WO2000043016A1 - DERIVE DE DICARBA-closo-DODECABORANE - Google Patents
DERIVE DE DICARBA-closo-DODECABORANE Download PDFInfo
- Publication number
- WO2000043016A1 WO2000043016A1 PCT/JP2000/000285 JP0000285W WO0043016A1 WO 2000043016 A1 WO2000043016 A1 WO 2000043016A1 JP 0000285 W JP0000285 W JP 0000285W WO 0043016 A1 WO0043016 A1 WO 0043016A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- dodecaborane
- hexane
- ethyl acetate
- lower alkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 57
- 239000003814 drug Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 20
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims description 50
- -1 p-hydroxyphenyl group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 10
- 230000002209 hydrophobic effect Effects 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000005647 linker group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 323
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000001257 hydrogen Substances 0.000 abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 346
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 274
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 142
- 239000000243 solution Substances 0.000 description 100
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 95
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 81
- 239000000203 mixture Substances 0.000 description 79
- 238000006243 chemical reaction Methods 0.000 description 76
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
- 239000012044 organic layer Substances 0.000 description 70
- 238000005481 NMR spectroscopy Methods 0.000 description 67
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 67
- 229910052938 sodium sulfate Inorganic materials 0.000 description 67
- 235000011152 sodium sulphate Nutrition 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 238000000921 elemental analysis Methods 0.000 description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 51
- 239000012267 brine Substances 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- 238000002844 melting Methods 0.000 description 49
- 230000008018 melting Effects 0.000 description 49
- 238000010898 silica gel chromatography Methods 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 48
- 239000003480 eluent Substances 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- 238000000746 purification Methods 0.000 description 40
- 238000003818 flash chromatography Methods 0.000 description 39
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- 210000000689 upper leg Anatomy 0.000 description 34
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- 230000000694 effects Effects 0.000 description 32
- 238000004519 manufacturing process Methods 0.000 description 32
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 31
- 239000012300 argon atmosphere Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 27
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 27
- 238000012360 testing method Methods 0.000 description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 24
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 24
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- 238000001816 cooling Methods 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 20
- 238000004896 high resolution mass spectrometry Methods 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 239000005711 Benzoic acid Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 235000010233 benzoic acid Nutrition 0.000 description 16
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 16
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 15
- 229940095102 methyl benzoate Drugs 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 229940011871 estrogen Drugs 0.000 description 13
- 239000000262 estrogen Substances 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 229940050390 benzoate Drugs 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 229910000085 borane Inorganic materials 0.000 description 10
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 10
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 230000004069 differentiation Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 102000006255 nuclear receptors Human genes 0.000 description 9
- 108020004017 nuclear receptors Proteins 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- 108060001084 Luciferase Proteins 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 229940043279 diisopropylamine Drugs 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- BUADUHVXMFJVLH-UHFFFAOYSA-N 7-chloro-3-imidazol-1-yl-2H-1,2,4-benzotriazin-1-ium 1-oxide Chemical compound N1[N+](=O)C2=CC(Cl)=CC=C2N=C1N1C=CN=C1 BUADUHVXMFJVLH-UHFFFAOYSA-N 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 208000032839 leukemia Diseases 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 5
- 230000001833 anti-estrogenic effect Effects 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 229960005309 estradiol Drugs 0.000 description 5
- 239000002198 insoluble material Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 5
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 5
- QCOGKXLOEWLIDC-UHFFFAOYSA-N N-methylbutylamine Chemical compound CCCCNC QCOGKXLOEWLIDC-UHFFFAOYSA-N 0.000 description 4
- 101150003085 Pdcl gene Proteins 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 235000011089 carbon dioxide Nutrition 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 239000006196 drop Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000003702 retinoic acid receptors Human genes 0.000 description 4
- 108090000064 retinoic acid receptors Proteins 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- 239000005089 Luciferase Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 230000000719 anti-leukaemic effect Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
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- 238000010438 heat treatment Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- QNMSVGSVISUZRN-UHFFFAOYSA-N methyl 4-(4-ethynylphenoxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=C(C#C)C=C1 QNMSVGSVISUZRN-UHFFFAOYSA-N 0.000 description 3
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
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- 239000012312 sodium hydride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RSHBAGGASAJQCH-UHFFFAOYSA-N 1-iodo-3-methoxybenzene Chemical compound COC1=CC=CC(I)=C1 RSHBAGGASAJQCH-UHFFFAOYSA-N 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- DLZRCTHPQQALDW-UHFFFAOYSA-N 3-trimethylsilylpropanal Chemical compound C[Si](C)(C)CCC=O DLZRCTHPQQALDW-UHFFFAOYSA-N 0.000 description 2
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- BDIULNLXBFXVLE-UHFFFAOYSA-N C(C)C=1C(=C(C(=O)OCC)C=CC1)C#C Chemical compound C(C)C=1C(=C(C(=O)OCC)C=CC1)C#C BDIULNLXBFXVLE-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical compound C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
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- 229960001727 tretinoin Drugs 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000005406 washing 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
- C07F5/027—Organoboranes and organoborohydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a novel dicarbazole chloride decaborane derivative.
- the present invention also relates to a medicament containing the above dicarba-clozo-dodecaborane derivative as an active ingredient.
- Dicarba-clozo-dodecaborane (hereinafter abbreviated as “carborane” in the present specification) is a 20-hedral class compound containing two carbon atoms and ten boron atoms, and both atoms are Six coordination. Depending on the arrangement of carbon atoms in the class, carborane has three isomers: 1,2-dicarbazole-closodecaborane (ortho-carborane), 1,7-dicarbazole-dosecaboderan (meta-carborane), 1 , 12-Dicarba-clozo-dodecaborane (para-carborane) exists. These structures are unique among boron compounds, are extremely stable thermally, and are characterized by having hydrophobicity comparable to hydrocarbons.
- Lfl B-Neutron Capture Therapy is mainly Irradiating 1 ⁇ ⁇ atoms with thermal neutrons (slow neutrons) emits 2.4 MeV energy rays and decomposes them into 7 Li and 4 He.
- the range of the line is about 10 ⁇ m, which is equivalent to the diameter of the cell, so that only the cells that have taken up the atoms can be destroyed, and other cells can be expected to have no effect.
- an object of the present invention is to provide a novel physiologically active substance by using carborane as a hydrophobic pharmacophore in a partial structure of a drug after understanding the physical and chemical properties of carborane itself. .
- the hydrogen-bonding and the molecular interaction contribute to the stabilization of the ligand-receptor complex, and therefore, by introducing carborane as a hydrophobic moiety, the ligand-receptor complex is formed. It is considered that stability can be enhanced and desired physiological activity can be enhanced.
- the carborane-containing nuclear receptor ligand provided by the present invention is a promising compound in terms of targeting cancer cells in the application to BNCT, and has an effect as an agonist via nuclear receptor nuclear. Is a compound that has excellent activity and is expected to have different pharmacokinetics than conventional drugs.
- an object of the present invention is to provide a physiologically active compound having a carborane skeleton as a pharmacophore. More specifically, it is an object of the present invention to provide a novel substance having excellent physiological activity and having low cytotoxicity and useful as a nuclear receptor modulator. It is also an object of the present invention to provide a medicament which contains the compound as an active ingredient and is useful as a therapeutic agent for inducing differentiation against leukemia or an estrogen agonist.
- a compound having a dicarbacrozo'-dodecaborane structure represented by the following general formula (I) has been excellent as a ligand for a nuclear receptor such as a retinoic acid receptor.
- a nuclear receptor such as a retinoic acid receptor.
- Has activity against leukemia The inventors have found that an excellent therapeutic effect can be exerted on a differentiation-inducing therapeutic agent and the like, and have completed the present invention.
- R 1 is a lower alkyl group, a lower alkenyl group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, a hydroxyl group, a lower hydroxyalkyl group, a mono- or di-lower alkyl group, a rubamoyl-substituted alkyl group, A dicarba group optionally having one or more substituents selected from the group consisting of an alkanol group, an aryl group optionally having substituent (s), and a lower aralkyl group optionally having substituent (s) - Kurozo - dodecaborane - shows the I le group; R 2 represents a carboxyl group, a lower an alkoxy carbonyl group, or a hydroxyl group; X is either a single bond, or the following formula:
- R 1 is a dicarba-clozo-dodecaborane-yl group which may have a lower alkyl group
- R 2 represents a carboxyl group or a lower alkoxycarbonyl group
- X is the above-mentioned linking group.
- a medicament comprising a compound of the formula (I) or a physiologically acceptable salt thereof as an active ingredient;
- (2) 1 ⁇ is a lower alkyl group, a lower alkenyl group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, a hydroxyl group, a lower hydroxyalkyl group, a lower alkanol group, a phenyl group which may have a substituent, A phenyl group, and a dicarboxy-dodecaborane-yl group which may have a substituent selected from the group consisting of a lower alkoxyphenyl group, R 2 is a hydroxyl group, and X is a single bond A compound of the formula (I) or a physiologically acceptable salt thereof as an active ingredient
- the compound represented by the above formula (I) or a physiologically acceptable salt thereof can act as a ligand for nuclear receptors. Therefore, this drug is useful as a retinoid agonist or estrogen agonist, and is also useful for treating and / or preventing cancer, rheumatism, arteriosclerosis, diabetes, rejection during organ transplantation, and graft-versus-host disease. It is.
- the medicament containing the compound defined in (1) or a physiologically acceptable salt thereof as an active ingredient can be used, for example, as a retinoid acting agent for the treatment of leukemia.
- the compound defined in (2) above or a physiologically acceptable compound is useful, for example, as an estrogen agent for regulating female hormone balance, preventing and / or treating menstrual disorders, osteoporosis, or cancer.
- the present invention relates to a method of using the compound represented by the above formula (I) or a salt thereof for the manufacture of the above medicament, and a method for treating leukemia.
- a therapeutically effective amount of the compound or a physiologically acceptable salt thereof is provided to a patient.
- the present invention provides a compound represented by the following general formula (I):
- R 1 is a lower alkyl group, a lower alkenyl group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, a hydroxyl group, a lower hydroxyalkyl group, a mono- or di-lower alkyl group, a rubamoyl-substituted alkyl group, A dicarba group optionally having one or more substituents selected from the group consisting of an alkanol group, an aryl group optionally having substituent (s), and a lower aralkyl group optionally having substituent (s)
- R 2 represents a carboxyl group, a lower alkoxycarbonyl group, or a hydroxyl group
- X represents a single bond, or a compound represented by the following formula:
- YY ⁇ ⁇ ⁇ 5 , ⁇ and ⁇ 7 each independently represent an oxygen atom or —N (R 3 ) — (wherein R 3 represents a hydrogen atom or a lower alkyl group); 8 represents an oxygen atom, —N (R 4 ) — (wherein R 4 represents a hydrogen atom or a lower alkyl group), —CO—, —CH 2 —, or —C (two CH 2 ) —, R 5 , R 6 , and R 7 each independently represent a hydrogen atom, or one or more substituents on a phenyl group, and 8 represents a lower alkyl group or a substituent.
- R 1 ( ⁇ represents an aryl group which may have a substituent).
- X is a single bond
- R 1 is an unsubstituted dicarbacrozo-dodecaborane-yl group
- R 2 is a hydroxyl group
- R 1 is a dicarbochloride decaborane-yl group substituted with a p-hydroxyphenyl group and R 2 is a hydroxy group
- 1,2-Dicarbochloride decaborane (ortho-carborane) is a compound described in the upper part of the following structural formula. It has 10 boron atoms with hydrogen atoms (indicated by “B” in the formula) and two carbon atoms with hydrogen atoms (indicated by “C” in the formula).
- the 1,2-dicarba-clozo-dodecaborane-11-yl group is a group corresponding to a residue in the formula except for a hydrogen atom on one carbon atom on a carborane ring.
- 1,7-Dicarbachloride-decaborane metal-carborane
- 1,12-dicarclozode-decaborane para-carborane
- dicarbaclodesodecaborane can form a 1,7-dicarbaclozo-dodecaborane-11-yl group and a 1,12-dicarbaclozo-dodecaborane-11-yl group similarly to ortho-carborane.
- dicarbachloride decaborane group is used to include the residues of three isomers of dicarbazole decaborane.
- one carbon atom and 10 boron atoms that do not participate in the formation of a residue may each independently have a substituent. it can.
- 1,12-dicarba-clozo-dodeforce borane para-carborane in which all 10 boron atoms are substituted with methyl groups.
- the medicament of the present invention is characterized in that it has a dicarberclosode decaborane-1 group as a hydrophobic pharmacophore.
- receptors In vivo macromolecules represented by receptors (hereinafter simply referred to as “receptors”) have a specific structure that recognizes a drug as a partial structure, and are stably bound by spatial interaction with the drug And exerts its action. The multiple functional groups or groups involved in this interaction are called “pharmacophores”.
- the hydrophobic part of the drug stabilizes the binding by hydrophobic interaction with the binding site of the receptor, and has important significance for the recognition of the shape of the drug by the receptor.
- the hydrophobic pharmacophore in the compound of the present invention is a partial structure of a pharmaceutical compound, which means a structure that contributes to stabilization of binding to a receptor or is expected to contribute as a hydrophobic moiety. ing.
- the compound of the present invention has a dicarbacrozodedecaboryl group as a hydrophobic pharmacophore and can be used as a medicament.
- retinoids, estrogens, androgens, or It can act as an agonist or an antagonist on nuclear receptors to which nuclear ligands such as Lloyd bind.
- dicarbaclozolone has been used for the purpose of stabilizing the binding to the receptor and enhancing the biological activity by stabilizing the binding to the receptor.
- a dodecaboryl group as a hydrophobic pharmacophore.
- a lower alkyl moiety of a lower alkyl group or a substituent containing a lower alkyl moiety (for example, a lower alkoxycarbonyl group, a lower alkenyl group, a lower hydroxyalkyl group, a lower alkanol group, a lower aralkyl group, etc.) It may be in the form of a chain, a branched chain, a ring, or a combination thereof, and has 1 to 6, preferably about 1 to 4 carbon atoms.
- Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a t-tert-butyl group.
- the lower alkenyl group those having about 1 to 6 carbon atoms can be used.
- the number of double bonds contained in the lower alkenyl group is not particularly limited, but is usually about 1 to 3, preferably 1.
- the substituent that can be present in the dicarba-clozo-dodecaboraneyl group is preferably a lower alkyl group such as a methyl group
- the lower alkoxycarbonyl group is a methoxycarbonyl group or an ethoxycarbonyl group.
- the amino group may have one or two substituents (for example, a lower alkyl group, a lower alkanoyl group, etc.). If the amino group has two alkyl groups, they are combined to form a ring. May be.
- the lower hydroxyalkyl group include a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, and a 3-hydroxypropyl group.
- the lower alkanoyl group include an acetyl group and a propanol group. Can be mentioned.
- the alkyl group substituted by the mono- or di-lower alkyl group rubamoyl group has 1 to 12 carbon atoms, preferably about 8 to 10 carbon atoms, and the two alkyl groups are bonded to form a ring. May be formed.
- the aryl group is preferably a phenyl group
- the aralkyl group is preferably a benzyl group.
- the type and number of the substituent are not particularly limited.
- a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group Etc. can be used as the substituent on the ring.
- the lower alkoxy group on the ring of the aryl or aralkyl group may be substituted with a mono- or di-lower alkylamino group or a cyclic amino group (pyrrolidinyl group, biperidinyl group, etc.).
- a mono- or di-lower alkylamino group or a cyclic amino group pyrrolidinyl group, biperidinyl group, etc.
- the position of the substituent on the ring of the aryl group or the aralkyl group is not particularly limited, and the substituent may be substituted at any of the ortho, methyl, and para positions.
- the position of the substituent is not particularly limited, and the substituent may be present on a carbon atom on the carborane ring and / or a part or all of the boron atom. Is also good.
- it has a lower alkyl group, a lower alkenyl group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, a hydroxyl group, a lower hydroxyalkyl group, a mono- or di-lower alkyl group, a rubamoyl-substituted alkyl group, a lower alkanoyl group, and a substituent.
- the substituent selected from the group consisting of an optionally substituted aryl group and an optionally substituted lower aralkyl group is preferably substituted on a carbon atom constituting the carborane ring.
- some or all of the boron atoms constituting the carborane ring may be substituted with, for example, an alkyl group.
- a carborane ring in which all boron atoms are alkylated, a carborane ring having a substituent only on a carbon atom, and the like are preferable.
- R 2 As the lower alkoxycarbonyl group represented by R 2 , for example, an ethoxycarbonyl group, a methoxycarbonyl group and the like are preferable.
- R 2 may be substituted at any position of the benzene ring, but is preferably substituted at the para position.
- ⁇ ⁇ ⁇ ⁇ ⁇ 5, ⁇ 6, and Upsilon 7 one ⁇ (R 3) - is preferably a group represented by alkyl as the lower alkyl group represented by R 3, as specifically described above Groups can be suitably used.
- R 3 is a hydrogen atom or a methyl group.
- R 4 is preferably a hydrogen atom or a methyl group.
- R 5 , R f ⁇ and R 7 represent a substituent on a phenyl group
- the type, number, and substitution position of the substituent are not particularly limited.
- the substituent on the phenyl group include a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a halogen atom, a carboxyl group, an amino group, an alkanol group, an aralkyl group, and a hydroxyl group. It is not limited to these.
- RR 6 and R 7 are preferably a hydrogen atom, but when Y 8 is —N (R 4 ) — (R 4 represents a lower alkyl group, preferably a methyl group), R 7 is It is preferably a lower alkyl group, for example, a methyl group.
- R 8 is preferably an ethyl group or a phenyl group having a substituent at the para position. When the phenyl group has a substituent, the substituent is a mono- or di-lower alkylamino group.
- the two alkyl groups may be bonded to each other to form a ring. Specific examples include a 2- (N, N-dimethylamino) ethoxy group.
- R 9 is preferably an ethyl group.
- R 10 is preferably a phenyl group having a substituent at the para-position. Examples of the substituent include a mono- or di-lower alkylamino group (two alkyl groups may be bonded to each other to form a ring), and more specifically, a pyrrolidinomethyl group.
- the bonding position is not particularly limited, but it is preferable that R 1 be bonded to the nitrogen atom or the carbonyl group of X at the meta or para position.
- R 1 is directly bonded to the phenyl group substituted by R 2 . In such a case, R 2 is preferably a hydroxyl group.
- R 1 is a dicarbazole-dodecaborane-yl group which may have a lower alkyl group
- R 2 is a carboxyl group or a lower group.
- a compound which represents an alkoxycarbonyl group and wherein X is the above-mentioned linking group is a preferred embodiment of the present invention.
- ⁇ ⁇ 3 , ⁇ 4 , ⁇ 5 , ⁇ 6 , and ⁇ 7 are preferably groups represented by ⁇ (R 3 ) —, and more preferably Preferably, R 3 is a hydrogen atom.
- R 4 , R 5 , and R 6 are preferably hydrogen atoms, but when Y 5 is —N ( 3 ) — (R 3 is a lower alkyl group, preferably a methyl group) R fi is preferably a lower alkyl group, for example, a methyl group.
- Another preferred compound is a compound represented by the formula (I): (2) wherein R 1 is a lower alkyl group, a lower alkenyl group, a carboxyl group, a lower alkoxy group, an amino group, an amino group, a hydroxyl group, Dicarbo-chlorozole which may have a substituent selected from the group consisting of a hydroxyalkyl group, a lower alkanoyl group, a phenyl group which may have a substituent, a hydroxyphenyl group, and a lower alkoxyphenyl group; Compounds which are a dodecaboryl group, R 2 is a hydroxyl group, and X is a single bond can be mentioned.
- R 1 is a lower alkyl group, a lower alkenyl group, a carboxyl group, a lower alkoxy group, an amino group, an amino group, a hydroxyl group, Dicarbo-chlorozole which may have a substituent selected from the group
- the compound represented by the formula (I) may have one or two or more asymmetric carbons, but any optically active isomers based on the asymmetric carbons, stereoisomers such as diastereoisomers, and stereoisomers. Any mixtures, racemates and the like of the isomers are included in the scope of the present invention.
- the compound of the formula (I) may exist as an acid addition salt or a base addition salt, and these are included in the scope of the present invention.
- the acid addition salt include mineral salts such as hydrochloric acid, sulfate, and nitrate, and organic acid salts such as p-toluenesulfonic acid salt and maleic acid salt.
- Examples of the base addition salt include: Examples thereof include metal salts such as sodium salt, potassium salt and calcium salt, and organic amine salts such as ammonium salt and triethylamine salt.
- amino acid salts such as glycine salts and internal salts ( ⁇ -bit ion) are also included in the scope of the present invention.
- the compound of the present invention or a salt thereof may form a hydrate or a solvate, and these are all included in the scope of the present invention.
- R H, BR350 a) ethynyltrimehylsilane, (PPh 3 ) 2 PdCI 2 , Cul, iPrNH. THF; b) K 2 CCV EtOH; c) decaborane (14) / CH 3 CN-C 6 H 6 ; d) KOH / H 2 0-THF; e) (C ⁇ CI) 2, DMF (cat) / CH 2 CI 2 ; f) methyl 4-aminobenzoate / pyridine
- n-BuLi (C 6 H 5 COO) 2 / benzene-Et 20 ; b) BBr ⁇ CH 2 CI 2 ; c) 1) n-BuLi, / benzene-Et 20 2) Br (CH2) n OTHP; d) p-TsOH H 2 0 / CH 3 OH; e) 1) n-BuLi, CuCI / DME 2) 3-iodoanisole / pyridine; f) n-BuLi, I benzene- Et 2 0 2) CICOOCH 3 ; g) LiAIH ⁇ THF ⁇
- the compound represented by the formula (i) has, for example, an action of specifically regulating transcriptional activation by a retinoic acid receptor as a ligand for a nuclear receptor (retinoic acid receptor). More specifically, it has an affinity for retinoic acid receptor RAR or retinoic acid receptor RXR, and can act as an agonist or angiogonist of these receptors, and enhance the action of retinoic acid. It may have an effect.
- the compound represented by the formula (I) can inhibit proliferation of leukemia cells and promote differentiation into normal cells, and is useful as a drug for the treatment of leukemia by differentiation-inducing therapy.
- cancer, rheumatism, atherosclerosis, diabetes It is useful for treating and / or preventing diseases, rejection in organ transplantation, and graft-versus-host disease.
- targeting cancer cells using affinity for nuclear receptors for 1Q targeting cancer cells using affinity for nuclear receptors for 1Q
- It can be used as a medicine in B-neutron capture therapy. Furthermore, it can be used as an estrogen agonist.
- the active ingredient of the medicament of the present invention a compound represented by the above formula (I) or a physiologically acceptable salt, a hydrate or a solvate thereof can be used.
- the above-mentioned active ingredient may be administered as it is, but generally, a pharmaceutical composition containing the above-mentioned active ingredient and one or more pharmaceutical additives is prepared and administered. It is desirable to do.
- the administration route of the medicament of the present invention is not particularly limited. It can be administered orally or parenterally.
- compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups.
- Pharmaceutical compositions suitable for parenteral administration include Examples thereof include injections, drops, suppositories, inhalants, eye drops, nasal drops, transdermal absorbents, ointments, creams, and patches.
- Pharmaceutical additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, dyes, diluents, bases, solubilizers or dissolution aids, isotonic agents, A pH adjuster, a stabilizer, a propellant, an adhesive, and the like can be used, and an appropriate one can be selected and used according to the form of the pharmaceutical composition.
- the dose of the drug of the present invention is not particularly limited, and depends on conditions such as the type of the compound as the active ingredient, the purpose of prevention or treatment, the type of disease to be applied, the age and symptoms of the patient, and the administration route. Appropriate dosages can be selected.
- BR30 was synthesized from 1,12-dicarbachloro-dodecaborane-carboxylic acid by the same production method as BRIO.
- Ethinyltrimethylsilane 5.0 50.9 dragon 01 was dissolved in 50 ml of dry getyl ether, and 35.0 ml (56.0 liter) of a 1.6 M n-butyllithium / hexane solution was added dropwise at 0 ° C under an argon atmosphere. The mixture was stirred at the same temperature for 1 hour. DMF (3.72 g, 50.9 alcohol) was dissolved in ethyl ether (20 ml), added dropwise at 5 ° C. or lower over 30 minutes, and then stirred at room temperature for 2 hours. The reaction was stopped by adding 2N hydrochloric acid, and extracted with getyl ether.
- 1,12-Dicarba-clozo-dodecaborane 3.5 (24.3 brain 01) was dissolved at 01 £ and 16.6 ml (25.6 t ol) of a 1.54 M n-butyllithium / hexane solution was added dropwise at 0 ° C in an argon atmosphere. .
- the reaction solution was stirred at room temperature for 30 minutes, 3.13 g (31.6 tmol) of copper chloride was added at once, and the mixture was further stirred at room temperature for 1 hour. Thereafter, 14.7 ml (183 awakens) of pyridine was added, and 5.97 (25.5 thigh 01) was added at a time, followed by heating at 100 ° C. for 48 hours.
- 0-Methyl-BE130 was demethylated by the same production method as BE160 to obtain 1-hydroxycarbonyl-12- (4-hydroxyphenyl) -1,12-dicarcloclozododecaborane (BE130). .
- Colorless needles ethyl acetate / dichloromethane / hexane); mp: 249-252.
- 0-Methyl-BE 15070m (0.239 t1) was suspended in 3 ml of ethanol, and 4.52 mg (0.119 mol) of sodium borohydride was added thereto, followed by stirring at room temperature for 30 minutes. The reaction was stopped by adding 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated.
- 0-Methyl-BE121 was demethylated by the same production method as BE160. Purified by flash column chromatography on silica gel (eluent: hexane / ethyl acetate 5/1), and trihydroxyethyl -12- (4-hydroxyphenyl) -1,12-dicarbazole chloride decaborane ( BE121) was obtained (94%).
- reaction solution was poured into dry ice, acidified with 1 N hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
- the residue was purified by silica gel column chromatography (developing solvent; n-hexane, 50% chloroform / n-hexane, chloroform), and the raw material (312.3 mg, 22.9%) was eluted from the n-hexane eluate. ) And 2,3,4,5,6,7,8,9,10,1 todecamethyl-1,12-dicarba-closed A white solid of decaborane-1-carboxylic acid (1.20 g, 76.4 I) was obtained.
- This compound (40.5 mg, 0.088 mol) was dissolved in 5 ml of methanol, 1 ml of a 1N aqueous potassium hydroxide solution was added, and the mixture was heated at 80 ° C for 1 hour.
- the reaction mixture was added with 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 4- (2,3,4,5,6). , 7,8,9,10,1 Todecamethyl-1,12-dicarbaclodecodecaborane-1-carbonylamino) benzoic acid (BR635) (39.7 mg, quant.) was obtained as a white solid.
- the crude product is purified by silica gel column chromatography (developing solvent; 20% ethyl acetate / n-hexane) (2,3,4,5,6,7,8,9,10, U-decamethyl).
- -A white solid of 1,12-dicarba-clozo-dodecaneborane-1-yl) (4-methoxycarbonylphenyl) perea (30.7 mg, 50.9%) was obtained.
- This compound (30.7 mg, 0.063 mol) was dissolved in 5 ml of ethanol, 1 ml of a 1N aqueous solution of potassium hydroxide was added, and the mixture was heated at 80 ° C for 1 hour.
- Methyl 4- (4-promophenoxy) benzoate (2.0 g, 6.51 mmol ol), ethynyltrimethylsilane (1.60 g, 16.2 recital ol), (PPh 3 ) 2 PdCl 2 (182 mg, 0.259 thigh ol), Cul (24.8 mg , 0.130 cited ol) in THF (30 ml), and diisopropylamine (1.38 g, 13.7 ol) was added dropwise thereto under an argon atmosphere. After stirring at 50 ° C for 24 hours, the mixture was heated to reflux for 6 hours. After cooling, add water to the reaction mixture, filter the insolubles through celite, and extract the filtrate with ethyl acetate.
- Methyl 4- [4- (2-n-propyl-1,2-dicarba-clozo-dodecaborane-1-yl) benzoyl] benzoate (50 mg, 0.118 mmol) in THF (1 ml) -dichloromethane (1 ml) solution, add trimethylsilane (274 mg, 2.36 t ol) and stir at 50 ° C for 5 hours. Pour the reaction mixture into ice water and extract with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated.
- 0-Methyl-BE200 was converted to trihydroxy-7- (4-hydroxyphenyl) -1,7-dicarclozo-dodecaborane (BE219) by the same production method as BE119.
- Colorless needles (dichloromethane-n-hexane)
- 0-Methyl-BE200 was derived into 1- (2-hydroxyethyl) -7- (4-hydroxyphenyl) -1,7-dicarba-clozo-dodecaborane (BE222) by the same production method as BE122.
- ⁇ ⁇ ⁇ -methyl-BE200 is converted to 1- (3-hydroxypro Pyr) -7- (4-hydroxyphenyl) -1,7-dicarclozode decaborane (BE323).
- 1,2-dicarbazole-dodecaborane was derived from 0-methyl-BE300 to tri (3-hydroxyphenyl) -1,12-dicarba-clozo-dodecaborane (BE300).
- 0-methyl-BE300 is converted to 1- (2-hydroxymethyl ) -12- (3-Hydroxyphenyl) -1,12-dicarclozode decaborane (BE320).
- 0_Methyl-BE300 was derived into 1- (2-hydroxyethyl) -12- (3-hydroxyphenyl) -1,12-dicarba-clozo-dodecaborane (BE322) by the same production method as BE1Z.
- 0-methyl-BE300 was derived into tri (3-hydroxypropyl) -12- (3-hydroxyphenyl) -1,12-dicarba-clozo-dodecaborane (-BE323).
- 0-Methyl-BE400 was derived into 1-hydroxy-7- (3-hydroxyphenyl) -1,7-dicarclozo-dodecaborane (BE419) by the same production method as BE119. Colorless needles (dichloromethane-n-hexane)
- ⁇ -methyl-BE400 was derived to 1- (2-hydroxymethyl) -7- (3-hydroxyphenyl) -1,7-dicarba-clozo-dodecaborane (BE420).
- 0-Methyl-BE400 was converted to tri (2-hydroxyethyl) -7- (3-hydroxyphenyl) -1,7-dicarba-clozo-dodecaborane (BE422) by the same production method as BE12.
- 0-Methyl-BE400 was derived into 1- (3-hydroxypropyl) -7- (3-hydroxyphenyl) -1,7-dicarba-clozo-dodecaborane (BE4Z3) by the same production method as BE123.
- 3-Ethynylanisol 347.0 mg (2.63 awake ol), 3-Ethyl anisol 670.0 mg (2.86 ol, 1.1 eq), (PPh 3 ) 2 PdCl 2 37.2 mg (0.0530 t ol, 0.02 eq) , Cul 5.1 mg (0.0268 ol, 0.01 eq) and 5 ml of THF were added with 0.57 g (5.63 mmol, 2.1 eq) of diisopropylamine under ice cooling and stirred at room temperature for 1 hour. Water is added to the reaction solution, and acetic acid is added. Extracted with ethyl.
- Proliferation suppression of human promyelocytic leukemia cells HL-60 was used as an index.
- Subcultured HL-60 cells were inoculated into RPMI 1640 medium containing fetal bovine serum and antibiotics at an initial cell number of 8 x 10 4 , test compounds at various concentrations were added, and the cells were cultured at 37 ° C. . Four days later, the number of cells was counted.
- the anti-leukemia activity of the test compound was determined by comparing the percentage of differentiated cells with the addition of the test compound ImM to the percentage of differentiated cells when no drug was added using the cell morphology observation and NBT reduction ability as indices. Is shown in the table. Table 1 shows the results when only the test compound was added.
- BR401, BR403 and BR453 were found to have a strong differentiation-inducing effect, and this activity was maintained even at a test compound concentration of 0.01.
- Table 2 shows the results when the differentiation inducer compound Am80 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid) was co-present.
- Am80 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid
- Table 3 shows that HX630 (4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo- [b, f] This is the result when l, 4] thiazepin-ll-yl] benzoic acid was co-present, and differentiation-inducing activity was found in BR110, BR251, and BR350.
- Table 4 shows, as the IC5 () value, the concentration that inhibits the differentiation-inducing effect by 50% when the test compound coexists with the differentiation-inducing compound Am80 1 ⁇ 10—. A remarkable anti-differentiating effect is found on BR630 and BR635. Table 4
- the estrogen activity was determined by measuring the estrogen receptor-dependent transcriptional activation ability of the test compound by a repo overnight gene assay using a luciferase gene.
- C ⁇ S- 1 cells with antibiotics and 5% ⁇ shea fetal serum 24 Anapu rate at D MEM medium containing (cell concentration: 5 to 6 X 10 4 cells / well) at 37 ° C, 5% dioxide
- the cells were cultured overnight in the presence of carbon. On the following day, the medium was replaced with phenol red-free DMEM medium, and the rat estrogen receptor expression plasmid pCI-rER and the estrogen response element were placed upstream of the luciferase gene using the gene transfer reagent Tfx_20 (Promega).
- EREx3-pGL-TK and galactosidase-expressing plasmid pCMV? Used as an internal standard were introduced into the cells. After culturing for 2 hours, phenol red-free DMEM medium containing activated carbon-treated serum was added.
- BE260 1.0 The estrogen activity was measured using the same test method as described above, and the estrogen receptor-dependent transcriptional activation ability of the test compound was measured by a repo overnight gene assay using a luciferase gene.
- Table 6 the estrogenic activities of the test compound at 0.1 nM, 1 nM and ⁇ were expressed as relative values with the luciferase activity expressed in the same volume of the control compound, ⁇ -estradiol, as 100, and the activity intensity was shown. Were compared. All of the compounds shown in this test example showed high estrogenic activity, and in particular, BE119, BE120, and BE320 showed much higher activities than /?-Estradiol used as a control.
- the anti-estrogenic activity was determined by measuring the estrogen receptor-dependent transcriptional activation ability of the test compound in the same manner as the estrogen activity by repo overnight Gene Atsie using a luciferase gene.
- Table 7 coexist antiestrogenic activity of the test compound /? - Estradiol 1 1 luciferase activity expressed at the nM 0 0 and the field IC inhibition concentration of 50% in case 5. It was shown as a value. All of the compounds shown in this test example showed antiestrogenic activity, and in particular, BE362 showed an activity comparable to that of the control antiestrogenic drug moxifen. Table 7
- the compound represented by the above formula (I) or a physiologically acceptable salt thereof has a physiological activity such as a retinoid action, and the medicament of the present invention containing the above substance as an active ingredient is useful for treating leukemia and the like. Useful.
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EP00900863A EP1145718A1 (en) | 1999-01-22 | 2000-01-21 | DICARBA-closo-DODECABORANE DERIVATIVES |
US09/868,934 US6838574B1 (en) | 1999-01-22 | 2000-01-21 | Dicarba-closo-dodecarborane derivatives |
JP2000594470A JP4618894B2 (ja) | 1999-01-22 | 2000-01-21 | ジカルバ−クロゾ−ドデカボラン誘導体 |
AU30758/00A AU3075800A (en) | 1999-01-22 | 2000-01-21 | Dicarba-(closo)-dodecaborane derivatives |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002064601A1 (fr) * | 2001-02-09 | 2002-08-22 | Hiroyuki Kagechika | Dérivés de dicarba-$i(closo)-dodécarborane |
WO2009041482A1 (ja) * | 2007-09-28 | 2009-04-02 | Fujifilm Corporation | アセチレン化合物 |
JP2012153647A (ja) * | 2011-01-26 | 2012-08-16 | Stella Pharma Corp | カルボラン修飾コウジ酸/シクロデキストリン包接錯体およびその製造方法 |
JP2018533621A (ja) * | 2015-09-17 | 2018-11-15 | オハイオ・ステート・イノヴェーション・ファウンデーション | カルボラン化合物及びその使用方法 |
CN109400635A (zh) * | 2018-11-15 | 2019-03-01 | 北京航空航天大学 | 一种非对称双官能度碳硼烷衍生物及制备方法和应用 |
WO2020117799A1 (en) * | 2018-12-03 | 2020-06-11 | Ohio State Innovation Foundation | Carborane compounds, carborane analogs, and methods of use thereof |
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PL387217A1 (pl) | 2009-02-06 | 2010-08-16 | Instytut Biologii Medycznej Polskiej Akademii Nauk | Boranowe pochodne adenozyny |
WO2012148295A1 (en) | 2011-04-28 | 2012-11-01 | Instytut Biologii Medycznej Polskiej Akademii Nauk | Antiviral drug derivative |
EP2793280B1 (en) * | 2011-12-12 | 2017-03-29 | Nippon Steel & Sumikin Chemical Co., Ltd. | Organic electroluminescent element material and organic electroluminescent element using same |
CN105859762B (zh) * | 2016-04-29 | 2016-12-21 | 南京远淑医药科技有限公司 | 邻碳硼烷衍生物、其制备方法和应用及制备该邻碳硼烷衍生物的中间体 |
US11591289B2 (en) | 2017-02-24 | 2023-02-28 | Xeniopro GmbH | Aromatic compounds |
WO2018154118A2 (en) * | 2017-02-24 | 2018-08-30 | Reinmueller Viktoria | Novel aromatic compounds |
WO2021183764A1 (en) * | 2020-03-11 | 2021-09-16 | Ohio State Innovation Foundation | Methods of modulating t-cell activation using carboranes and carborane analogs |
CN111303194B (zh) * | 2020-04-07 | 2022-09-23 | 西安近代化学研究所 | 一种b(4,5)烯基取代碳硼烷衍生物的合成方法 |
CN114591357B (zh) * | 2022-03-07 | 2023-05-16 | 郑州大学 | B(9)-胺基邻碳硼烷类化合物的合成方法 |
WO2023239764A1 (en) * | 2022-06-08 | 2023-12-14 | Ohio State Innovation Foundation | Methods and compositions for treating lupus |
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- 2000-01-21 JP JP2000594470A patent/JP4618894B2/ja not_active Expired - Fee Related
- 2000-01-21 AU AU30758/00A patent/AU3075800A/en not_active Abandoned
- 2000-01-21 WO PCT/JP2000/000285 patent/WO2000043016A1/ja not_active Application Discontinuation
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002064601A1 (fr) * | 2001-02-09 | 2002-08-22 | Hiroyuki Kagechika | Dérivés de dicarba-$i(closo)-dodécarborane |
US7084133B2 (en) | 2001-02-09 | 2006-08-01 | Hiroyuki Kagechika | Dicarba-closo-dodecaborane derivatives |
CN1329400C (zh) * | 2001-02-09 | 2007-08-01 | 影近弘之 | 二碳代-闭合式-十二硼烷衍生物 |
WO2009041482A1 (ja) * | 2007-09-28 | 2009-04-02 | Fujifilm Corporation | アセチレン化合物 |
JP2012153647A (ja) * | 2011-01-26 | 2012-08-16 | Stella Pharma Corp | カルボラン修飾コウジ酸/シクロデキストリン包接錯体およびその製造方法 |
JP2018533621A (ja) * | 2015-09-17 | 2018-11-15 | オハイオ・ステート・イノヴェーション・ファウンデーション | カルボラン化合物及びその使用方法 |
JP2021120390A (ja) * | 2015-09-17 | 2021-08-19 | オハイオ・ステート・イノヴェーション・ファウンデーション | カルボラン化合物及びその使用方法 |
CN109400635A (zh) * | 2018-11-15 | 2019-03-01 | 北京航空航天大学 | 一种非对称双官能度碳硼烷衍生物及制备方法和应用 |
WO2020117799A1 (en) * | 2018-12-03 | 2020-06-11 | Ohio State Innovation Foundation | Carborane compounds, carborane analogs, and methods of use thereof |
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AU3075800A (en) | 2000-08-07 |
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EP1145718A1 (en) | 2001-10-17 |
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