 2021-01-27 |
CA3101824C (en) | 2023-08-15 |
US11542283B2 (en) | 2023-01-03 |
EP3805237A1 (en) | 2021-04-14 |
CN110540547A (zh) | 2019-12-06 |
AU2019277933A1 (en) | 2021-01-07 |
KR102558265B1 (ko) | 2023-07-20 |
WO2019228299A1 (zh) | 2019-12-05 |
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