WO1993003012A1 - Derives d'indole - Google Patents
Derives d'indole Download PDFInfo
- Publication number
- WO1993003012A1 WO1993003012A1 PCT/JP1992/000981 JP9200981W WO9303012A1 WO 1993003012 A1 WO1993003012 A1 WO 1993003012A1 JP 9200981 W JP9200981 W JP 9200981W WO 9303012 A1 WO9303012 A1 WO 9303012A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- compound
- formula
- alkyl
- defined above
- Prior art date
Links
- 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 9
- 150000002475 indoles Chemical class 0.000 title abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 104
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims abstract description 26
- 229940113178 5 Alpha reductase inhibitor Drugs 0.000 claims abstract description 5
- 239000002677 5-alpha reductase inhibitor Substances 0.000 claims abstract description 5
- -1 6H-dibenzo[b,d]pyranyl Chemical group 0.000 claims description 183
- 150000001875 compounds Chemical class 0.000 claims description 98
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 45
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 25
- 125000002947 alkylene group Chemical group 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 18
- 238000003379 elimination reaction Methods 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000004450 alkenylene group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 340
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
- 239000000203 mixture Substances 0.000 description 114
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 92
- 239000000243 solution Substances 0.000 description 83
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 238000002360 preparation method Methods 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 46
- 235000019341 magnesium sulphate Nutrition 0.000 description 46
- 239000012044 organic layer Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 22
- 150000002148 esters Chemical group 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 11
- 230000008020 evaporation Effects 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 125000005907 alkyl ester group Chemical group 0.000 description 9
- 229960003604 testosterone Drugs 0.000 description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 230000008030 elimination Effects 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 239000002480 mineral oil Substances 0.000 description 7
- 235000010446 mineral oil Nutrition 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- WORJEOGGNQDSOE-ASTXPPQBSA-N trichloro(deuterio)methane;trideuterio(deuteriooxy)methane Chemical compound [2H]C(Cl)(Cl)Cl.[2H]OC([2H])([2H])[2H] WORJEOGGNQDSOE-ASTXPPQBSA-N 0.000 description 5
- RVQOLTBRWHPYTM-UHFFFAOYSA-N 1-(chloromethyl)-4-(2-methylpropyl)benzene Chemical compound CC(C)CC1=CC=C(CCl)C=C1 RVQOLTBRWHPYTM-UHFFFAOYSA-N 0.000 description 4
- QWBBPBRQALCEIZ-UHFFFAOYSA-N 2,3-dimethylphenol Chemical compound CC1=CC=CC(O)=C1C QWBBPBRQALCEIZ-UHFFFAOYSA-N 0.000 description 4
- JVEREWIHHWATNO-UHFFFAOYSA-N 4-[1-[3-[2-[4-(2-methylpropyl)phenyl]ethenyl]benzoyl]indol-3-yl]butanoic acid Chemical compound C1=CC(CC(C)C)=CC=C1C=CC1=CC=CC(C(=O)N2C3=CC=CC=C3C(CCCC(O)=O)=C2)=C1 JVEREWIHHWATNO-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 201000004384 Alopecia Diseases 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- IPNDFDUOWHDOSW-UHFFFAOYSA-N C1=CC(CC(C)C)=CC=C1C(=O)NC(C=1C=C(C=CC=1)C(=O)N1C2=CC=CC=C2C(CCCC(O)=O)=C1)C1=CC=CC(CC(C)C)=C1 Chemical compound C1=CC(CC(C)C)=CC=C1C(=O)NC(C=1C=C(C=CC=1)C(=O)N1C2=CC=CC=C2C(CCCC(O)=O)=C1)C1=CC=CC(CC(C)C)=C1 IPNDFDUOWHDOSW-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
- 108010029908 3-oxo-5-alpha-steroid 4-dehydrogenase Proteins 0.000 description 3
- 102000001779 3-oxo-5-alpha-steroid 4-dehydrogenase Human genes 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 0 CC1C=CC(C)(*)CCC1NC Chemical compound CC1C=CC(C)(*)CCC1NC 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- WHSROYYJBJDRBV-UHFFFAOYSA-N 1-(1-bromoethyl)-4-(2-methylpropyl)benzene Chemical compound CC(C)CC1=CC=C(C(C)Br)C=C1 WHSROYYJBJDRBV-UHFFFAOYSA-N 0.000 description 2
- FRSGXIIUDGMRIR-UHFFFAOYSA-N 1-(2-methylpropyl)-4-[[4-(2-methylpropyl)phenyl]methyl]benzene Chemical compound C1=CC(CC(C)C)=CC=C1CC1=CC=C(CC(C)C)C=C1 FRSGXIIUDGMRIR-UHFFFAOYSA-N 0.000 description 2
- SYSTWMVKUFDLBN-UHFFFAOYSA-N 1-(2-methylpropyl)-4-phenoxybenzene Chemical compound C1=CC(CC(C)C)=CC=C1OC1=CC=CC=C1 SYSTWMVKUFDLBN-UHFFFAOYSA-N 0.000 description 2
- SFSNTNLIUVOWQF-UHFFFAOYSA-N 1-(methoxymethyl)-4-[4-(2-methylpropyl)cyclohexen-1-yl]benzene Chemical compound C1=CC(COC)=CC=C1C1=CCC(CC(C)C)CC1 SFSNTNLIUVOWQF-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- XROFADGNNZRBGG-UHFFFAOYSA-M 1-[4-(2-methylpropyl)phenyl]ethyl-triphenylphosphanium;bromide Chemical compound [Br-].C1=CC(CC(C)C)=CC=C1C(C)[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XROFADGNNZRBGG-UHFFFAOYSA-M 0.000 description 2
- XYQFDMWLYLHRRD-UHFFFAOYSA-N 1-[4-(methoxymethyl)phenyl]-4-(2-methylpropyl)cyclohexan-1-ol Chemical compound C1=CC(COC)=CC=C1C1(O)CCC(CC(C)C)CC1 XYQFDMWLYLHRRD-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
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- MRMPLXWVMSKDKF-UHFFFAOYSA-N phenyl 3-[[4-(3-methylbutyl)phenoxy]methyl]benzoate Chemical compound C1=CC(CCC(C)C)=CC=C1OCC1=CC=CC(C(=O)OC=2C=CC=CC=2)=C1 MRMPLXWVMSKDKF-UHFFFAOYSA-N 0.000 description 1
- DXMWZHGQMPXOSV-UHFFFAOYSA-N phenyl 3-[[n-benzoyl-4-(2-methylpropyl)anilino]methyl]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1N(C(=O)C=1C=CC=CC=1)CC1=CC=CC(C(=O)OC=2C=CC=CC=2)=C1 DXMWZHGQMPXOSV-UHFFFAOYSA-N 0.000 description 1
- ZLTAKFLXRFPSED-UHFFFAOYSA-N phenyl 3-[bis[4-(2-methylpropyl)phenyl]methylsulfanyl]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1C(C=1C=CC(CC(C)C)=CC=1)SC1=CC=CC(C(=O)OC=2C=CC=CC=2)=C1 ZLTAKFLXRFPSED-UHFFFAOYSA-N 0.000 description 1
- ZACJSFRKRHNUIC-UHFFFAOYSA-N phenyl 3-[bis[[4-(2-methylpropyl)phenyl]methyl]amino]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1CN(C=1C=C(C=CC=1)C(=O)OC=1C=CC=CC=1)CC1=CC=C(CC(C)C)C=C1 ZACJSFRKRHNUIC-UHFFFAOYSA-N 0.000 description 1
- PMRJNQLWRYLGCJ-UHFFFAOYSA-N phenyl 3-[methyl-[4-(2-methylpropyl)benzoyl]amino]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1C(=O)N(C)C1=CC=CC(C(=O)OC=2C=CC=CC=2)=C1 PMRJNQLWRYLGCJ-UHFFFAOYSA-N 0.000 description 1
- HAZAXSFZTQULFE-UHFFFAOYSA-N phenyl 3-aminobenzoate Chemical compound NC1=CC=CC(C(=O)OC=2C=CC=CC=2)=C1 HAZAXSFZTQULFE-UHFFFAOYSA-N 0.000 description 1
- ZNEWOPJNPWLHTQ-UHFFFAOYSA-N phenyl 4-(methoxymethoxy)benzoate Chemical compound C1=CC(OCOC)=CC=C1C(=O)OC1=CC=CC=C1 ZNEWOPJNPWLHTQ-UHFFFAOYSA-N 0.000 description 1
- PPSGTRYVJQTFHT-UHFFFAOYSA-N phenyl 4-[(4-propylphenoxy)methyl]benzoate Chemical compound C1=CC(CCC)=CC=C1OCC1=CC=C(C(=O)OC=2C=CC=CC=2)C=C1 PPSGTRYVJQTFHT-UHFFFAOYSA-N 0.000 description 1
- JZZWIZWGZRFRJA-UHFFFAOYSA-N phenyl 4-[2,2-bis[4-(2-methylpropyl)phenyl]ethyl]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1C(C=1C=CC(CC(C)C)=CC=1)CC1=CC=C(C(=O)OC=2C=CC=CC=2)C=C1 JZZWIZWGZRFRJA-UHFFFAOYSA-N 0.000 description 1
- MEUZYZIADCLSEO-UHFFFAOYSA-N phenyl 4-[2-[4-(2-methylpropyl)phenyl]prop-1-enyl]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1C(C)=CC1=CC=C(C(=O)OC=2C=CC=CC=2)C=C1 MEUZYZIADCLSEO-UHFFFAOYSA-N 0.000 description 1
- OJLHFVBJTVIORT-UHFFFAOYSA-N phenyl 4-[4-(2-methylpropyl)phenoxy]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1OC1=CC=C(C(=O)OC=2C=CC=CC=2)C=C1 OJLHFVBJTVIORT-UHFFFAOYSA-N 0.000 description 1
- DZQOHTLDDTUDQL-UHFFFAOYSA-N phenyl 4-[4-(2-methylpropyl)phenyl]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1C1=CC=C(C(=O)OC=2C=CC=CC=2)C=C1 DZQOHTLDDTUDQL-UHFFFAOYSA-N 0.000 description 1
- ZOUUQWPTFIAURY-UHFFFAOYSA-N phenyl 4-[[4-(2-methylpropyl)phenyl]methoxy]benzoate Chemical compound C1=CC(CC(C)C)=CC=C1COC1=CC=C(C(=O)OC=2C=CC=CC=2)C=C1 ZOUUQWPTFIAURY-UHFFFAOYSA-N 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 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
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- LTSUHJWLSNQKIP-UHFFFAOYSA-J tin(iv) bromide Chemical compound Br[Sn](Br)(Br)Br LTSUHJWLSNQKIP-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 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
- 125000003944 tolyl group Chemical group 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
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
Definitions
- the present invention relates to novel indole
- novel indole derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as inhibitory activity on testosteron 5 ⁇ -reductase and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.
- one object of the present invention is to provide novel indole derivatives and a
- Another object of the present invention is to provide process for preparation of said indole derivatives or a salt thereof.
- a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said indole derivatives or a
- Still further object of the present invention is to provide a use of said indole derivatives or a
- testosteron 5 ⁇ -reductase inhibitor useful for treating or preventing testosteron 5 ⁇ -reductase mediated diseases such as alopecia, acnes, prostatism, and the like in human being or animals.
- testosteron 5 ⁇ -reductase inhibitor useful for treating or preventing testosteron 5 ⁇ -reductase mediated diseases such as alopecia, acnes, prostatism, and the like in human being or animals.
- the indole derivatives of the present invention are novel and can be represented by the formula (I) :
- R 1 is carboxy or protected carboxy
- R 2 is hydrogen, lower alkyl or halogen
- R 3 is aryl or ar( lower) alkyl, each of which may have suitable substituent(s), or a group of the formula : in which - is heterocyclic group
- n 0 or 1
- A is lower alkylene which may be substituted by oxo or lower alkenylene
- Q is carbonyl, sulfonyl or lower alkylene
- R 4 is hydrogen or lower alkyl
- R 5 is hydrogen, lower alkyl or
- Y is bond or lower alkylene
- Z is bond, lower alkylene, lower alkenylene, -O-,
- R 6 is lower alkyl, ar( lower) alkyl which may have suitable
- X-Y-Z-R is 6H-dibenzo[b,d]pyranyl which may have suitable substituent(s).
- the object compound (I) and a salt thereof can be prepared by the following processes.
- R 1 , R 2 , R 3 , R 4 , R 5 , A, Q, X, Y and Z are each as defined above,
- ar(lower)alkyl which may have suitable substituent(s) or a group of the formula :
- R 7 is aryl which may have suitable substituent(s)
- R 8 is carboxy protective group
- R 9 is amino which may have suitable substituent(s)
- W 1 , W 2 , W 3 and W 4 are each acid residue.
- Y 1 is lower alkylene
- Z 1 is -O-, -S- or
- Z 2 is -O-, -S- or
- Suitable salts of the compounds (I) are conventional non-toxic, pharmaceutically acceptable salt and may
- a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g.
- an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
- an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
- a salt with a basic or acidic amino acid e.g.
- lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
- Suitable “lower alkyl” may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
- halogen means fluoro, chloro, bromo and iodo.
- Suitable "lower alkylene” means straight or branched bivalent lower alkane such as methylene, ethylene,
- trimethylene tetramethylene, pentamethylene
- Suitable "acid residue” may include halogen (e.g.
- acyloxy e.g. acetoxy, tosyloxy, mesyloxy, etc.
- aryloxy e.g. phenoxy, etc.
- Suitable "lower alkenylene” may include one having 2 to 6 carbon atoms such as vinylene, propenylene, and the like.
- substituent(s) may include a conventional group such as aryl (e.g. phenyl, naphthyl, etc.), substituted aryl, for example, lower alkylaryl (e.g. tolyl, xylyl, mesityl, cumenyl, isobutylphenyl, isopentylphenyl, etc.), haloaryl (e.g. chlorophenyl, bromophenyl, dichlorophenyl, etc.), lower alkoxyaryl (e.g. isopropoxyphenyl, etc.), lower alkylcarbamoylaryl (e.g. t-butylcarbamoylphenyl, etc.), and the like.
- aryl e.g. phenyl, naphthyl, etc.
- substituted aryl for example, lower alkylaryl (e.g. tolyl, xylyl, mesityl, cumenyl, iso
- Suitable "ar(lower)alkyl which may have suitable substituent(s)” may include a conventional group such as ar(lower)alkyl (e.g. trityl, benzhydryl, benzyl,
- ar(lower) alkyl for example, ar(lower) alkyl substituted by one or more substituents such as lower alkyl as mentioned above, halogen as mentioned above, cyano, carboxy, protected carboxy as mentioned below, aryl which may have suitable substituent(s) as mentioned above, amidated carboxy as mentioned below and oxo.
- substituents such as lower alkyl as mentioned above, halogen as mentioned above, cyano, carboxy, protected carboxy as mentioned below, aryl which may have suitable substituent(s) as mentioned above, amidated carboxy as mentioned below and oxo.
- aromatic(lower)alkyl which may have suitable substituents may be methylbenzyl, propylbenzyl,
- Suitable "amino protective group” may be a
- conventional protective group which is used in the field of organic chemistry, that is, may include acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
- acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
- Suitable "protected carboxy” may include an
- esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable
- substituent(s) for example, lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
- lower alkanoyloxy(lower)alkyl ester e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester
- alkanesulfonyl(lower) alkyl ester e.g. 2-mesylethyl ester, etc.
- mono( or di or tri)-halo(lower)alkyl ester e.g.
- alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester e.g.
- lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
- lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
- ar(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester,
- substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
- substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
- phthalidyl ester e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
- esterified carboxy as mentioned above may include lower alkoxycarbonyl (e.g.
- Suitable “carboxy protective group” may be the ester moiety of the above defined “protected carboxy” and may include lower alkyl (e.g. methyl, ethyl, etc.),
- ar(lower)alkyl e.g. benzyl, etc.
- ar(lower)alkyl e.g. benzyl, etc.
- pharmaceutical field may include amino, mono or
- di(lower)alkylamino e.g. methylamino, dimethylamino, ethylamino, diethylamino, butylamino, t-butylamino, etc.
- arylamino e.g. phenylamino, etc.
- lower alkylarylamino e.g. isobutylphenylamino, etc.
- Suitable "heterocyclic group containing nitrogen atom” may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom.
- Especially preferable heterocyclic group may be 5- or 6- membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl,
- piperidyl, piperazinyl, etc. unsaturated condensed heterocyclic group such as dibenzo[6 or 7-membered unsaturated]heteromonocyclic group (e.g. phenoxazinyl, phenothiazinyl, 10,11-dihydro-5H-dibenzoazepinyl, etc.), and the like.
- unsaturated condensed heterocyclic group such as dibenzo[6 or 7-membered unsaturated]heteromonocyclic group (e.g. phenoxazinyl, phenothiazinyl, 10,11-dihydro-5H-dibenzoazepinyl, etc.), and the like.
- Suitable "amidated carboxy” may carbamoyl which may have suitable substituent( s) and may include carbamoyl, mono or di( lower)alkylcarbamoyl (e.g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl diethylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, etc.), lower alkylaryl- carbamoyl (e.g. isobutylphenylcarbamoyl, etc.), and the like.
- lower alkylaryl- carbamoyl e.g. isobutylphenylcarbamoyl, etc.
- Suitable "6H-dibenzo[b,d]pyranyl which may have suitable substituent(s)" may include
- 6H-dibenzo[b,d]pyranyl substituted by lower alkyl as mentioned above e.g. 8-isobutyl-3,4,6,6-tetramethyl-6H- dibenzo[b,d]pyranyl, etc., and the like.
- R 1 , R 2 , R 3 , A, Q, X, Y and Z are as follows.
- R 1 is carboxy;
- alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, etc.
- ar(lower)alkoxycarbonyl more preferably mono- or di- or triphenyl(C 1 -C 4 )alkoxycarbonyl (e.g.
- R 2 is hydrogen
- lower alkyl more preferably C 1 -C 4 alkyl (e.g.
- R 3 is aryl which may be substituted by one to three substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and lower
- alkylcarbamoyl more preferably phenyl which may be substituted by one to three substituent(s) selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and C 1 -C 4 alkylcarbamoyl (e.g.
- ar(lower) alkyl which may be substituted by one to three substituents selected from the group consisting of lower alkyl, halogen, cyano, carboxy, protected carboxy, amidated carboxy, and oxo, more preferably mono- or di- or triphenyK lower)alkyl which may be substituted by one or two the groups selected from lower alkyl, halogen, cyano, carboxy, phenyl(lower)- alkoxycarbonyl, mono or di(lower)alkylcarbamoyl, phenylcarbamoyl and lower alkylphenylcarbamoyl, most preferably mono- or di- or triphenyl(C 1 -C 6 )alkyl which may be substituted by the group selected from (C 1 -C 4 )alkyl, halogen, cyano, carboxy,
- (C 1 -C 4 )alkylphenylcarbamoyl and oxo e.g. benzyl, propylbenzyl, isobutylbenzyl, isobutylphenylethyl, isobutylphenylpropyl, isobutylphenylpentyl,
- A is lower alkylene which may be substituted by oxo, more preferably C 1 -C 4 alkylene which may be substituted by oxo (e.g. ethylene, trimethylene, oxotrimethylene, etc.); or
- lower alkylene more preferably C 1 -C 4 alkylene (e.g. methylene, etc.),
- R 4 is hydrogen; or lower alkyl, more
- C 1 -C 4 alkyl e.g. methyl, etc.
- R 5 is hydrogen; lower alkyl, more preferably C 1 -C 4 alkyl (e.g. methyl, etc.); or ar(lower)alkylamino which may be
- alkylbenzylamino e.g.
- Y is bond
- lower alkylene more preferably C 1 -C 4 alkylene (e.g. methylene, etc.), and
- lower alkylene more preferably C 1 -C 4 alkylene (e.g. methylene, etc.);
- alkenylene more preferably C 2 -C 4 alkenylene (e.g. propenylene, etc.),
- R 6 is lower alkyl, preferably
- C 1 -C 4 alkyl e.g. methyl, ethyl, etc.
- lower alkoxycarbonyl preferably C 1 -C 4 alkoxycarbonyl (e.g. t-butoxycarbonyl, etc.);
- ar(lower)alkyl which may be substituted by lower alkyl, more preferably mono- or di- or triphenyKlower)alkyl which may be substituted by lower alkyl, most
- triphenyl(C 1 -C 6 ) alkyl which may be
- C 1 -C 4 alkyl e.g. benzyl, isobutylbenzyl, etc.
- X-Y-Z-R 3 is 6H-dibenzo[b,d]pyranyl which may be substituted by lower alkyl, more preferably 6H-dibenzo[b,d]pyranyl
- the object compound (I-a) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
- This reaction is usually carried out in a solvent such as alcohol [e.g. methanol, ethanol, etc.],
- the reaction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc.], an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), tri(lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridine or its derivative [e.g. picoline, lutidine,
- an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
- an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
- an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate
- the base to be used is liquid, it can also be used as a solvent.
- the reaction temperature is not critical, and the reaction can be carried out under cooling, at room
- the object compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
- reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
- the object compound (I-b) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
- reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
- the object compound (I-c) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (III) or a salt thereof.
- reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
- the present reaction includes, within its scope, the case that when R is carboxy, it is protected during the reacting or at the post-treating step of the present process.
- the object compound (I-e) or a salt thereof can be prepared by subjecting the compound (I-d) or a salt thereof to elimination reaction of the carboxy protective group.
- hydrolysis is preferably carried out in the presence of a base or an acid.
- Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium bicarbonate), sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
- alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
- alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
- alkaline earth metal carbonate e.g. magnesium carbonate, calcium
- alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
- alkali metal acetate e.g. sodium acetate, potassium acetate, etc.
- alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
- alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
- an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline-, N-methylpyrrolidine, N-methylmorpholine,
- the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
- Suitable acid may include an organic acid (e.g.
- formic acid acetic acid, propionic acid, etc.
- an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
- the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
- the reaction temperature is not critical, and it may suitable be selected in accordance with the kind of the carboxy protective group and the elimination method.
- the elimination using Lewis acid is preferable to eliminate substituted or unsubstituted ar(lower)alkyl ester and carried out by reacting the compound (Ig) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium
- tetrabromide e.g. tin
- tetrachloride tin tetrabromide, etc.
- aluminum halide e.g. aluminum chloride, aluminum bromide, etc.
- trihaloacetic acid e.g. trichloroacetic acid
- This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylene chloride, etc.), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof.
- the reduction elimination can be applied preferably for elimination of the protective group such as
- halo(lower)alkyl e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.
- ar(lower)alkyl e.g. benzyl, etc.
- the reduction method applicable for the elimination reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or an inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the
- the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
- the object compound (I-g) or a salt thereof can be prepared by subjecting the compound (I-f) or a salt thereof to elimination reaction of the carboxy protective group.
- reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 5.
- reaction mode and reaction conditions e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.
- the object compound (I-h) or a salt thereof can be prepared by reacting a compound (I-g) or its reactive derivative at the carboxy group or a salt thereof with a compound (IX) or its reactive derivative at the amino group or a salt thereof.
- Suitable reactive derivative at the amino group of the compound (IX) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IX) wit a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (IX) with a silyl compound such as bis(trimethylsilyl)acetamide,
- Suitable reactive derivative at the carboxy group of the compound (I-g) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
- Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride within acid such as substituted phosphoric acid [e.g.
- halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, is ⁇ butyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole,
- dimethylpyrazole, triazole or tetrazole or an activated ester
- N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
- N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
- These reactive derivatives can optionally be selected from them according to the kind of the
- the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
- a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
- a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
- N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
- triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt
- reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine,
- N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, or the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
- the object compound (I-i) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XI) or a salt thereof.
- reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
- the present reaction includes, within its scope, the case that when R 1 is carboxy, it is protected during the reaction or at the post-treating step of the present process.
- the object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-e) or a salt thereof to introduction reaction of the carboxy protective group.
- reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvent,s reaction
- the starting compounds (II), (IV) and (VI) can be prepared by the details of which are shown in Preparations mentioned below, or a conventional manner.
- the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional
- the object compound (I) of the present invention is useful as a testosteron 5 ⁇ -reductase inhibitor and
- testosteron 5 ⁇ -reductase mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism, etc.), androgenic alopecia (or male-pattern baldness), acne (e.g. acne vulgarism, pimple etc.), other hyperandrogenism, and the like.
- Test Compound (1) 4-[1-[3-(3-Isobutylphenoxymethyl)benzoyl]indol-3-yl]- butyric acid
- 1,2,6,7- 3 H-Testosterone (85-105 Ci/mmol) is a mixture of 1,2,6,7- 3 H-testosterone and testosterone which includes 85-105 Ci of 1,2,6,7- 3 H-testosterone per mmol of testosterone and is purchased from New
- the reaction solution contains 1 mM dithiothreitol, 40 mM sodium phosphate pH 6.5, 50 ⁇ M NADPH,
- the object compound (I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external
- the pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, lotion and the like.
- auxiliary substances such as lactose, citric acid, tartaric acid, stearic acid,
- magnesium stearate magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
- While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 rag, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
- dichloromethane 300 ml was added a solution of bromine (8.20 ml) in dichloromethane (20 ml) at -20°C. After stirred for 1.5 hours, the mixture was washed with water. The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was
- Triphenylphosphine (7.23 g) was added to a mixture of 3-bromo-4,5-dimethylbenzyl alcohol (3.95 g) and carbon tetrabromide (9.14 g) in ether (100 ml) at 0°C, and the mixture was allowed to warm up to 25°C. The reaction mixture was stirred at 25°C for 2 hours, and then the precipitates were filtered off. The filtrate was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was
- 1,4-cyclohexanedione mono-ethylene acetal (10.0 g) in tetrahydrofuran (100 ml). The mixture was stirred at room temperature for 3 days and partitioned between diethyl ether and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (300 g) using a mixture of n-hexane and 5% ethyl acetate as the eluent. Appropriate fractions were combined and evaporated to give 4-(2-methyl-1-propylidene)cyclohexan ⁇ ne ethylene acetal (12.16 g) as a colorless oil.
- tetrahydrofuran (30 ml) was added a solution of potassium tert-butoxide (1.67 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 1 hour. To the mixture was added a solution of 3-bromobenzaldehyde (1.6 ml) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 3 hours, and portioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and then a solution of 4-isobutylcyclohexanone (2.0 g) in tetrahydrofuran (30 ml) was added at 25°C.
- reaction mixture was poured into a mixture of ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate.
- triphenylphosphonium iodide (5.82 g) in tetrahydrofuran (50 ml) at 0°C.
- the reaction mixture was allowed to warm up to 25°C and stirred at the same temperature for 1 hour .
- a solution of methyl 3- ( 3-formylphenoxymethyl)benzoate (2.8 g) in tetrahydrofuran (20 ml) was added to the mixture at 0°C.
- the reaction mixture was stirred at 0°C for 30 minutes and the solvent was evaporated off.
- the residue was quenched with 1N hydrochloric acid and the mixture was extracted with ether.
- the extract was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was
- n-Butyl lithium (1.6 M solution in hexane) (6 ml) was added to a solution of bis(4-isobutylphenyl)methane (2.25 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 5 hours and cooled at 0°C. To the mixture was added a solution of 4-bromobenzylbromide (2.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at 0°C for 30 minutes and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated.
- Acetic anhydride (20 ml) was added to a solution of bis (4-isobutylphenyl)methanol (11.07 g) in pyridine (40 ml). The mixture was stirred at room temperature for 5 hours and partitioned between ethyl acetate and water.
- Acetyl chloride (0.94 ml) was added to a suspension of aluminum chloride (1.76 g) in dichloromethane (15 ml) at 3°C. The mixture was stirred at 3°C for 15 minutes. To the mixture was added a solution of 4-isobutylphenyl phenyl ether (2.67 g) in dichloromethane (15 ml). The mixture was stirred at 0°C for 1 hour and poured into 7% hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give 4-(4-isobutylphenoxy)acetophenone (3.30 g) as a colourless oil.
- Trifluoroacetic acid (10 ml) was added to a solution of methyl 3-[N-t-butoxycarbonyl-N-'(4-isobutylphenyl)- aminomethyl]benzoate (1.5 g) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours and evaporated. The residue was dissolved in
- 6-chloroindole (3.0 g) in dichloromethane (20 ml) at 25°C.
- the reaction mixture was stirred at 25°C for.1 hour, and poured into a mixture of ice and 1N hydrochloric acid.
- reaction mixture was stirred at 25°C for 15 minutes and poured into a mixture of ethyl acetate and 1N hydrochloric acid.
- the organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (50 g) eluting with
- Methyl 4-(6-chloroindol-3-yl)butyrate (1.2 g) was hydrolyzed with 1N aqueous solution of sodium hydroxide (12 ml) and the crude product was recrystallized from a mixture of ethyl acetate and hexane to give 4-(6- chloroindol-3-yl)butyric acid (1.09 g) as colorless crystals.
- N,N-dimethylformamide (20 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 1.05 g) in N,N-dimethylformamide (30 ml) at 25°C over 15 minutes. The mixture was stirred at 25°C for 1.5 hours and cooled to -40°C. A solution of phenyl 3-(methoxymethoxy)benzoate (3.07 g) in tetrahydrofuran (40 ml) was added at -40°C over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes.
- Benzyl 4-[1-[4-(methoxymethoxy)benzoyl]indol-3-yl]- butyrate was dissolved in trifluoroacetic acid (12 ml) at 25°C and the mixture was stirred at the same temperature for 15 minutes. After evaporation of the solvent, the residue was dissolved with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated.
- Chloromethyl methyl ether (0.17 ml) was added to a mixture of 4-[1-[4-(4'-benzyloxycarbonyl)biphenylcarbonyl]indol-3-yl]butyric acid (0.55 g) and potassium carbonate (0.21 g) in dimethylformamide (10 ml). The mixture was stirred at room temperature for 5 hours and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (40 g) using a mixture of n-hexane and ethyl acetate (5:1) as an eluent.
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Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5503471A JPH06511238A (ja) | 1991-08-02 | 1992-08-03 | インドール誘導体 |
EP92916519A EP0600084A1 (fr) | 1991-08-02 | 1992-08-03 | Derives d'indole |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919116732A GB9116732D0 (en) | 1991-08-02 | 1991-08-02 | Indole derivatives |
GB9116732.0 | 1991-08-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993003012A1 true WO1993003012A1 (fr) | 1993-02-18 |
Family
ID=10699428
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1992/000981 WO1993003012A1 (fr) | 1991-08-02 | 1992-08-03 | Derives d'indole |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0600084A1 (fr) |
JP (1) | JPH06511238A (fr) |
GB (1) | GB9116732D0 (fr) |
WO (1) | WO1993003012A1 (fr) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0757982A1 (fr) * | 1995-08-08 | 1997-02-12 | Roussel Uclaf | Composés biphényles, leur procédé de préparation et les intermédiaires de ce procédé, leur application en tant qu'inhibiteur de la 5-alpha-réductase et les compositions pharmaceutiques les contenant |
EP0967195A1 (fr) * | 1998-03-30 | 1999-12-29 | Quest International B.V. | Cétones aldéhydiques et leur utilisation dans des parfums |
US6448220B1 (en) | 1998-03-30 | 2002-09-10 | Quest International B.V. | Fragrance compound |
US7022708B2 (en) | 2002-10-18 | 2006-04-04 | Roche Palo Alto Llc | 4-piperazinyl benzenesulfonyl indoles and uses thereof |
US7196089B2 (en) | 2003-01-29 | 2007-03-27 | Asterand Uk Limited | EP4 receptor antagonists |
US7417068B2 (en) | 2003-10-16 | 2008-08-26 | Asterand Uk Limited | EP4 receptor antagonists |
US7855225B2 (en) | 2006-03-02 | 2010-12-21 | Astellas Pharma Inc. | 17βHSD type 5 inhibitor |
US8513422B2 (en) | 2007-08-31 | 2013-08-20 | Astellas Pharma Inc. | Piperidine derivative |
WO2018154118A3 (fr) * | 2017-02-24 | 2018-12-06 | Xeniopro GmbH | Nouveaux composés aromatiques |
JP2019513703A (ja) * | 2016-03-17 | 2019-05-30 | ゼニオプロ ゲーエムベーハー | NotchシグナリングのエンハンサーならびにNotchのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用 |
US11591289B2 (en) | 2017-02-24 | 2023-02-28 | Xeniopro GmbH | Aromatic compounds |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA67754C2 (uk) * | 1997-10-10 | 2004-07-15 | Пфайзер, Інк. | Агоністи простагландину, фармацевтична композиція на їх основі (варіанти), спосіб нарощення та збереження кісткової маси у хребетних та спосіб лікування (варіанти) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991013060A1 (fr) * | 1990-02-26 | 1991-09-05 | Fujisawa Pharmaceutical Co., Ltd. | Derives d'indole |
-
1991
- 1991-08-02 GB GB919116732A patent/GB9116732D0/en active Pending
-
1992
- 1992-08-03 WO PCT/JP1992/000981 patent/WO1993003012A1/fr not_active Application Discontinuation
- 1992-08-03 JP JP5503471A patent/JPH06511238A/ja active Pending
- 1992-08-03 EP EP92916519A patent/EP0600084A1/fr not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991013060A1 (fr) * | 1990-02-26 | 1991-09-05 | Fujisawa Pharmaceutical Co., Ltd. | Derives d'indole |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0757982A1 (fr) * | 1995-08-08 | 1997-02-12 | Roussel Uclaf | Composés biphényles, leur procédé de préparation et les intermédiaires de ce procédé, leur application en tant qu'inhibiteur de la 5-alpha-réductase et les compositions pharmaceutiques les contenant |
FR2737721A1 (fr) * | 1995-08-08 | 1997-02-14 | Roussel Uclaf | Nouveaux composes biphenyles, leur procede de preparation et les intermediaires de ce procede, leur application a titre de medicament et les compositions pharmaceutiques les contenant |
US5827887A (en) * | 1995-08-08 | 1998-10-27 | Roussel Uclaf | Biphenyl compounds |
EP0967195A1 (fr) * | 1998-03-30 | 1999-12-29 | Quest International B.V. | Cétones aldéhydiques et leur utilisation dans des parfums |
US6448220B1 (en) | 1998-03-30 | 2002-09-10 | Quest International B.V. | Fragrance compound |
US7022708B2 (en) | 2002-10-18 | 2006-04-04 | Roche Palo Alto Llc | 4-piperazinyl benzenesulfonyl indoles and uses thereof |
US7196089B2 (en) | 2003-01-29 | 2007-03-27 | Asterand Uk Limited | EP4 receptor antagonists |
US7858644B2 (en) | 2003-01-29 | 2010-12-28 | Asterand Uk Limited | EP4 receptor antagonists |
US7507754B2 (en) | 2003-01-29 | 2009-03-24 | Asterand Uk Limited | EP4 receptor antagonists |
US7528157B2 (en) | 2003-01-29 | 2009-05-05 | Asterand Uk Limited | EP4 receptor antagonists |
US7569602B2 (en) | 2003-10-16 | 2009-08-04 | Asterand Uk Limited | Furan derivatives as EP4 receptor antagonists |
US7417068B2 (en) | 2003-10-16 | 2008-08-26 | Asterand Uk Limited | EP4 receptor antagonists |
US7855225B2 (en) | 2006-03-02 | 2010-12-21 | Astellas Pharma Inc. | 17βHSD type 5 inhibitor |
US8513422B2 (en) | 2007-08-31 | 2013-08-20 | Astellas Pharma Inc. | Piperidine derivative |
JP2019513703A (ja) * | 2016-03-17 | 2019-05-30 | ゼニオプロ ゲーエムベーハー | NotchシグナリングのエンハンサーならびにNotchのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用 |
JP2023002688A (ja) * | 2016-03-17 | 2023-01-10 | ゼニオプロ ゲーエムベーハー | NotchシグナリングのエンハンサーならびにNotchのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用 |
JP2023027160A (ja) * | 2016-03-17 | 2023-03-01 | ゼニオプロ ゲーエムベーハー | NotchシグナリングのエンハンサーならびにNotchのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用 |
JP7402300B2 (ja) | 2016-03-17 | 2023-12-20 | ゼニオプロ ゲーエムベーハー | NotchシグナリングのエンハンサーならびにNotchのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用 |
WO2018154118A3 (fr) * | 2017-02-24 | 2018-12-06 | Xeniopro GmbH | Nouveaux composés aromatiques |
US11591289B2 (en) | 2017-02-24 | 2023-02-28 | Xeniopro GmbH | Aromatic compounds |
Also Published As
Publication number | Publication date |
---|---|
GB9116732D0 (en) | 1991-09-18 |
EP0600084A1 (fr) | 1994-06-08 |
JPH06511238A (ja) | 1994-12-15 |
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