JP7152078B2 - ホウ酸塩ベースの薬物およびその使用 - Google Patents
ホウ酸塩ベースの薬物およびその使用 Download PDFInfo
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- JP7152078B2 JP7152078B2 JP2021538880A JP2021538880A JP7152078B2 JP 7152078 B2 JP7152078 B2 JP 7152078B2 JP 2021538880 A JP2021538880 A JP 2021538880A JP 2021538880 A JP2021538880 A JP 2021538880A JP 7152078 B2 JP7152078 B2 JP 7152078B2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 37
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- JKWMSGQKBLHBQQ-UHFFFAOYSA-N diboron trioxide Chemical compound O=BOB=O JKWMSGQKBLHBQQ-UHFFFAOYSA-N 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
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- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 14
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- MBOMYENWWXQSNW-AWEZNQCLSA-N ixazomib citrate Chemical compound N([C@@H](CC(C)C)B1OC(CC(O)=O)(CC(O)=O)C(=O)O1)C(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MBOMYENWWXQSNW-AWEZNQCLSA-N 0.000 description 14
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 10
- ABYVMYOJMTTYAX-LBPRGKRZSA-N [(1R)-1-[[2-[(5-bromo-2-fluorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid Chemical compound FC1=C(C(=O)NCC(=O)N[C@@H](CC(C)C)B(O)O)C=C(C=C1)Br ABYVMYOJMTTYAX-LBPRGKRZSA-N 0.000 description 10
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- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960002951 ixazomib citrate Drugs 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 201000006691 pancreatic squamous cell carcinoma Diseases 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl 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
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
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- 208000028466 reproductive system neoplasm Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940127020 second-generation proteasome inhibitor Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
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- 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
-
- 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
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
X1、X2は、ヒドロキシ基からなる群から選択されるか、または X1とX2とが一緒になって、O、NおよびSからなる群から選択される1~4個のヘテロ原子を含む、置換または非置換の4~10の員環を形成する。
または、n=1のとき、R3とR4が一緒になって、ベンゼン環、0~2個の不飽和エチレン結合を含有するシクロヘキシル、および0~2個の不飽和エチレン結合を含有するシクロペンチルからなる群から選択される、飽和または不飽和の5~6員環を形成し;
n=0のとき、R3は存在せず、R4とR5は、H、置換または非置換のC1-C6アルキル、自己置換または非置換のシクロアルキル、置換または非置換のC3-C8アルキノキシ、置換または非置換のC1-C6アルキル-COOH、-CH2-COOH、-COOH、置換または非置換のベンジル、および置換または非置換のフェニルからなる群から選択される。
n=1のとき、R3はHで、R4およびR5はH、-COOH、-CH2-COOH、フェニルおよびベンジルからなる群から選択され、好ましくはR4およびR5は-COOHおよび-CH2-COOHからなる群から選択されるか、またはR4およびR5は代替的にフェニルおよび水素原子からなる群から選択され、さらに好ましくは、R4およびR5は代替的に-CH2-COOHおよび-COOHからなる群から選択されるか;
または、n=1のとき、R3とR4が一緒になって、ベンゼン環、または0~2個の不飽和エチレン結合を含むシクロヘキシルからなる群から選択される置換または非置換の6員環を形成し、R5は存在せず、6員環は好ましくはベンゼン環であるか;
または、n=0のとき、R3は存在せず、R4およびR5はH、-COOH、CH2-COOH、フェニルおよびベンジルからなる群から選択され;好ましくはR4およびR5は-COOHおよび-CH2-COOHからなる群から選択されるか、またはR4およびR5はフェニルおよび水素原子からなる群から選択され;さらに好ましくはR4およびR5は両方とも-CH2-COOHであり、またはR4およびR5は代替的にフェニルおよび水素原子からなる群から選択され、フェニルと連結する5員環上の炭素原子はS配置である。
またはn=1であり、R3とR4が一緒になって次の構造の6員環を形成し
X1とX2はOHであるか;または
X1とX2が接続されているホウ素原子と一緒に環構造を形成し、環構造が
ここで、R3、R4、R5、R6、R7、R8およびR9はそれぞれ独立に、水素、C1 -C6アルキル、C1-C6アルケニル、C1-C6アルキニル、C1-C6アルコキシ、C3-C8シクロアルキル、3~7員ヘテロシクロアルキル、フェニル、ベンジル、5~10員ヘテロアリール、COOH、C1-C6アルキル-COOH、OHまたはハロゲンであり、ここでC1 -C6アルキル、C1-C6アルケニル、C1-C6アルキニル、C1-C6アルコキシ、C3-C8シクロアルキル、3~7員ヘテロシクロアルキル、フェニル、ベンジル、5~10員ヘテロアリール、およびC1-C6アルキル-COOHは、ハロゲン、C1 -C6アルキル、C1 -C6ハロアルキル、アミノ、シアノ、カルボキシル、C1-C6アルキル-COOH、ヒドロキシ、C1-C6アルコキシ、C1-C6ハロアルコキシ、カルボニル、3~7員ヘテロシクロアルキル、C5-C10アリールおよび5~10員ヘテロアリールからなる群から選択される群で任意に置換される。
本出願の1つ以上の実施形態では、環構造は
ここで、R3およびR4はそれぞれ独立して、水素、C1-C6アルキル、C1-C6アルコキシ、C3-C8シクロアルキル、3~7員ヘテロシクロアルキル、フェニル、ベンジル、5~10員ヘテロアリール、COOHまたはC1-C6アルキル-COOHであり、C1-C6アルキル、C1-C6アルコキシ、C3-C8シクロアルキル、3~7員ヘテロシクロアルキル、フェニル、ベンジル、5~10員ヘテロアリール、およびC1-C6アルキル-COOHは、ハロゲン、C1-C6アルキル、C1-C6ハロアルキル、アミノ、シアノ、アシル、カルボキシル、C1-C6アルキルCOOH、ヒドロキシ、C1-C6アルコキシ、C1-C6ハロアルコキシ、カルボニル、3~7員ヘテロシクロアルキル、C5-C10アリール、および5~10員ヘテロアリールからなる群から選択される基で任意に置換される。
ここで、
R5およびR6はそれぞれ独立して、水素、C1-C6アルキルまたはC1-C6アルコキシであり;
R7およびR8はそれぞれ独立して、水素、C1-C6アルキル、C1-C6アルコキシ、C3-C8シクロアルキル、3~7員ヘテロシクロアルキル、フェニル、ベンジル、5~10員ヘテロアリール、COOHまたはC1-C6アルキル-COOHであり;
C1-C6アルキル、C1-C6アルコキシ、C3-C8シクロアルキル、3~7員ヘテロシクロアルキル、フェニル、ベンジル、5~10員ヘテロアリール、およびC1-C6アルキル-COOHは、ハロゲン、C1-C6アルキル、C1 -C6ハロアルキル、アミノ、シアノ、アシル、カルボキシル、C1-C6アルキル-COOH、ヒドロキシ、C1-C6アルコキシ、C1-C6ハロアルコキシ、カルボニル、3~7員ヘテロシクロアルキル、C1-C6アリール、および5~10員ヘテロアリールからなる群から選択される基によって任意に置換される。
R1がFのとき、R2はBrである。
「化合物」とはすべての立体異性体、幾何異性体、互変異性体を含む。本明細書で使用する「化合物」は非対称であってもよい。例えば、それは1つ以上の立体異性体を有する。特に断らない限り、すべての立体異性体には例えば、個々の鏡像異性体、ジアステレオマー、または他の立体異性体、またはそれらの混合物が含まれる。本明細書中の不斉炭素原子を含む化合物は、光学活性が純粋な形態またはラセミ形態で分離することができる。光学活性が純粋な形態はラセミ混合物から分離することができ、またはキラル原料またはキラル試薬を使用することによって合成することができる。本明細書で使用する場合、「化合物」は幾何異性体も含み、これは化合物の二重結合または環における置換基がキラル性を有さない異なるシス-トランス異性を有することを意味する。本明細書で使用する場合、「化合物」には互変異性体も含まれる。互変異性体は、プロトンの移動により、単結合と隣接する二重結合との交換により誘導され得る。
2-フルオロ-5-ブロモ-N-[2-({(1R)-3-メチル-1-[(5R)-4-オキソ-5-フェニル-1,3,2-ジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミド;および
2-フルオロ-5-ブロモ-N-[2-({(1R)-3-メチル-1-[(5S)-4-オキソ-5-フェニル-1,3,2-ジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンゾイル;など、またはそれらの塩、ホウ酸錯体、ホウ酸エステル、ホウ酸無水物。
化合物3b:2-フルオロ-5-ブロモ-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-エンド-メチレン-1,3,2-ベンゾジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物4b:[(1R)-1-({[(2-フルオロ-5-ブロモ-ベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ホウ酸の調製
化合物6b:(R)-2,2’-(2-(1-(2-(2-フルオロ-5-ブロモ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-5-オキソ-1,3,2-ジオキサボロラン-4,4-ジイル)二酢酸の調製
化合物6d:4-(R,S)-(カルボキシルメチル)-2-((R)-1-(2-(2-フルオロ-5-ブロモ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-6-オキソ-1,3,2-ジオキサボロラン-4-ギ酸の調製
化合物6e:2-フルオロ-5-ブロモ-N-(2-{[(1R)-3-メチル-1-(4-オキソ-4H-1,3,2-ベンゾジオキサボロラン-2-イル)ブチル]アミノ}-2-オキソエチル)ベンズアミドの調製
化合物6f:2-フルオロ-5-ブロモ-N-[2-({(1R)-3-メチル-1-[4-オキソ-5-フェニル-1,3,2-ジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6g:{(4S)-2-[(1R)-1-({[(2-フルオロ-5-ブロモベンゾイル)アミノ]-アセチル}アミノ)-3-メチルブチル]-5-オキソ-1,3,2-ジオキサボロラン-4-イル}酢酸の調製
化合物6h:4-(R,S)-(カルボキシルメチル)-2-((R)-1-(2-(2-ブロモ-5-フルオロ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-6-オキソ-1,3,2-ジオキサボロラン-4-ギ酸の調製
化合物6hは、[(1R)-1-({[(2-フルオロ-5-ブロモ-ベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ホウ酸を[(1R)-1-({[(2-ブロモ-5-フルオロ-ベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ホウ酸で置き換えたこと以外、調製例4の方法に従って調製した。
化合物6i:2-ブロモ-5-フルオロ-N-(2-{[(1R)-3-メチル-1-(4-オキソ-4H-1,3,2-ベンゾジオキサボロラン-2-イル)ブチル]アミノ}-2-オキソエチル)ベンズアミドの調製
化合物6j:2-ブロモ-5-フルオロ-N-[2-({(1R)-3-メチル-1-[4-オキソ-5-フェニル-1,3,2-ジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6k:{(4S)-2-[(1R)-1-({[(2-ブロモ-5-フルオロ-ベンゾイル)アミノ]-アセチル}アミノ)-3-メチルブチル]-5-オキソ-1,3,2-ジオキサボロラン-4-イル}酢酸の調製
化合物6l:(R)-2,2’-(2-(1-(2-(2-ブロモ-5-フルオロ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-5-オキソ-1,3,2-ジオキサボロラン-4,4-ジイル)二酢酸の調製
化合物6m:4-(R,S)-(カルボキシルメチル)-2-((R)-1-(2-(2-フルオロ-5-クロロ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-6-オキソ-1,3,2-ジオキサボロラン-4-ギ酸の調製
化合物6n:2-フルオロ-5-クロロ-N-(2-{[(1R)-3-メチル-1-(4-オキソ-4H-1,3,2-ベンゾジオキサボロラン-2-イル)ブチル]アミノ}-2-オキソエチル)ベンズアミドの調製
化合物6o:2-フルオロ-5-クロロ-N-[2-({(1R)-3-メチル-1-[4-オキソ-5-フェニル-1,3,2-ジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6p:{(4S)-2-[(1R)-1-({[(2-フルオロ-5-クロロ-ベンゾイル)アミノ]-アセチル}アミノ)-3-メチルブチル]-5-オキソ-1,3,2-ジオキサボロラン-4-イル}酢酸の調製
工程1:化合物3q:2-フルオロ-5-クロロ-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-エンド-メチレン-1,3,2-ベンゾジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6a:(R)-2,2’-(2-(1-(2-(2-クロロ-5-ブロモ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-5-オキソ-1,3,2-ジオキサボロラン-4,4-ジイル)二酢酸の調製
工程1:化合物3a:2-クロロ-5-ブロモ-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-エンド-メチレン-1,3,2-ベンゾジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6c:(R)-2,2’-(2-(1-(2-(2-フルオロ-5-トリフルオロメチル-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-5-オキソ-1,3,2-ジオキサボロラン-4,4-ジイル)二酢酸の調製
工程1:化合物3c:2-フルオロ-5-トリフルオロメチル-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-エンド-メチレン-1,3,2-ベンゾジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6r:(R)-2,2’-(2-(1-(2-(2-フルオロ-5-メチル-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-5-オキソ-1,3,2-ジオキサボロラン-4,4-ジイル)二酢酸の調製
工程1:化合物3r:2-フルオロ-5-メチル-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-エンド-メチレン-1,3,2-ベンゾジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
化合物6s:(R)-2,2’-(2-(1-(2-(2-フルオロ-5-フルオロ-ベンゾイルアミノ)アセチルアミノ)-3-メチルブチル)-5-オキソ-1,3,2-ジオキサボロラン-4,4-ジイル)二酢酸の調製
工程1:化合物3s:2-フルオロ-5-フルオロ-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-エンド-メチレン-1,3,2-ベンゾジオキサボロラン-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドの調製
細胞RPMI-8226(ATCC(American type culture collection)由来のヒト多発性骨髄腫細胞、ATCC CCL-155)および細胞MM.1S(ATCC(American type culture collection)由来のヒト多発性骨髄腫細胞、ATCC CRL-2974)を、37℃および5%CO2において10%ウシ胎仔血清を含むRPMI1640培地中で対数増殖期まで培養した。細胞をウェル当たりの適切な量で96ウェル培養プレートに接種した。37℃および5%CO2で24時間培養した後、溶媒対照DMSOまたはDMSOに溶解した試験化合物をウェルに添加し、試験化合物の出発濃度を0.3μMとし、各回3倍希釈で合計6回希釈して6つの濃度勾配を得た。細胞は試験化合物と一緒に37℃および5%CO2で48時間インキュベートした。CCK-8試薬を各ウェルに添加し、細胞を試薬の指示に従って37℃で2時間インキュベートし、各ウェルの光学密度値を450nm波長で分光光度計を用いて読み取った。
この実験で使用したモデルは、CB17-SCIDマウス(Beijing Weitong Lihua Experimental Animal Technology Co、Ltd.から購入)におけるヒト多発性骨髄腫細胞株MM.1Sの移植腫瘍モデルであった。凍結保存したMM.1S細胞を蘇生後に通常の方法で試験管内にて培養した。対数増殖期に細胞を回収し、無血清培地またはPBSで希釈して、5×107/mlの腫瘍細胞懸濁液を形成させた。上記で調製した腫瘍細胞懸濁液を1mlシリンジで採取し、マウスの左脇腹背もたれ側に皮下注射し、各接種部位に0.2mlを注射した。培養した腫瘍細胞をCB17-SCIDマウスに注入して約1~2週間後、わきの下の腫瘍に触れた。腫瘍体積が100mm3を超える場合、腫瘍体積を測定および計算し、マウスを腫瘍体積に従って無作為にグループに分けた。
細胞KMS-11(JCRB(Japanese Collection of Research Bioresources Cell Bank)からのヒト多発性骨髄腫細胞、AJCRB1179)を、37℃および5%CO2で10%ウシ胎仔血清を含むRPMI1640培地中で対数増殖期まで培養した。細胞を、ウェル当たり適切な量で96ウェル培養プレートに接種した。37℃、5%CO2で24時間培養した後、溶媒対照DMSOもしくはDMSOに溶解した試験化合物を細胞に添加し、そのとき試験化合物の出発濃度は0.3μMであり、それぞれ3倍ごとに合計6回希釈して6つの濃度勾配を得た。細胞を試験化合物と共に37℃および5%CO2で48時間インキュベートした。CCK-8試薬を各ウェルに添加し、細胞を試薬の指示に従って37℃で2時間インキュベートし、各ウェルの光学密度値を450nm波長にて分光光度計で読み取った。
本実験で用いたモデルは、CB17-SCIDマウスにおけるヒト多発性骨髄腫細胞株MM.1Sの移植腫瘍モデルであった。凍結保存したMM.1S細胞を蘇生後に通常通りに試験管内で培養した。対数増殖期に細胞を回収し、無血清培地またはPBSで希釈して、5×107/mlの腫瘍細胞懸濁液を形成した。上記で調製した腫瘍細胞懸濁液を1mlシリンジで採取し、マウスの左脇腹背もたれ側に皮下注射し、各接種部位に0.2mlを注射した。培養した腫瘍細胞をCB17-SCIDマウスに注入してから約1~2週間後、わきの下の腫瘍に触れた。腫瘍体積が100mm3を超える場合、腫瘍体積を測定し、計算し、マウスを腫瘍体積に従って無作為にグループに分けた。
Claims (14)
- 式(I)の化合物、またはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物であって、
X 1、X2は、ヒドロキシルからなる群から選択されるか、またはX 1 およびX 2 がホウ素原子と共に以下に示す構造を形成し:
またはn=1のとき、R 3 およびR 4 は一緒になって、ベンゼン環からなる群から選択される不飽和の6員環を形成し;
n=0のとき、R 3 は存在せず、R 4 、R 5 はH、C 1 -C 6 アルキル、C 1 -C 6 アルコキシ、C 1 -C 6 アルキル-COOH、ベンジル、およびフェニルからなる群から選択される、
化合物、またはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物。 - n=0の場合、前記C 1 -C 6 アルキル-COOHは-CH 2 -COOHである、請求項1に記載の化合物、またはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物。
- R1はFであり、R2はBrである;
ここで、n=1の場合、R3はHであり、R4およびR5は-COOH、-CH2-COOH、フェニルおよびベンジルからなる群から選択され;
もしくは、n=1の場合、R3およびR4は一緒になって、ベンゼン環からなる群から選択される6員環を形成し、;
またはn=0の場合、R4およびR5はH、-CH2-COOH、フェニルおよびベンジルからなる群から選択される;請求項1に記載の化合物、またはその薬学的に許容される塩、溶媒和物もしくはホウ酸無水物。 - n=1の場合、R 4 およびR 5 は-COOHおよび-CH 2 -COOHからなる群から選択されるか、またはR 4 およびR 5 が代替的に、フェニルおよびHからなる群から選択される、請求項3に記載の化合物、またはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物。
- n=1の場合、R 4 およびR 5 が代替的に-CH 2 -COOHおよび-COOHからなる群から選択される、請求項3に記載の化合物、またはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物。
- n=0の場合、R 4 およびR 5 が-CH 2 -COOHからなる群から選択されるか、またはR 4 およびR 5 がフェニルおよび水素原子からなる群から選択される、請求項3に記載の化合物、またはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物。
- n=0の場合、R 4 およびR 5 が両方とも、-CH 2 -COOHであるか、またはR 4 およびR 5 は代替的にフェニルおよび水素原子からなる群から選択され、フェニルと結合している5員環上の炭素原子はS配置である、請求項3に記載の化合物、もしくはその薬学的に許容される塩、または溶媒和物、もしくはホウ酸無水物。
- 請求項1~9のいずれか1項に記載の化合物、もしくはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物、と、
薬学的に許容される賦形剤とを含む、薬学的調製物。 - 請求項1~9のいずれか1項に記載の化合物、もしくはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物、と、
腫瘍を予防または治療するための1つ以上の他の薬物とを含む、薬学的組成物。 - 腫瘍を予防および/または治療するための薬剤の調製における、請求項1~9のいずれか1項に記載の化合物、もしくはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物、請求項10に記載の薬学的調製物、または請求項11に記載の薬学的組成物の、使用。
- 前記腫瘍は、形質細胞腫、マントル細胞腫瘍、多発性骨髄腫、黒色腫、乳癌、肝癌、子宮頸癌、肺癌、リンパ腫、白血病、卵巣癌、腎癌、胃癌、上咽頭癌、甲状腺癌、膵癌、前立腺癌、腺癌、口腔癌、食道がん、扁平上皮癌および結腸癌から選択される、請求項12に記載の使用。
- プロテアソーム阻害剤の調製における、請求項1~9のいずれか1項に記載の化合物、もしくはその薬学的に許容される塩、溶媒和物、もしくはホウ酸無水物、請求項10に記載の薬学的調製物、または請求項11に記載の薬学的組成物の、使用。
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JP2018506550A (ja) | 2015-02-17 | 2018-03-08 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | 癌治療のための併用療法 |
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JP2018506550A (ja) | 2015-02-17 | 2018-03-08 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | 癌治療のための併用療法 |
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CN110903310B (zh) | 2022-11-22 |
CN110903310A (zh) | 2020-03-24 |
KR102542264B1 (ko) | 2023-06-13 |
CN115403603A (zh) | 2022-11-29 |
EP3851108A4 (en) | 2022-06-01 |
EP3851108C0 (en) | 2023-08-09 |
EP3851108B1 (en) | 2023-08-09 |
US20210332069A1 (en) | 2021-10-28 |
WO2020052488A1 (zh) | 2020-03-19 |
KR20210046025A (ko) | 2021-04-27 |
EP3851108A1 (en) | 2021-07-21 |
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