WO1993016996A1 - Indole derivatives as testosterone-5-alpha-reductase inhibitors - Google Patents
Indole derivatives as testosterone-5-alpha-reductase inhibitors Download PDFInfo
- Publication number
- WO1993016996A1 WO1993016996A1 PCT/JP1993/000201 JP9300201W WO9316996A1 WO 1993016996 A1 WO1993016996 A1 WO 1993016996A1 JP 9300201 W JP9300201 W JP 9300201W WO 9316996 A1 WO9316996 A1 WO 9316996A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- salt
- formula
- ester
- carboxy
- Prior art date
Links
- 239000002677 5-alpha reductase inhibitor Substances 0.000 title abstract description 4
- 150000002475 indoles Chemical class 0.000 title description 8
- 229940054051 antipsychotic indole derivative Drugs 0.000 title description 7
- 229940095585 testosterone-5-alpha reductase inhibitors for benign prostatic hypertrophy Drugs 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 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 33
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 7
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 5
- 230000001404 mediated effect Effects 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 14
- 238000003379 elimination reaction Methods 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 229940123934 Reductase inhibitor Drugs 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 102000004316 Oxidoreductases Human genes 0.000 claims 1
- 108090000854 Oxidoreductases Proteins 0.000 claims 1
- 201000004384 Alopecia Diseases 0.000 abstract description 7
- 206010000496 acne Diseases 0.000 abstract description 6
- 208000002874 Acne Vulgaris Diseases 0.000 abstract description 4
- 206010020112 Hirsutism Diseases 0.000 abstract description 4
- 206010036976 Prostatism Diseases 0.000 abstract description 3
- 231100000360 alopecia Toxicity 0.000 abstract description 3
- 229940113178 5 Alpha reductase inhibitor Drugs 0.000 abstract description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 abstract description 2
- 206010060862 Prostate cancer Diseases 0.000 abstract description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 abstract description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 2
- 206010068168 androgenetic alopecia Diseases 0.000 abstract description 2
- 201000002996 androgenic alopecia Diseases 0.000 abstract description 2
- 201000010066 hyperandrogenism Diseases 0.000 abstract description 2
- 201000004240 prostatic hypertrophy Diseases 0.000 abstract description 2
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 abstract 1
- -1 alkali metal salt Chemical class 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- 239000000203 mixture Substances 0.000 description 37
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 35
- 238000002360 preparation method Methods 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical group 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 229960003604 testosterone Drugs 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000005907 alkyl ester group Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 230000008030 elimination Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 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 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 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
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- SYMCOBUELYUSNB-UHFFFAOYSA-N 2-ethoxy-1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CCOCC(=O)C1=CC=C(CC(C)C)C=C1 SYMCOBUELYUSNB-UHFFFAOYSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KEAGRYYGYWZVPC-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(C)=O)C=C1 KEAGRYYGYWZVPC-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- JYGWKFINRSSRSG-UHFFFAOYSA-N 2-chloro-1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(=O)CCl)C=C1 JYGWKFINRSSRSG-UHFFFAOYSA-N 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-pentanol Substances CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- UYLRCKCVZFMZPK-UHFFFAOYSA-N 3-chloro-1-[4-(2-methylpropyl)phenyl]propan-1-one Chemical compound CC(C)CC1=CC=C(C(=O)CCCl)C=C1 UYLRCKCVZFMZPK-UHFFFAOYSA-N 0.000 description 2
- JIDABXGUMGITFC-UHFFFAOYSA-N 4-(2-propylpentyl)benzoyl chloride Chemical compound CCCC(CCC)CC1=CC=C(C(Cl)=O)C=C1 JIDABXGUMGITFC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 2
- LXAKVLBCNLKTKI-UHFFFAOYSA-N 6-bromoundecane Chemical compound CCCCCC(Br)CCCCC LXAKVLBCNLKTKI-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- LOOOGVGAVUQDTP-UHFFFAOYSA-N C(C(C)C)C1=CC=C(C=C1)C(C=CCC)=O Chemical compound C(C(C)C)C1=CC=C(C=C1)C(C=CCC)=O LOOOGVGAVUQDTP-UHFFFAOYSA-N 0.000 description 2
- GTUWTUMQQKGQLW-UHFFFAOYSA-N C(C(C)C)C1=CC=C(C=C1)C(C=CCC)O Chemical compound C(C(C)C)C1=CC=C(C=C1)C(C=CCC)O GTUWTUMQQKGQLW-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- SAZDHCJWMDBHMQ-UHFFFAOYSA-N ethyl 4-[3-(4-fluorobenzoyl)indol-1-yl]butanoate Chemical compound C12=CC=CC=C2N(CCCC(=O)OCC)C=C1C(=O)C1=CC=C(F)C=C1 SAZDHCJWMDBHMQ-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002985 plastic film Substances 0.000 description 2
- 239000001205 polyphosphate Substances 0.000 description 2
- 235000011176 polyphosphates Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 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 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- OQFITNTXYYDXLY-AWEZNQCLSA-N (1r)-2-ethoxy-1-[4-(2-methylpropyl)phenyl]ethanol Chemical compound CCOC[C@H](O)C1=CC=C(CC(C)C)C=C1 OQFITNTXYYDXLY-AWEZNQCLSA-N 0.000 description 1
- OQFITNTXYYDXLY-CQSZACIVSA-N (1s)-2-ethoxy-1-[4-(2-methylpropyl)phenyl]ethanol Chemical compound CCOC[C@@H](O)C1=CC=C(CC(C)C)C=C1 OQFITNTXYYDXLY-CQSZACIVSA-N 0.000 description 1
- VWIPMQNJODLVFA-UHFFFAOYSA-N (4-fluorophenyl)-(1h-indol-3-yl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CNC2=CC=CC=C12 VWIPMQNJODLVFA-UHFFFAOYSA-N 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- CTYJGUDXWIAZCM-UHFFFAOYSA-N 2-ethyl-3h-1,2-benzoxazol-7-ol Chemical compound C1=CC(O)=C2ON(CC)CC2=C1 CTYJGUDXWIAZCM-UHFFFAOYSA-N 0.000 description 1
- IIRKKHLLOOXHFJ-UHFFFAOYSA-N 2-methoxy-1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound COCC(=O)C1=CC=C(CC(C)C)C=C1 IIRKKHLLOOXHFJ-UHFFFAOYSA-N 0.000 description 1
- NSHAOELVDPKZIC-UHFFFAOYSA-N 3-(2-ethyl-1,2-oxazol-2-ium-5-yl)benzenesulfonic acid;hydroxide Chemical compound [OH-].O1[N+](CC)=CC=C1C1=CC=CC(S(O)(=O)=O)=C1 NSHAOELVDPKZIC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FZPXDEFBEYPBAB-UHFFFAOYSA-N 3-ethoxy-1-[4-(2-methylpropyl)phenyl]propan-1-one Chemical compound CCOCCC(=O)C1=CC=C(CC(C)C)C=C1 FZPXDEFBEYPBAB-UHFFFAOYSA-N 0.000 description 1
- PUMGRMDZOJMBRN-UHFFFAOYSA-N 3-methoxy-1-[4-(2-methylpropyl)phenyl]propan-1-one Chemical compound COCCC(=O)C1=CC=C(CC(C)C)C=C1 PUMGRMDZOJMBRN-UHFFFAOYSA-N 0.000 description 1
- 108010051372 3-oxo-5 beta-steroid delta 4-dehydrogenase Proteins 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- SFJQROPCKHFNJJ-UHFFFAOYSA-N 4-[3-(4-heptan-4-yloxybenzoyl)indol-1-yl]butanoic acid Chemical compound C1=CC(OC(CCC)CCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 SFJQROPCKHFNJJ-UHFFFAOYSA-N 0.000 description 1
- LVIJUJLOBQHPPO-UHFFFAOYSA-N 4-[3-(4-hexoxybenzoyl)indol-1-yl]butanoic acid Chemical compound C1=CC(OCCCCCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 LVIJUJLOBQHPPO-UHFFFAOYSA-N 0.000 description 1
- ULPCWIRYHBCUPY-UHFFFAOYSA-N 4-[3-(4-pentadecan-8-yloxybenzoyl)indol-1-yl]butanoic acid Chemical compound C1=CC(OC(CCCCCCC)CCCCCCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 ULPCWIRYHBCUPY-UHFFFAOYSA-N 0.000 description 1
- CFKAZZLFSZDHTN-UHFFFAOYSA-N 4-[3-(4-tridecan-7-yloxybenzoyl)indol-1-yl]butanoic acid Chemical compound C1=CC(OC(CCCCCC)CCCCCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 CFKAZZLFSZDHTN-UHFFFAOYSA-N 0.000 description 1
- ODSGLTDBUSRGOK-UHFFFAOYSA-N 4-[3-(4-undecan-4-yloxybenzoyl)indol-1-yl]butanoic acid Chemical compound C1=CC(OC(CCC)CCCCCCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 ODSGLTDBUSRGOK-UHFFFAOYSA-N 0.000 description 1
- WBRNWBFYKFOEBE-UHFFFAOYSA-N 4-[3-(4-undecan-6-yloxybenzoyl)indol-1-yl]butanoic acid Chemical compound C1=CC(OC(CCCCC)CCCCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 WBRNWBFYKFOEBE-UHFFFAOYSA-N 0.000 description 1
- DMPIHMLPNRVEOX-UHFFFAOYSA-N 4-[3-[4-(2-propylpentyl)benzoyl]indol-1-yl]butanoic acid Chemical compound C1=CC(CC(CCC)CCC)=CC=C1C(=O)C1=CN(CCCC(O)=O)C2=CC=CC=C12 DMPIHMLPNRVEOX-UHFFFAOYSA-N 0.000 description 1
- NFFXGZQLXNKXSE-WJOKGBTCSA-N 4-[3-[4-[(1s)-2-ethoxy-1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]indol-1-yl]butanoic acid Chemical compound C1([C@H](OC=2C=CC(=CC=2)C(=O)C=2C3=CC=CC=C3N(CCCC(O)=O)C=2)COCC)=CC=C(CC(C)C)C=C1 NFFXGZQLXNKXSE-WJOKGBTCSA-N 0.000 description 1
- BNUTXEKPXPZAIT-UHFFFAOYSA-N 4-bromoheptane Chemical compound CCCC(Br)CCC BNUTXEKPXPZAIT-UHFFFAOYSA-N 0.000 description 1
- WJYWOKBLBXTEAS-UHFFFAOYSA-N 4-bromoundecane Chemical compound CCCCCCCC(Br)CCC WJYWOKBLBXTEAS-UHFFFAOYSA-N 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- OXARGPFODPTIHC-UHFFFAOYSA-N 7-bromotridecane Chemical compound CCCCCCC(Br)CCCCCC OXARGPFODPTIHC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- YVESLJYIWHENDY-UHFFFAOYSA-N 8-bromopentadecane Chemical compound CCCCCCCC(Br)CCCCCCC YVESLJYIWHENDY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229910000497 Amalgam Inorganic materials 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- YQEGMGOLYBKWPO-UHFFFAOYSA-N CC(C1)C23C1CCCC2C3 Chemical compound CC(C1)C23C1CCCC2C3 YQEGMGOLYBKWPO-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021623 Tin(IV) bromide Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- HFEHLDPGIKPNKL-UHFFFAOYSA-N allyl iodide Chemical compound ICC=C HFEHLDPGIKPNKL-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- UFBHSXXPAZMVSI-UHFFFAOYSA-N but-2-ynoyl chloride Chemical compound CC#CC(Cl)=O UFBHSXXPAZMVSI-UHFFFAOYSA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000005622 butynylene group Chemical group 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- PSEHHVRCDVOTID-NAVXHOJHSA-N chloro-bis[(1s,3s,4r,5s)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@@H]([C@H]1C)B(Cl)[C@@H]2[C@@H](C)[C@@]3(C[C@](C2)(C3(C)C)[H])[H])[C@]2([H])C(C)(C)[C@@]1([H])C2 PSEHHVRCDVOTID-NAVXHOJHSA-N 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001845 chromium compounds Chemical class 0.000 description 1
- LRCIYVMVWAMTKX-UHFFFAOYSA-L chromium(ii) acetate Chemical compound [Cr+2].CC([O-])=O.CC([O-])=O LRCIYVMVWAMTKX-UHFFFAOYSA-L 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- 229940109126 chromous chloride Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- YTKRILODNOEEPX-NSCUHMNNSA-N crotyl chloride Chemical compound C\C=C\CCl YTKRILODNOEEPX-NSCUHMNNSA-N 0.000 description 1
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- 238000001085 differential centrifugation Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- WRNSUHITTDEJEQ-UHFFFAOYSA-N ethyl 4-[3-(4-heptadecan-9-yloxybenzoyl)indol-1-yl]butanoate Chemical compound C1=CC(OC(CCCCCCCC)CCCCCCCC)=CC=C1C(=O)C1=CN(CCCC(=O)OCC)C2=CC=CC=C12 WRNSUHITTDEJEQ-UHFFFAOYSA-N 0.000 description 1
- DBEKZLDBDZOJFU-UHFFFAOYSA-N ethyl 4-[3-(4-heptan-4-yloxybenzoyl)indol-1-yl]butanoate Chemical compound C1=CC(OC(CCC)CCC)=CC=C1C(=O)C1=CN(CCCC(=O)OCC)C2=CC=CC=C12 DBEKZLDBDZOJFU-UHFFFAOYSA-N 0.000 description 1
- ZAXWXJJDLACDJS-UHFFFAOYSA-N ethyl 4-[3-(4-hexoxybenzoyl)indol-1-yl]butanoate Chemical compound C1=CC(OCCCCCC)=CC=C1C(=O)C1=CN(CCCC(=O)OCC)C2=CC=CC=C12 ZAXWXJJDLACDJS-UHFFFAOYSA-N 0.000 description 1
- QUGIIPDRGIDZIC-UHFFFAOYSA-N ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butanoate Chemical compound C12=CC=CC=C2N(CCCC(=O)OCC)C=C1C(=O)C1=CC=C(O)C=C1 QUGIIPDRGIDZIC-UHFFFAOYSA-N 0.000 description 1
- NZNMMPKHXCQDKV-UHFFFAOYSA-N ethyl 4-[3-(4-pentadecan-8-yloxybenzoyl)indol-1-yl]butanoate Chemical compound C1=CC(OC(CCCCCCC)CCCCCCC)=CC=C1C(=O)C1=CN(CCCC(=O)OCC)C2=CC=CC=C12 NZNMMPKHXCQDKV-UHFFFAOYSA-N 0.000 description 1
- MJQYMZMRVDROSH-UHFFFAOYSA-N ethyl 4-[3-(4-undecan-6-yloxybenzoyl)indol-1-yl]butanoate Chemical compound C1=CC(OC(CCCCC)CCCCC)=CC=C1C(=O)C1=CN(CCCC(=O)OCC)C2=CC=CC=C12 MJQYMZMRVDROSH-UHFFFAOYSA-N 0.000 description 1
- RLXQBHCEENFPGN-UHFFFAOYSA-N ethyl 4-[3-[4-(2-propylpentyl)benzoyl]indol-1-yl]butanoate Chemical compound C1=CC(CC(CCC)CCC)=CC=C1C(=O)C1=CN(CCCC(=O)OCC)C2=CC=CC=C12 RLXQBHCEENFPGN-UHFFFAOYSA-N 0.000 description 1
- BASGOMBSBNTRLR-XIFFEERXSA-N ethyl 4-[3-[4-[(1r)-2-ethoxy-1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]indol-1-yl]butanoate Chemical compound C1([C@@H](OC=2C=CC(=CC=2)C(=O)C=2C3=CC=CC=C3N(CCCC(=O)OCC)C=2)COCC)=CC=C(CC(C)C)C=C1 BASGOMBSBNTRLR-XIFFEERXSA-N 0.000 description 1
- BASGOMBSBNTRLR-MGBGTMOVSA-N ethyl 4-[3-[4-[(1s)-2-ethoxy-1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]indol-1-yl]butanoate Chemical compound C1([C@H](OC=2C=CC(=CC=2)C(=O)C=2C3=CC=CC=C3N(CCCC(=O)OCC)C=2)COCC)=CC=C(CC(C)C)C=C1 BASGOMBSBNTRLR-MGBGTMOVSA-N 0.000 description 1
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000015122 lemonade Nutrition 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- SCEZYJKGDJPHQO-UHFFFAOYSA-M magnesium;methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=CC=C1 SCEZYJKGDJPHQO-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- JVHPKYBRJQNPAT-UHFFFAOYSA-N n-cyclohexyl-2,2-diphenylethenimine Chemical compound C1CCCCC1N=C=C(C=1C=CC=CC=1)C1=CC=CC=C1 JVHPKYBRJQNPAT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 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
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-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
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 239000000843 powder Substances 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 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
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 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
- 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- LTSUHJWLSNQKIP-UHFFFAOYSA-J tin(iv) bromide Chemical compound Br[Sn](Br)(Br)Br LTSUHJWLSNQKIP-UHFFFAOYSA-J 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- 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
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- YBIXBBGRHOUVBB-UHFFFAOYSA-N undecan-6-ol Chemical compound CCCCCC(O)CCCCC YBIXBBGRHOUVBB-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- 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
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
Definitions
- the present invention relates to novel indole derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to novel indole derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities such as inhibitory activity on testosteron 5a-reductase and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament- Disclosure of the Invention
- one object of the present invention is to provide novel indole derivatives and pharmaceutically acceptable salts thereof, which are useful as a testosteron 5a--reductase inhibitor.
- Another object of the present invention is to provide a process for preparation of said indole derivatives or salts thereof.
- a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said indole derivative or a pharmaceutically acceptable salt thereof.
- a still further object of the present invention is to provide a use of said indole derivative or a pharmaceutically acceptable salt thereof as a medicament such as testosteron 5 ⁇ - reductase inhibitor useful for treating or preventing testosteron 5ot-reductase mediated diseases such as alopecia, acnes, prostatism, and the like in human being or animals.
- R 1 is carboxy or protected carboxy
- R z is hydrogen, lower alkyl or halogen
- R 3 is aryl which may have suitable substituent(s),
- A is lower alkylene
- X is methylene, -0- or -NH-
- Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R 3 is alkyl.
- the object compound (I) and a salt thereof can be prepared by the following processes.
- R 1 , R 2 , R 3 , A, X and Y are each as defined above,
- X 1 is -0- or -NH-, 1 is leaving group
- W 2 and 3 are each acid residue.
- Suitable salts of the compounds (I) are conventional non- toxic, pharmaceutically acceptable salts and may include 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. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc. ), etc.
- 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,
- 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. arginine, aspartic acid, glutamic acid, etc.
- the preferable example thereof is an acid addition salt.
- 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, t-butyl, pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atoms.
- Suitable "halogen” may include fluoro, chloro, bromo and iodo.
- Suitable "lower alkylene” may include straight or branched bivalent lower alkane such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexa ethylene, propylene, and the like.
- Suitable "lower alkylene substituted by lower alkoxy” may include lower alkylene as mentioned above, which is substituted by lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.). Specific examples of thus defined “lower alkylene substituted by lower alkoxy” may be methoxyethylene, ethoxyethylene, methoxypropylene, ethoxypropylene, and the like.
- Suitable "lower alkenylene” may include one having 2 to 6 carbon atoms such as vinylene, propenylene, butenylene, pentenylene, hexenylene, and the like.
- Suitable “lower alkynylene” may include one having 2 to 6 carbon atoms such as ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like.
- Suitable “leaving group” may include hydroxy, reactive group derived from hydroxy, and the like.
- Suitable "reactive group derived from hydroxy” may include acid residue and the like.
- Suitable “acid residue” may include halogen (e.g. fluoro, chloro, bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc. ) and the like.
- Suitable "aryl which may have suitable 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, etc. ), haloaryl (e.g. chlorophenyl, etc. ), and the like.
- aryl e.g. phenyl, naphthyl, etc.
- substituted aryl for example, lower alkylaryl (e.g. tolyl, xylyl, mesityl, cumenyl, isobutylphenyl, etc. ), haloaryl (e.g. chlorophenyl, etc. ), and the like.
- Suitable “alkyl” may include straight or branched one, having 1 to 20 carbon atom(s), preferably one having 6 to 17 carbon atoms.
- Suitable "protected carboxy” may include an esterified carboxy group.
- ester moiety of 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 substituent(s), for example, lower alkanoyloxy( lower) alkyl ester (e.g.
- acetoxymethyl ester propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxy- methyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or 3 or 4)- acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or 3)-propionyloxypropyl ester, l(or 2)-butyryloxyethyl ester, l(or 2)-isobutyryloxyethyl ester, l(or 2)-pivaloyloxyethyl ester, l(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2- ethylbutyryloxymethyl ester, 3, 3-dimethyl
- 2-mesylethyl ester, etc. mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2- trichloroethyl ester, etc. ), lower alkoxycarbonyloxy(lower)- alkyl ester (e.g.
- aryl(lower)alkyl ester which may have at least one suitable sub- stituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitro- benzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3, 4-dimethoxybenzyl ester, 4- hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g.
- phenyl ester 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cu enyl ester, etc.); phthalidyl ester; and the like.
- esterified carboxy may include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxy- carbonyl, tert-pentyloxycarbonyl , hexyloxycarbonyl , 1-cyclo- propylethoxycarbonyl, etc. ).
- lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxy- carbonyl, tert-pentyloxycarbonyl , hexyloxycarbonyl , 1-cyclo- propylethoxycarbonyl, etc.
- R 1 is carboxy; or lower alkoxycarbonyl, more preferably C1-C4 alkoxycarbonyl
- R 2 is hydrogen
- R 3 is aryl which may be substituted by lower alkyl, more preferably phenyl substituted by C1-C4 alkyl (e.g. isobutylphenyl, etc.)
- A is lower alkylene, more preferably C1-C4 alkylene (e.g. ethylene, trimethylene, etc.)
- X is methylene, -0- or -NH-
- Y is lower alkylene substituted by lower alkoxy, more preferably
- C1-C4 alkylene substituted by C1-C4 alkoxy e.g. methoxyethylene, ethoxyethylene, methoxypropylene, ethoxypropylene, etc.
- lower alkenylene more preferably
- C 2 -C ⁇ alkenylene e.g. pentenylene, etc.
- lower alkynylene more preferably C 2 -C ⁇ alkynylene (e.g. butynylene, etc. )
- Y-R 3 is alkyl, more preferably C1-C20 alkyl, most preferably
- 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.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent which does not adversely affect the reaction.
- a solvent such as alcohol [e.g. methanol, ethanol, etc.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent which does not adversely affect the reaction.
- the reaction when W 1 in the compound (III) is acid residue, 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.), tr ⁇ (lower)alkylamine [e.g.
- 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,
- the base to be used is liquid, it can also be used as a solvent.
- ethyl chloroformate isopropyl chloroformate, etc.
- a combination of triarylphosphine e.g. triphenylphosphine, etc.
- tri(lower)- alkylphosphine e.g. triethylphosphine, etc.
- di(lower)- alkyl azodicarboxylate e.g. diethyl azodicarboxylate, etc.
- reaction temperature is not critical, and the reaction can be carried out under cooling, at room temperature or under warming or heating.
- 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.
- This 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 temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
- Process 3 the reaction mode and reaction conditions [e.g. solvents, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
- the object compound (I-c) or a salt thereof can be prepared by subjecting the compound (I-b) or a salt thereof to elimination reaction of the caboxy-protective group.
- Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbo ⁇ nate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phos- phate (e.g.
- an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g
- alkali metal hydrogen phosphate e.g. disodium hydrogen phos ⁇ phate, dipotassium hydrogen phosphate, etc.
- an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methyl- orpholine, 1,5-diazabicyclo[4.3.0]non-5-one, 1,4-diazabicyclo- [2.2.2]octane, l,5-diazabicyclo[5.4.0]undecene-5 or the like.
- 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. ) and an inorganic acid
- 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 aryl (lower)alkyl ester and carried out by reacting the compound (I-b) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetra- chloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. tin tetrachloride, tin tetrabromide, etc.), aluminum halide (e.g. aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (e.g.
- boron trihalide e.g. boron trichloride, boron trifluoride, etc.
- titanium tetrahalide e.g. titanium tetra- chloride, titanium tetrabromide, etc
- 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 nitro- alkane (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.) ester, ar(lower) alkyl (e.g. benzyl, etc. ) ester or the like.
- the protective group such as halo(lower)alkyl (e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.) ester, ar(lower) alkyl (e.g. benzyl, etc. ) ester or the like.
- 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 presence of a conventional metallic catalyst (e.g. palladium carbon, Raney nickel, etc. ).
- a metal e.g. zinc, zinc amalgam, etc.
- a salt of chromium compound e.g. chromous chloride, chromous acetate, etc.
- an organic or an inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid, etc.
- a conventional metallic catalyst e.g. palladium carbon, Raney nickel, etc.
- reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
- the object compound (I-a) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
- This 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 temperature, etc. ] of this reaction are to be referred to those as explained in Process 1.
- reaction mode and reaction conditions e.g. solvents, reaction temperature, etc.
- R 1 , R 2 , R 3 , A, X, Y, W 2 and W 3 are each as defined above, and W 4 and W 5 are each acid residue.
- Methods A and B can be carried out in 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 crystallization, recrystall ization, chromatography, and the like.
- the object compound (I) thus obtained can be converted to its salt by a conventional method.
- the object compound (I) of the present invention is useful as a testosteron 5a.-reductase inhibitor and effective to 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 vulgaris, pimple, etc.), other hyperandrogenism, and the like.
- testosteron 5a.-reductase inhibitor and effective to 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 vulgaris, pimple, etc.), other hyperandrogenism, and
- Test Compound :
- the reaction solution contains 1 mM dithiothreitol, 40 mM sodium phosphate pH 6.5, 50 ⁇ M NADPH, 1,2,6,7- H- testosterone/testosterone (2.2 x 10 -9 M) and the suspension prepared above (0.8 mg of protein) in a total volume of 565 ⁇ l.
- Test Compound was added in 10 ⁇ l of 10% ethanol whereas control tubes received the same volume of 10% ethanol.
- the reaction was started with the addition of the enzyme suspension. After incubation at 37°c for 30 minutes, the reaction was extracted with 1 ml of ethyl acetate.
- the object compound (I) of the present invention is used in the form of a 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 administration.
- pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
- 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 stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stear ⁇ c acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
- 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 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
A compound of formula (I), wherein R1 is carboxy or protected carboxy, R2 is hydrogen, lower alkyl or halogen, R3 is aryl which may have suitable substituent(s), A is lower alkylene, X is methylene, -O- or -NH-, and Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R3 is alkyl, and a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a testosteron 5α-reductase inhibitor and effective to testosteron 5α-reductase mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism, etc.), androgenic alopecia (or malepattern baldness), acne (e.g. acne vulgaris, pimple, etc.), other hyperandrogenism, and the like.
Description
DESCRIPTION
INDOLE DERIVATIVES AS TESTOSTERONE-5-ALPHA-REDUCTASE INHIBITORS
Technical Field
The present invention relates to novel indole derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to novel indole derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities such as inhibitory activity on testosteron 5a-reductase and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament- Disclosure of the Invention
Accordingly, one object of the present invention is to provide novel indole derivatives and pharmaceutically acceptable salts thereof, which are useful as a testosteron 5a--reductase inhibitor.
Another object of the present invention is to provide a process for preparation of said indole derivatives or salts thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said indole derivative or a pharmaceutically acceptable salt thereof.
A still further object of the present invention is to provide a use of said indole derivative or a pharmaceutically acceptable salt thereof as a medicament such as testosteron 5α-
reductase inhibitor useful for treating or preventing testosteron 5ot-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):
wherein R1 is carboxy or protected carboxy,
Rz is hydrogen, lower alkyl or halogen,
R3 is aryl which may have suitable substituent(s),
A is lower alkylene,
X is methylene, -0- or -NH-, and
Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R3 is alkyl. According to the present invention, the object compound (I) and a salt thereof can be prepared by the following processes.
Process 1
+
Process 2
(IV) (V) or a salt thereof or a salt thereof
(I) or a salt thereof
Process 3
A-R1,
(I-C) or a salt thereof
Process 4
wherein R1 , R2 , R3 , A, X and Y are each as defined above,
Ri is protected carboxy,
X1 is -0- or -NH-, 1 is leaving group,
W2 and 3 are each acid residue.
Suitable salts of the compounds (I) are conventional non- toxic, pharmaceutically acceptable salts and may include 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. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc. ), etc. ; 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. arginine, aspartic acid, glutamic acid, etc.); and the like, and the preferable example thereof is an acid addition salt.
With respect to the salt of the compounds (I-a) to (I-c), (II), (III), (IV), (V), (VI) and (VII) in Processes 1 to 4, suitable examples of the salts of these compounds are to be referred to those as exemplified for the object compound (I).
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
The term "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, t-butyl, pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atoms.
Suitable "halogen" may include fluoro, chloro, bromo and iodo.
Suitable "lower alkylene" may include straight or branched bivalent lower alkane such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexa ethylene, propylene, and the like.
Suitable "lower alkylene substituted by lower alkoxy" may include lower alkylene as mentioned above, which is substituted by lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.). Specific examples of thus defined "lower alkylene substituted by lower alkoxy" may be methoxyethylene, ethoxyethylene, methoxypropylene, ethoxypropylene, and the like.
Suitable "lower alkenylene" may include one having 2 to 6 carbon atoms such as vinylene, propenylene, butenylene, pentenylene, hexenylene, and the like.
Suitable "lower alkynylene" may include one having 2 to 6 carbon atoms such as ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like.
Suitable "leaving group" may include hydroxy, reactive group derived from hydroxy, and the like.
Suitable "reactive group derived from hydroxy" may include acid residue and the like.
Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc. ) and the like.
Suitable "aryl which may have suitable 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, etc. ), haloaryl (e.g. chlorophenyl, etc. ), and the like.
Suitable "alkyl" may include straight or branched one, having 1 to 20 carbon atom(s), preferably one having 6 to 17 carbon atoms.
Suitable "protected carboxy" may include an esterified carboxy group.
Suitable examples of the ester moiety of 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 substituent(s), for example, lower alkanoyloxy( lower) alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxy- methyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or 3 or 4)- acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or 3)-propionyloxypropyl ester, l(or 2)-butyryloxyethyl ester, l(or 2)-isobutyryloxyethyl ester, l(or 2)-pivaloyloxyethyl ester,
l(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2- ethylbutyryloxymethyl ester, 3, 3-dimethylbutyryloxymethyl ester, l(or 2)-pentanoyloxyethyl ester, etc.) lower alkanesulfonyl- (lower)alkyl ester (e.g. 2-mesylethyl ester, etc. ), mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2- trichloroethyl ester, etc. ), lower alkoxycarbonyloxy(lower)- alkyl ester (e.g. methoxycarbonyloxymethyl ester, ethoxy- carbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1- ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2- oxo-1,3-dioxol-4-yl) (lower)alkyl ester (e.g. (5-meth l-2-oxo- l,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-l,3-dioxol-4-yl)- methyl ester, (5-propyl-2-oxo-l,3-dioxol-4-yl)ethyl ester, etc. ; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc. ); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); aryl(lower)alkyl ester which may have at least one suitable sub- stituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitro- benzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3, 4-dimethoxybenzyl ester, 4- hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cu enyl ester, etc.); phthalidyl ester; and the like.
Preferable examples of the esterified carboxy as mentioned above may include lower alkoxycarbonyl (e.g. methoxycarbonyl,
ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxy- carbonyl, tert-pentyloxycarbonyl , hexyloxycarbonyl , 1-cyclo- propylethoxycarbonyl, etc. ).
Particularly, the preferred embodiments of R1 , R2 , R3 , A, X and Y are as follows. R1 is carboxy; or lower alkoxycarbonyl, more preferably C1-C4 alkoxycarbonyl
(e.g. methoxycarbonyl, ethoxycarbonyl, etc. ), R2 is hydrogen, R3 is aryl which may be substituted by lower alkyl, more preferably phenyl substituted by C1-C4 alkyl (e.g. isobutylphenyl, etc.), A is lower alkylene, more preferably C1-C4 alkylene (e.g. ethylene, trimethylene, etc.), X is methylene, -0- or -NH-, and Y is lower alkylene substituted by lower alkoxy, more preferably
C1-C4 alkylene substituted by C1-C4 alkoxy (e.g. methoxyethylene, ethoxyethylene, methoxypropylene, ethoxypropylene, etc. ); lower alkenylene, more preferably
C2-Cβ alkenylene (e.g. pentenylene, etc.); or lower alkynylene, more preferably C2-Cβ alkynylene (e.g. butynylene, etc. ), or Y-R3 is alkyl, more preferably C1-C20 alkyl, most preferably
C6-Ci7 alkyl (e.g. hexyl, heptyl, undecyl, tridecyl, pentadecyl, heptadecyl, etc.).
The processes 1 to 4 for preparing the object compound (I) of the present invention are explained in detail in the following. Process 1
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.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent which does not adversely affect the reaction.
In this reaction, when W1 in the compound (III) is acid residue, 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.), trϊ (lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridϊne or its derivative [e.g. picoline, lutidine, 4-dimethyl- aminopyridine, etc.], or the like. In case that the base to be used is liquid, it can also be used as a solvent.
When W1 in the compound (III) is hydroxy, this reaction is usually carried out in the presence of a conventional condensing
agent such as N,N' -dicyclohexylcarbodi imide; N-cyclohexyl-N' - morphol inoethylcarbodi imide; N-cyclohexyl-N' -(4-diethylamino- cyclohexyl )carbodi imide; N,N' -diethylcarbodi imide, N,N'-diiso- propylcarbodi imide; N-ethyl-N' -(3-di ethylaminopropyl)carbodi- imide, N,N' carbonyl-bis(2-methyl i idazole) ; pentamethylene- ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxy- chloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc. ]; a combination of triarylphosphine [e.g. triphenylphosphine, etc. ] or tri(lower)- alkylphosphine [e.g. triethylphosphine, etc. ], and di(lower)- alkyl azodicarboxylate [e.g. diethyl azodicarboxylate, etc. ]; 2-ethyl-7-hydroxybenzisoxazol iu salt; 2-ethyl-5-(m-sulfo- phenyl )isoxazolium hydroxide intramolecular salt; l-(p-chloro- benzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylform- amide with thionyl chloride, phosgene, trichloromethyl chloro¬ formate, phosphorus oxychloride, etc. ; or the like.
The reaction temperature is not critical, and the reaction can be carried out under cooling, at room temperature or under warming or heating. Process 2
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.
This 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 temperature, etc.] of this reaction are to be referred to those as explained in Process 1. Process 3
The object compound (I-c) or a salt thereof can be prepared by subjecting the compound (I-b) or a salt thereof to elimination reaction of the caboxy-protective group.
In the present elimination reaction, all conventional methods used in the elimination reaction of the carboxy- protective group, for example, hydrolysis, reduction, elimination using Lewis acid, etc. are applicable. When the carboxy protective group is an ester, it can be eliminated by hydrolysis or elimination using Lewis acid. The 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 hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbo¬ nate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phos-
phate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phos¬ phate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methyl- orpholine, 1,5-diazabicyclo[4.3.0]non-5-one, 1,4-diazabicyclo- [2.2.2]octane, l,5-diazabicyclo[5.4.0]undecene-5 or the like. 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. ) and 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 aryl (lower)alkyl ester and carried out by reacting the compound (I-b) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetra- chloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. tin tetrachloride, tin tetrabromide, etc.), aluminum halide (e.g. aluminum chloride, aluminum bromide, etc.), trihaloacetic
acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc. ) or the like. 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 nitro- alkane (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.) ester, ar(lower) alkyl (e.g. benzyl, etc. ) ester or the like.
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 presence of a conventional metallic catalyst (e.g. palladium carbon, Raney nickel, etc. ).
The reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
Process 4
The object compound (I-a) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
This 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 temperature, etc. ] of this reaction are to be referred to those as explained in Process 1.
Some of the starting compounds (IV) and (VI) are new and can be prepared by the following methods or conventional manners, the details of which are shown in Preparations mentioned below, or a conventional manner. Method A-(l)
(VIII) (IX) or a salt thereof or a salt thereof
(X) or a salt thereof
Method A-(2)
(X) (V) or a salt thereof or a salt thereof
Method B
(IV) or a salt thereof
wherein R1 , R2, R3 , A, X, Y, W2 and W3 are each as defined above, and W4 and W5 are each acid residue.
Methods A and B can be carried out in 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 crystallization, recrystall ization, chromatography, and the like.
The object compound (I) thus obtained can be converted to its salt by a conventional method.
The object compound (I) of the present invention is useful as a testosteron 5a.-reductase inhibitor and effective to testosteron 5ø-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 vulgaris, pimple, etc.), other hyperandrogenism, and the like.
In order to illustrate the usefulness of the object compounds (I), pharmacological activity of representative compounds of the present invention is shown below. [1] Test Compound :
(1) 4-[3-[4-[l-(4-Isobutylphenyl )-2-butynyloxy]benzoyl ]-indol- l-yl]butyric acid
(2) (E)-4-[3-[4-[l-(4-Isobutylphenyl)-3-pentenyloxy]benzoyl]- indol-1-yl Jbutyric acid
(3) 4-[3-[4-[l-(4-Isobutylphenyl)-2-ethoxyethoxy]benzoyl]- indol-1-yl ]butyric acid
[2] Inhibitory activity on testosterone 5a-reductase in rats
Test Methods i) Materials l,2,6,7-3H-Testosterone (85-105 Ci/mmol) : l,2,6,7-3H-Testosterone (85-105 Ci/mmol) is a mixture of 1, 2, 6, 7-3H-testosterone and testosterone which includes 85- 105 Ci of 1, 2, 6, 7-3H-testosterone per mmol of testosterone and is purchased from New England Nuclear, Boston, Mass. , U.S.A.. Aquazol-2 (Aquazol-2 Universal LSC Cocktail) : trademark,purchased from New England Nuclear, Boston, Mass. , U. S. A.. ii) Preparation of prostatic testosterone 5α.-reductase
Mature Spraque-Dawley male rats (7-8 weeks old) were sacrificed by diethyl ether. The ventral prostates were dissected to be free of their capsules and their combined volume was measured by displacement in several milliliters of ice-cold medium A (0.32 M sucrose, 0.1 mM dithiothreitol and 20 mM sodium phosphate, pH 6.5). Unless specified, all the following procedures were carried out at 0-4°c . The prostates were drained, minced, and then homogenized in 3-4 tissue volumes of medium A with Pyrex-glass homogenizer. The homogenate was fractioned by differential centrifugations at 3,000 g for 15 minutes. The resulting pellets were resuspended in medium A. The suspension (20-30 mg protein/ml) was stored at
iii) Testosterone 5β-reductase assay
The reaction solution contains 1 mM dithiothreitol, 40 mM sodium phosphate pH 6.5, 50 μM NADPH, 1,2,6,7- H- testosterone/testosterone (2.2 x 10-9 M) and the suspension prepared above (0.8 mg of protein) in a total volume of 565 μl. Test Compound was added in 10 μl of 10% ethanol whereas control tubes received the same volume of 10% ethanol. The reaction was started with the addition of the enzyme suspension. After incubation at 37°c for 30 minutes, the reaction was extracted with 1 ml of ethyl acetate. Fifty μl of ethyl acetate phase was chro atographed on a Merck silica plastic sheet Kieselgel 60 F254, using ethyl acetate : cyclohexane (1:1) as the developing solvent system. The plastic sheet was air dried and cut the testosterone and the 5of- dihydrotestosterone areas. The radioactivity was counted in 5 ml of Aquazol-2 in Packard scintillation counter (PACKARD TRI - CARB 4530), and an inhibitory ratio was calculated. [3] Test Results :
For therapeutic or preventive administration, the object compound (I) of the present invention is used in the form of a
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 administration. 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.
If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearϊc acid, 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 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
The following Preparations and Example are given for the purpose of illustrating the present invention.
Preparation 1
To a solution of (E)-l-(4-isobutylphenyl )-2-penten-l-one (840 mg) in toluene (15 ml) was added a solution of diisobutyl- aluminum hydride (1.0 M in toluene : 3.4 ml) at -78°C • After 2 hours, a solution of potassium sodium tartrate (1 M in water : 5 ml) was added and the resulting mixture was filtered through celite and washed with toluene. The combined filtrate and washings were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane : ethyl acetate = 9 : 1) to give (E)-l-(4- isobutylphenyl )-2-penten-l-ol (366 mg).
NMR (CDCla, δ ) '• 0.89 (6H, d, J=7Hz), 1.01 (3H, t, J=7Hz), 1.7 - 2.2 (3H, m), 2.48 (2H, d, J=7Hz), 5.14 (1H, ), 5.55 - 5.9 (2H, iff), 7.12 (2H, d, J=8Hz), 7.28 (2H, d, J=8Hz). Preparation 2
To a stirred solution of lithium bis(trimethylsilyl )amide (0.57 M in tetrahydrofuran; 20 ml) was added 4-isobutylaceto- phenone (1.0 g) in tetrahydrofuran (3 ml) at -20°C After 30 minutes, to the mixture was added allyl iodide (0.57 ml) and warmed at 0°C • After 2 hours, the reaction was quenched by aqueous ammonium chloride and the resulting mixture extracted with ether. The organic layers were washed with water and brine, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel (hexane : methylene chloride = 1 : 1) to give l-(4-isobutylphenyl )-4-penten-l-one (86 mg). NMR (CDCI3, δ ) • 0.89 (6H, d, J=7Hz), 1.89 (1H, m), 2.4 - 2.6
(2H, m), 2.53 (2H, d, J=7Hz), 3.07 (2H, t, J=7Hz), 5.45 - 5.65 (2H, m), 5.9 (1H, m), 7.22 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz). Preparation 3
To a stirred suspension of magnesium (783 mg) and iodine (5 mg) in tetrahydrofuran (50 ml) was added a solution of 2- butenyl chloride (2.64 ml) in tetrahydrofuran (15 ml) dropwise at 50°C. After stirring for 30 minutes, aluminum chloride (4.7 g) in ether (17 ml) was added at -78°C, and then stirred for additional 10 minutes, 4-isobutylbenzene (3.9 g) in tetrahydrofuran (2 ml) was added and the reaction mixture was warmed to 0°C. After 1.5 hours, a solution of ammonium chloride in water was added and the mixture was extracted with ether. The organic layers were washed with water and brine, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel (hexane : ether = 5 : 1) to give
(E)-l-(4-isobutylρhenyl)-3-penten-l-ol (2.07 g). NMR (CDClβ, δ ) ' 0.89 (12H, d, J=7Hz), 1.59 (3H, d, J=7Hz),
1.84 (1H, m), 2.46 (4H, d, J=7Hz), 2.35 - 2.7 (2H, m), 4.68 (1H, dd, J=7.5Hz), 5.3 - 5.75 (2H, m), 7.12 (2H, d, J=8Hz), 7.26 (2H, d, J=8Hz). Preparation 4
To a solution of chlorotrimethylsilane (16.3 g) and triethylamine (30.3 g) in N,N-dimethylformamide (50 ml) was added 4' -isobutylacetophenone (22.0 g). The yellow solid was immediately filtered off, and the filtrate was refluxed for 20
hours. The mixture was cooled, diluted with hexane, and washed with cooled aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 4-isobutyl-a-- trimethylsi lyloxystyrene (9.0 g) as an oil.
NMR (CDCla, δ ) : 0.16 (9H, s), 1.65 - 1.85 (1H, m), 2.35 (2H, d, J=7Hz), 4.27 (1H, d, J=1.5Hz), 4.76 (1H, d, J=1.5Hz), 6.98 (2H, d, J=8.5Hz), 7.38 (2H, d, J=8.5Hz). Preparation 5
Iodosylbenzene (2.18 g) was dissolved in ethanol (45 ml), and boron trifluoride etherate (2.55 g) was added. The mixture was stirred at -70°C, and then 4-isobutyl-a-trimethylsilyl- oxylstyrene (2.24 g) was added. The mixture was stirred at -70°c for 30 minutes, and then the temperature was slowly raised to room temperature. The ethanol was evaporated and water was added. The mixture was neutralized with aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, and concentrate. The residue was chromatographed on silica gel column eluting with hexane-ethyl acetate (94 : 6) to give 4' -isobutyl-2-ethoxyacetophenone (1.90 g) as an oil. NMR (CDCh, δ ) : 0.91 (6H, d, J=7Hz), 1.30 (3H, t, J=7Hz), 1.8 - 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.65 (2H, q, J=7Hz), 4.74 (2H, s), 7.24 (2H, d, J=8Hz), 7.87 (2H, d, J=8Hz). Preparation 6
4' -Isobutyl-2-ethoxyacetophenone (1.02 g) was added to a
solution of (+)-B-chlorodi isopinocampheylborane (1.78 g) in tetrahydrofuran (5 ml) at -20°C- After 4 hours, the solvent was removed and the residue was dissolved in diethyl ether (40 ml), diethanola ine (1.1 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off and washed with diethyl ether, the combined filtrates were concentrated and the residue was chromatographed on silica gel column (hexane : ethyl acetate = 6 : 1 as eluent) to give (S)- l-(4-isobutylphenyl )-2-ethoxyethanol (960 mg) as an oil. NMR (CDCla, δ ) : 0.89 (6H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.75 - 1.95 (1H, m), 2.47 (2H, d, J=7Hz), 2.79 (1H, s), 3.35 - 3.7 (4H, m), 4.87 (1H, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz). Preparation 7
The following compound was obtained by treating 4'- isobutyl-2-ethoxyacetophenone with (-)-B-chlorodiiso¬ pinocampheylborane according to a similar manner to that of Preparation 6.
(R)-l-(4-Isobutylphenyl)-2-ethoxyethanol
NMR (CDCla, δ ) • 0.89 (6H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.75 - 1.95 (1H, m), 2.47 (2H, d, J=7Hz), 2.79 (1H, s ) , 3.35 - 3.7 (4H, ), 4.87 (1H, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz). Preparation 8
To a solution of benzylmagnesium chloride (1.51 g) in diethyl ether (100 ml) was added 4-heptanone (1.14 g). The
mixture was stirred at 0°C for 30 minutes, and then aqueous ammonium chloride was added. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9 : 1) to give l-phenyl-2-propyl-2-pentanol (0.41 g) as an oil. NMR (CDC13, δ ) : 0.8 - 1.0 (6H, m), 1.3 - 1.7 (9H, m), 2.38 (1H, t, J=7.5Hz), 2.74 (1H, s), 7.15 - 7.4 (5H, m). Preparation 9
To a solution of l-phenyl-2-propyl-2-pentanol (1.60 g) in pyridine (20 ml) was added thionyl chloride (5 ml) at 0°C . The mixture was stirred at 0°C. for 1 hour, and poured into ice water and extracted with diethyl ether. The organic layer was washed with 0.5 N hydrochloric acid and water, dried over magnesium sulfate and concentrated. The residue was dissolved in a mixture of methanol (10 ml) and 1,4-dioxane (15 ml), and 10% palladium on carbon (0.2 g) was added. The mixture was stirred under hydrogen atmosphere (3 atm) at room temperature for 2 hours. Removal of catalyst and evaporation of solvent gave l-phenyl-2-propylpentane (374 mg) as an oil. NMR (CDCls, δ ) ■ 0.86 (6H, t, J=7Hz), 1.1 - 1.45 (8H, m), 1.55
- 1.75 (1H, m), 2.52 (2H, d, J=7Hz), 7.1 - 7.35 (5H, ). Preparation 10
Sodium (cut to small pieces) was slowly added to methanol (25 ml), and then 4' -isobutyl-2-chloroacetophenone in methanol (10 ml) was added. The mixture was stirred at 50°C for 1 hour,
and then neutralized with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (9 : 1) to give 4'-isobutyl- 2-methoxyacetophenone (142 mg) as an oil. NMR (CDCla, δ ) : 0-91 (6H, d, J=7Hz), 1.75 - 2.05 (1H, m), 2.53
(2H, d, J=7Hz), 3.51 (3H, s), 4.70 (2H, s), 7.24 (2H, d,
J=8.5Hz), 7.86 (2H, d, J=8.5Hz). Preparation 11
The following compound was obtained according to a similar manner to that of Preparation 10. 4' -Isobutyl-2-ethoxyacetophenone NMR (CDCla, δ ) ■ 0.91 (6H, d, J=7Hz), 1.30 (3H, t, J=7Hz), 1.8
- 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.66 (2H, q, J=7Hz),
4.73 (2H, s), 7.24 (2H, d, J=8.5Hz), 7.87 (2H, d, J=8.5Hz). Preparation 12
The mixture of 4' -isobutyl-3-chloropropionophenone (1.12 g) and potassium carbonate (2.07 g) in methanol (10 ml) was stirred at room temperature for 5 hours. The insoluble materials were filtered off and the filtrate was poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and concentrated to give 4' -isobutyl-3- methoxypropionophenone (1.10 g) as an oil.
NMR (CDCla, δ ) - 0.90 (6H, d, J=7Hz), 1.8 - 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.23 (2H, t, J=7Hz), 3.38 (3H, s), 3.82 (2H, t, J=7Hz), 7.23 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz).
Preparation 13
The following compound was obtained according to a similar manner to that of Preparation 12.
4' -Isobutyl-3-ethoxypropionophenone
NMR (CDCla, δ ) • 0.91 (6H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.80 - 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.26 (2H, t, J=7Hz), 3.55 (2H, q, J=7Hz), 3.87 (2H, t, J=7Hz), 7.23 (2H, d, J=8.5Hz), 7.89 (2H, d, J=8.5Hz).
Preparation 14
To a stirred solution of 2-butynoyl chloride (556 mg) in methylene chloride (10 ml) was added aluminum chloride (721 mg). After 10 minutes, isobutylbenzene (0.85 ml) was added to the reaction mixture. After 30 minutes, water was added to the reaction mixture and extracted with methylene chloride. The organic layers were washed with sodium hydrogencarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (hexane : methylene chloride = 1 : 1) to give l-(4-isobutylphenyl )-2- butyn-1-one (496 mg).
NMR (CDCla, δ ) • 0.91 (6H, d, J=7Hz), 1.91 (1H, m), 2.16 (3H, s), 2.55 (2H, d, J=7Hz), 7.25 (2H, d, J=8Hz), 8.06 (2H, d, J=8Hz).
Preparation 15
The following compounds were obtained according to a similar manner to that of Preparation 14.
(1) (E)-l-(4-Isobutylphenyl)-2-penten-l-one
NMR (CDCla, δ ) •• 0.91 (6H, d, J=7Hz), 1.14 (3H, t, J=7Hz), 1.90 (1H, m), 2.34 (2H, m), 2.54 (2H, d, J=7Hz), 6.88 (1H, dt, J=ll.lHz), 7.12 (1H, dt, J=11.6Hz), 7.23 (2H, d, J=9Hz),
7.87 (2H, d, J=9Hz).
(2) 4' -Isobutyl-3-chloropropionophenone
NMR (CDCla, δ ) ■ 0.91 (6H, d, J=7Hz), 1.7 - 2.05 (1H, ), 2.55 (2H, d, J=7Hz), 3.45 (2H, t, J=7Hz), 3.93 (2H, t, J=7Hz), 7.26 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz).
(3) 4' -Isobutyl-2-chloroacetophenone
NMR (CDCla, δ ) 0.91 (6H, d, J=7Hz), 1.75 - 2.05 (1H, ), 2.55(211, d, J=7Hz), 4.70 (2H, s), 7.27 (2H, d, J=8.5Hz),
7.88 (2H, d, J=8.5Hz).
(4) 4-(2-Propylpentyl)benzoyl chloride
NMR (CDCla, δ ) • 0.87 (6H, t, J=7Hz), 1.1 - 1.45 (8H, m), 1.6 - 1.8 (1H, m), 2.61 (2H, d, J=7Hz), 7.28 (2H, d, J=8.5Hz), 8.03 (2H, d, J=8.5Hz).
(5) 3-(4-Fluorobenzoyl) indole
NMR (DMSO-de, δ ) : 7.2 - 7.55 (5H, m), 7.55 - 7.6 (2H, m), 7.8
- 8.0 (3H, m), 8.22 (1H, m). Preparation 16
To a solution of indole (936 mg) in tetrahydrofuran (15 ml) was added 3 M solution of methylmagnesium bromide (2 ml). The mixture was stirred at room temperature for 30 minutes, and then
4-(2-propylpentyl )benzoyl chloride (445 mg) in tetrahydrofuran (10 ml) was added. After stirred for 1 hour, the mixture was poured into ice - 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (4 : 1) to give 3-[4-(2-propylpentyl Jbenzoyl ] indole (114 mg) as solid. NMR (DMSO-dβ, δ ) • 0.86 (6H, t, J=7Hz), 1.15 - 1.45 (8H, m),
1.6 - 1.8 (1H, m), 2.60 (2H, d, J=7Hz), 7.2 - 7.35 (4H, ),
7.5 - 7.6 (1H, m), 7.72 (2H, d, J=8.5Hz), 7.95 (1H, s),
8.2 - 8.3 (1H, m). Preparation 17
To a stirred solution of l-(4-isobutylphenyl )-2-butyn-l-one (467 mg) in ethanol (8 ml) was added sodium borohydride (101 mg) at ambient temperature. After 1 hour, aqueous potassium biphosphate solution was added and concentrated in vacuo. The residue was extracted with ether. The organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane : ethyl acetate = 4 : 1) to give l-(4- isobutylphenyl)-2-butyn-l-ol (338 mg). NMR (CDCls, δ ) : 0.89 (6H, d, J=7Hz), 1.85 (1H, m), 1.91 (3H, d, J=2Hz), 2.47 (2H, d, J=7Hz), 5.41 (1H, m), 7.04 (2H, d,
J=8Hz), 7.43 (2H, d, J=8Hz).
Preparation 18
The following compounds were obtained according to a similar manner to that of Preparation 17.
(1 ) l-(4-Isobutylphenyl )-4-penten-l-ol
NMR (CDCla, δ ) ■ 0.89 (6H, d, J=7Hz), 1.7 - 2.3 (5H, m), 2.45 (2H, d, J=7Hz), 4.67 (IH, t, J=7Hz), 4.9 - 5.1 (2H, ), 5.84 (IH, ), 7.11 (2H, d, J=8Hz), 7.24 (2H, d, J=8Hz).
(2) l-(4-Isobutylphenyl)-3-methoxy-l-propanol
NMR (CDCla, δ ) • 0.89 (6H, t, J=7Hz), 1.75 - 2.15 (3H, m), 2.47 (2H, d, J=7Hz), 3.38 (3H, s), 3.5 - 3.7 (2H, m), 4.85 - 4.95 (IH, m), 7.12 (2H, d, J=8.5Hz), 7.27 (2H, d, J=8.5Hz).
(3) l-(4-Isobutylphenyl)-3-ethoxy-l-propanol
NMR (CDCla, δ ) • 0.90 (6H, d, J=7Hz), 1.23 (3H, t, J=7Hz), 1.75 - 2.15 (3H, m), 2.47 (2H, d, J=7Hz), 3.45 - 3.7 (5H, m), 4.85 - 4.95 (IH, m), 7.11 (2H, d, J=8.5Hz), 7.28 (2H, d, J=8.5Hz).
(4) l-(4-Isobutylphenyl)-2-methoxyethanol
NMR (CDCla, δ ) : 0.89 (6H, d, J=7Hz), 1.7 - 1.95 (IH, m), 2.47 (2H, d, J=7Hz), 3.35 - 3.6 (5H, ), 4.87 (IH, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz).
(5) l-(4-Isobutylphenyl)-2-ethoxyethanol
NMR (CDC13, δ ) : 0.89 (6H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.75 - 1.95 (IH, m), 2.47 (2H, d, J=7Hz), 2.79 (IH, s), 3.35 - 3.7 (4H, m), 4.87 (IH, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz).
Preparation 19
To a solution of 6-undecanol (10.0 g) and carbon tetrabromide (38.5 g) in tetrahydrofuran (400 ml) was added triphenylphosphine (30.4 g). The mixture was stirred at room temperature for 5 hours. After the white solid was filtered off, the filtrate was concentrated. n-Hexane (400 ml) was added to the residue and the pricipitate was filtered off. The filtrate was concentrated and the residual oil was distilled under reduced pressure to give 6-bromoundecane (9.38 g) as a colorless oil. NMR (CDCls, δ ) : 0.90 (6H, t, J=7Hz), 1.15 - 1.65 (12H, m), 1.7
- 1.95 (4H, m), 3.95 - 4.1 (IH, m). Preparation 20
The following compounds were obtained according to a similar manner to that of Preparation 19.
(1) 4-Bromoheptane
NMR (CDCI3, δ ) '■ 0.93 (6H, t, J=7Hz), 1.35 - 1.65 (4H, m), 1.7 - 1.9 (4H, m), 4.0 - 4.15 (IH, m).
(2) 7-Bromotridecane
NMR (CDC , δ ) ■ 0.89 (6H, t, J=7Hz), 1.2 - 1.7 (16H, ), 1.75
- 1.9 (4H, m), 3.95 - 4.1 (IH, m).
(3) 8-Bromopentadecane
NMR (CDCh, δ ) • 0.88 (6H, t, J=7Hz), 1.2 - 1.6 (20H, m), 1.7 - 1.9 (4H, m), 3.95 - 4.1 (IH, m).
(4) 9-Bromoheρtadecane
NMR (CDCla, δ ) • 0.88 (6H, t, J=7Hz), 1.2 - 1.65 (24H, m), 1.75
- 1.9 (4H, m), 3.95 - 4.1 (IH, m).
(5) 4-Bromoundecane
NMR (CDCla, δ ) : 0.8 - 1.0 (6H, m), 1.2 - 1.65 (12H, m), 1.7 -
1.9 (4H, m), 3.95 - 4.1 (IH, m). Preparation 21
The following compound was obtained according to a similar manner to that of Example 5.
Ethyl 4-[3-(4-fluorobenzoyl ) indol-l-yl]butyrate NMR (CDCla, δ ) : 1.22 (3H, t, J=7Hz), 2.1 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.27 (2H, t, J=7Hz), 7.18 (2H, t, J=9Hz), 7.3 - 7.5 (3H, m), 7.54 (IH, s), 7.86 (2H, m), 8.38 (IH, m). Example 1
To a mixture of ethyl 4-[3-(4-hydroxybenzoyl) indol-1- yl]butyrate (188 mg), l-(4-isobutylphenyl)-2-butyn-l-ol (108 mg) and triphenylphosphine (140 mg) in tetrahydrofuran (5 ml) was added diethyl azodicarboxylate (0.084 ml) at 0°C. After 1 hour, the mixture was evaporated in vacuo and chromatographed on silica gel (hexane : ethyl acetate = 3 : 1) to give ethyl 4- [3-[4-[l-(4-isobutylphenyl )-2-butynyloxy]benzoyl ]indol-1- yljbutyrate (28 mg). NMR (CDCla, δ ) • 0.90 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz),
1.8 - 2.0 (IH, m), 1.92 (3H, d, J=2Hz), 2.15 - 2.4 (4H, m), 2.50 (2H, d, J=7Hz), 4.11 (2H, q, J=7Hz), 4.27 (2H, t, J=7Hz), 5.87 (IH, d, J=2Hz), 7.1 - 7.5 (7H, m), 7.52 (2H, d, J=8Hz), 7.60 (IH, s), 7.84 (2H, d, J=9Hz), 8.39 (IH, m). Example 2
The following compounds were obtained according to a
similar manner to that of Example 1.
(1) Ethyl 4-[3-[4-[l-(4-isobutylphenyl )-4-pentenyloxy]benzoyl ]- indol-1-yl ]butyrate
NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.7
- 2.4 (9H, m), 2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz), 4.23 (2H, t, J = 7Hz), 4.95 - 5.25 (2H, m), 5.87 (IH, m), 6.92 (2H, d, J=9Hz), 7.12 (2H, d, J=8Hz), 7,2 - 7.45 (5H, m), 7.53 (IH, s), 7.73 (2H, d, J=9Hz), 8.37 (IH, m).
(2) Ethyl (E)-4-[3-[4-[l-(4-isobutylphenyl)-3-pentenyloxy]- benzoyl ] indol-1-yl ]butyrate
NMR (CDCla, δ ) : 0.88 (6H, d, J=7Hz), 1.19 (3H, t, J=7Hz), 1.55 (3H, d, J=7Hz), 1.84 (IH, m), 2.1 - 2.35 (4H, m), 2.44 (2H, d, J=7Hz), 2.55 - 2.9 (2H, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.18 (IH, t, J=7Hz), 5.4 - 5.7 (2H, m), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2 - 7.45 (5H, m), 7.52 (IH, s), 7.72 (2H, d, J=9Hz), 8.35 (IH, m),
(3) Ethyl 4-[3-[4-[l-(4-isobutylphenyl )-3-methoxypropoxy]- benzoyl ] indol-1-yl ]butyrate
NMR (CDCla, δ ) ■ 0.89 (6H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.75
- 1.95 (IH, m), 2.0 - 2.4 (6H, m), 2.46 (2H, d, J=7Hz), 3.3
- 3.5 (4H, m), 3.55 - 3.7 (IH, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.40 (IH, dd, J=2.5 Hz, 7Hz), 6.95 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, S), 7.74 (2H, d, J=8.5Hz), 8.3 - 8.4 (IH, m),
(4) Ethyl 4-[3-[4-[l-(4-isobutylphenyl )-3-ethoxypropoxy]benzoyl ] indol-1-yl ]butyrate
NMR (CDCla, δ ) : 0.88 (6H, d, J=7Hz), 1.20 (6H, t, J=7Hz),
1.75 - 1.95 (IH, m), 2.0 - 2.4 (6H, m), 3.4 - 3.7 (4H, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.40 (IH, dd, J=2.5Hz, 7Hz), 6.96 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m),
(5) Ethyl 4-[3-[4-[l-(4-isobutylphenyl )-2-methoxyethoxy]benzoyl] indol-1-yl]butyrate
NMR (CDCla, δ ) ■• 0.89 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.7
- 1.95 (IH, m), 2.1 - 2.35 (4H, m), 2.46 (2H, d, J=7Hz), 3.48 (3H, s), 3.6 - 3.72 (IH, m), 3.78 - 3.9 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.42 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.52 (IH, s), 7.74 (2H, d, J=8.5Hz), 8.3 - 8.4 (IH, m),
(6) Ethyl 4-[3-[4-[l-(4-isobutylphenyl)-2-ethoxyethoxy]benzoyl]- indol-1-yl ]butyrate
NMR (CDCla, δ ) • 0.89 (6H, d, J=7Hz), 1.15 - 1.3 (6H, m), 1.75
- 1.95 (IH, ), 2.1 - 2.35 (4H, m), 2.46 (2H, d, J=7Hz), 3.5 - 3.75 (3H, ), 3.8 - 3.95 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).
(7) Ethyl 4-[3-[4-[(R)-l-(4-isobutylphenyl)-2-ethoxyethoxy]- benzoyl] indol-1-yl]butyrate
NMR (CDCla, δ ) '■ 0.88 (6H, d, J=7Hz), 1.15 - 1.3 (6H, m), 1.7 -
2.0 (IH, ), 2.1 - 2.4 (4H, m), 2.47 (2H, d, J=7Hz), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.42 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=8.5Hz), 8.3 - 8.4 (IH, m). (8) Ethyl 4-[3-[4-[(S)-l-(4-isobutylphenyl)-2-ethoxyethoxy]- benzoyl ] indol-1-yl ]butyrate
NMR (CDCla, δ ) : 0.89 (6H, d, J=7Hz), 1.15 - 1.35 (6H, m), 1.7 - 2.0 (IH, m), 2.1 - 2.4 (4H, ), 2.46 (2H, d, J=7Hz), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m). Example 3
A mixture of ethyl 4-[3-[4-hydroxybenzoyl )indol-l- yl]butyrate (176 mg), 6-bromoundecane (176 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (4 ml) was stirred at room temperature for 15 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3 : 1) to give ethyl 4-[3-[4-(l-pentylhexyloxy)benzoyl ] indol-1-yl ]butyrate (118 mg) as an oi 1. NMR (CDCh, δ ) ■ 0.89 (6H, m), 1.15 - 1.8 (19H, m), 2.1 - 2.4
(4H, m), 4.12 (2H, q, J=7Hz), 4.2 - 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
Example 4
The following compounds were obtained according to a similar manner to that of Example 3.
(1) Ethyl 4-[3-[4-(l-propylbutoxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) : 0.94 (6H, t, J=7Hz), 1.22 (3H, t, J=7Hz), 1.3
- 1.8 (8H, m), 2.1 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.3 - 4.45 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.82 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(2) Ethyl 4-[3-[4-(l-hexylheplyloxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) 0.89 (6H, t, J=7Hz), 1.15 - 1.5 (19H, m), 1.55
- 1.8 (4H, m), 2.15 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2
- 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, ), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(3) Ethyl 4-[3-[4-(l-heptyloctyloxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) : 0.88 (6H, t, J=7Hz), 1.2 - 1.5 (23H, m), 1.55
- 1.8 (4H, m), 2.15 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2
- 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(4) Ethyl 4-[3-[4-(l-octylnonyloxy)benzoyl ]indol-l-yl]butyrate NMR (CDCh, δ ) •■ 0.88 (6H, t, J=7Hz), 1.2 - 1.5 (27H, m), 1.55
- 1.8 (4H, m), 2.15 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2
- 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.82 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(5) Ethyl 4-[3-[4-(l-ρropyloctyloxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) : 0.8 - 1.0 (6H, m), 1.2 - 1.8 (19H, m), 2.15 -
2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2 - 4.4 (3H, ), 6.97 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(6) Ethyl 4-[3-(4-hexyloxybenzoyl ) indol-1-yl ]butyrate
NMR (CDCh, δ ) : 0.91 (3H, t, J=7Hz), 1.22 (3H, t, J=7Hz), 1.3
- 1.6 (6H, m), 1.75 - 1.9 (2H, m), 2.15 - 2.4 (4H, ), 4.0 - 4.2 (4H, m), 4.27 (2H, t, J=7Hz), 6.98 (2H, d, J=9Hz), 7.25
- 7.5 (3H, ), 7.58 (IH, s), 7.84 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
Example 5
A mixture of 3-[4-(2-propylpentyl )benzoyl Jindole (109 mg), ethyl 4-bromobutyrate (77 mg) and potassium carbonate (136 mg) in dimethylformamide (3 ml) was stirred at room temperature for 16 hours. The insoluble materials were filtered off, and the filtrate was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (4 : 1) to give ethyl 4-[3-[4-(2- propylpentyl )benzoyl ]indol-l-yl]butyrate (142 mg) as an oil. NMR (CDCh, δ ) ■ 0.89 (6H, t, J=7Hz), 1.15 - 1.5 (IH, m), 1.6 - 1.8 (IH, m), 2.1 - 2.4 (4H, m), 2.61 (2H, d, J=7Hz), 4.11 (2H, q, J=7Hz), 4.27 (2H, t, J=7Hz), 7.2 - 7.5 (5H, m), 7.59 (IH, s), 7.75 (2H, d, J=8.5Hz), 8.35 - 8.45 (IH, m).
Example 6
To a solution of ethyl 4-[3-[4-(l-pentylhexyIoxy)benzoyl]- indol-l-yl]butyrate (112 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml) was added 1 N aqueous solution of sodium hydroxide (1 ml). The mixture was stirred at room temperature for 2 hours, and then poured into a mixture of ethyl acetate and 0.5 N hydro¬ chloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[4-(l-pentylhexyloxy)benzoyl]indol-l-yl]butyric acid
(86 mg) as an oil. NMR (CDCh, δ ) : 0.89 (6H, t, J=7Hz), 1.2 - 1.8 (16H, m), 2.1 - 2.3 (2H, m), 2.40 (2H, t, J=7Hz), 4.2 - 4.4 (3H, ), 6.95 (2H, d, J=9Hz), 7.25 - 7.45 (3H, m), 7.61 (IH, s), 7.82 (2H, d, J=9Hz), 8.3 - 8.4 (IH, ). Example 7
The following compounds were obtained according to a similar manner to that of Example 6.
(1) 4-[3-[4-[l-(4-Isobutylphenyl)-2-butynyloxy]benzoyl]indoI-l- yl]butyric acid
NMR (CDCh, δ ) : 0.90 (6H, d, J=7Hz), 1.75 - 2.0 (IH, m), 1.90 (3H, d, J=2Hz), 2.1 - 2.3 (2H, m), 2.3 - 2.45 (2H, m), 2.49 (2H, d, J=7Hz), 4.27 (2H, t, J=7Hz), 5.84 (IH, d, J=2Hz), 7.1 - 7.45 (7H, m), 7.51 (2H, d, J=8Hz), 7.60 (2H, d, J=9Hz), 8.37 (IH, m).
(2) (E)~4-[3-[4-[l-(4-Isobutylphenyl)-2-pentenyloxy]benzoyl]- indol-l-yl]butyric acid
NMR (CDCh, δ ) • 0.88 (6H, d, J=7Hz), 0.93 (3H, t, J=7Hz),
1.47(2H, m), 1.82 (IH, m), 2.1 - 2.5 (6H, m), 4.25 (2H, t, J=7Hz), 5.88 (IH, t, J=7Hz), 7.0 - 7.1 (4H, m), 7.2 - 7.45 (7H, m), 7.57 (IH, s), 7.77 (2H, d, J=8Hz), 8.35 (IH, m).
(3) 4-[3-[4-[l-( -Isobutylphenyl )-4-pentenyloxy]benzoyl ] indol-1- yl]butyric acid
NMR (CDCh, δ ) • 0.88 (6H, d, J=7Hz), 1.7 - 2.3 (7H, ), 2.38 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 4.23 (2H, t, J=7Hz), 4.9 - 5.25 (2H, m), 5.86 (IH, m), 6.91 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.72 (2H,d, J=9Hz), 8.33 (IH, ).
(4) (E)-4-[3-[4-[l-(4-Isobutylphenyl )-3-pentenyloxy]benzoyl ]- indol-1-yl ]butyric acid
NMR (CDCh, δ ) • 0.87 (6H, d, J=7Hz), 1.54 (3H, d, J=7Hz),
1.83(1H, m), 2.18 (2H, m), 2.37 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 2.5 - 2.9 (2H, m), 4.23 (2H, t, J=7Hz), 5.17 (IH, t, J=7Hz), 5.35 - 5.6 (2H, m), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.72 (2H, d, J=8Hz), 8.33 (IH, ).
(5) 4-[3-[4-(l-Propylbutoxy)benzoyl ]indol-1-yl ]butyric acid
NMR (CDCh, δ ) •• 0.94 (6H, t, J=7Hz), 1.3 - 1.8 (8H, m), 2.15 - 2.35 (2H, m), 2.40 (2H, t, J=7Hz), 4.2 - 4.45 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.45 (3H, m), 7.61 (IH, s), 7.82 (2H, d, J=9Hz), 8.35 - 8.4 (IH, m).
(6) 4-[3-[4-(l-Hexylheptyloxy)benzoyl ] indol-1-yl ]butyric acid NMR (CDCh, δ ) : 0.89 (6H, t, J=7Hz), 1.2 - 1.5 (16H, m), 1.55
- 1.8 (4H, ), 2.15 - 2.3 (2H, m), 2.41 (2H, t, J=7Hz), 4.2
- 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(7) 4-[3-[4-(l-Heptyloctyloxy)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) ■ 0.88 (6H, t, J=7Hz), 1.15 - 1.5 (20H, m),
1.55- 1.8 (4H, m), 2.15 - 2.3 (2H, m), 2.40 (2H, t, J=7Hz),
4.2 - 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.3 - 8.45 (IH, m).
(8) 4-[3-[4-(l-0ctylnonyloxy)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) • 0.88 (6H, t, J=7Hz), 1.2 - 1.5 (24H, m), 1.55
- 1.8 (4H, m), 2.15 - 2.3 (2H, m), 2.41 (2H, t, J=7Hz), 4.2
- 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).
(9) 4-[3-[4-(l-Propyloctyloxy)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) ■ 0.8 - 1.0 (6H, m), 1.2 - 1.8 (16H, m), 2.15 -
2.3 (2H, m), 2.40 (2H, t, J=7Hz), 4.2 - 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.3 - 8.45 (IH, m).
(10) 4-[3-(4-Hexyloxybenzoyl)indol-l-yl]butyric acid
NMR (DMSO-de, δ ) • 0.89 (3H, t, J=7Hz), 1.2 - 1.55 (6H, m), 1.65 - 1.85 (2H, m), 1.95 - 2.15 (2H, m), 2.24 (2H, t, J=7Hz), 4.07 (2H, t, J=7Hz), 4.30 (2H, t, J=7Hz), 7.07 (2H, d, J=9Hz), 7.2 - 7.4 (2H, m), 7.65 (IH, d, J=7Hz), 7.80 (2H,d, J=9Hz), 8.02 (IH, s), 8.2 - 8.3 (IH, m).
(11) 4-[3-[4-[l-(4-Isobutylphenyl)-3-methoxypropoxy]benzoyl]- indol-l-yl]butyric acid
NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 1.7 - 1.95 (IH, m),
2.0 - 2.5 (8H, m), 3.3 - 3.5 (4H, m), 3.55 - 3.7 (IH, m), 4.23 (2H, t, J=7Hz), 5.39 (IH, dd, J=3Hz, 7Hz), 6.94 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).
(12) 4-[3-[4-[l-(4-Isobutylphenyl )-3-ethoxypropoxy] indol-1- yl]butyric acid
NMR (CDCh, δ ) : 0.88 (6H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.7 - 1.95 (IH, m), 2.0 - 2.5 (8H, m), 3.4 - 3.7 (4H, m), 4.23 (2H, t, J=7Hz), 5.41 (IH, dd, J=2.5Hz, 7Hz), 6.95 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, ), 7.53 (IH, s), 7.73 (2H, d, .J=9Hz), 8.3 - 8.4 (IH, m).
(13) 4-[3-[4-[l-(4-Isobutylphenyl )-2-methoxyethoxy]benzoyl ]- indol-1-yl ]butyric acid
NMR (CDCh, δ ) : 0.89 (6H, d, J=7Hz), 1.7 - 1.95 (IH, m), *2.1 - 2.5 (6H, m), 3.47 (3H, s), 3.6 - 3.7 (IH, m), 3.75 - 3.9 (IH, m), 4.23 (2H, t, J=7Hz), 5.42 (IH, dd, J=4.5Hz, 6Hz), 6.97 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.52 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, ).
(14) 4-[3-[4-[l-(4-Isobutylphenyl )-2-ethoxyethoxy]benzoyl]indol- l-yl]butyric acid
NMR (CDCh, δ ) '• 0.88 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz), 1.7 - 1.95 (IH, m), 2.1- 2.25 (2H, m), 2.3 - 2.5 (4H, m), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.22 (2H, t, J=7Hz), 5.40 (IH, dd, J=4.5Hz, 6Hz), 6.97 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.52 (IH, s), 7.72 (2H, d,
J=9Hz ) , 8. 3 - 8. 4 ( IH, m ) .
(15) 4-[3-[4-[(R)-l-(4-Isobutylphenyl)-2-ethoxyethoxy]benzoyl]- ϊndol-l-yl]butyric acid
NMR (CDCh, δ ) : 0.88 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz), 1.7
- 2.0 (IH, m), 2.1- 2.5 (6H, m), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.23 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.97 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).
(16) 4-[3-[4-[(S)-l-(4-Isobutylphenyl)-2-ethoxyethoxy]benzoyl]- indol-l-yl]butyric acid
NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz), 1.7
- 1.95 (IH, m), 2.1- 2.5 (6H, m), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, ), 4.24 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, ), 7.52 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).
(17) 4-[3-[4-(2-Propylpentyl)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) 0.88 (6H, t, J=7Hz), 1.15 - 1.55 (8H, ), 1.6
- 1.8 (IH, m), 2.1 - 2.5 (4H, m), 2.60 (2H, d, J=7Hz), 4.27 (2H, t, J=7Hz, ), 7.2 - 7.5 (5H, m), 7.60 (IH, s), 7.76 (2H, d, J=8.5Hz), 8.35 - 8.45 (IH, m).
Example 8
To a solution of (E)-l-(4-isobutylphenyl)-2-penten-l-ol (202 mg) in dimethylformamide (3 ml) was added sodium hydride (41 mg) and heated at 40°C for 30 minutes. To the solution
was then added ethyl 4-[3-(4-fluorobenzoyl ) indol-1-yl ]butyrate (327 mg) and the mixture was heated at 50 °c for 30 minutes. After cooling and dilution with toluene, the mixture was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane : ethyl acetate = 3 : 1) to give ethyl (E)-4-[3-[4-[l- (4-isobutylphenyl)-2-pentenyloxy]benzoyl]indol-l-yl ]butyrate (93 mg).
NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 0.94 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz), 1.4 - 1.6 (2H, m), 1.83 (IH, m), 1.9 - 2.4 (4H, m), 2.44 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz, ), 4.24 (2H, t, J=7Hz), 5.89 (IH, t, J=7Hz), 7.0 - 7.4 (11H, ), 7.54 (IH, s), 7.78 (2H, d, J=9Hz), 8.38 (IH, m).
Claims
CLAIMS 1. A compound of the formula :
wherein R1 is carboxy or protected carboxy,
R2 is hydrogen, lower alkyl or halogen,
R3 is aryl which may have suitable substituent(s),
A is lower alkylene,
X is methylene, -0- or -NH-, and
Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R3 is alkyl, and a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, wherein
R1 is carboxy or esterified carboxy, and
R3 is aryl which may be substituted by lower alkyl.
3. A compound of claim 2, wherein
R1 is carboxy or lower alkoxycarbonyl, and R3 is phenyl substituted by lower alkyl.
wherein R1 is carboxy or protected carboxy,
R2 is hydrogen, lower alkyl or halogen,
R3 is aryl which may have suitable substituent(s),
A is lower alkylene,
X is methylene, -0- or -NH-, and
Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R3 is alkyl, or a salt thereof, which comprises, (1) reacting a compound of the formula :
wherein R1 , Rz and A are each as defined above, and
X1 is -0- or -NH- or a salt thereof, with a compound of the formula : wherein R3 and Y are each as defined above, and
wherein R1, R2, R3, A, X1 and Y are each as defined above, or a salt thereof, or (2) reacting a compound of the formula :
wherein R2, R3, X and Y are each as defined above, or a salt thereof, with a compound of the formula :
W2-A-R1 wherein R1 and A are each as defined above, and
W2 is acid residue, or a salt thereof, to give a compound of the formula:
A-R1
wherein R1, R2, R3, A, X and Y are each as defined above, or a salt thereof, or ( 3 ) sub ject i ng a compound of the formu l a
R1, is protected carboxy, or a salt thereof, to elimination reaction of the carboxy protective group, to give a compound of the formula :
wherein R2, R3 , A, X and Y are each as defined above, or a salt thereof, or (4) reacting a compound of the formula :
wherein R1 , R2 and A are each as defined above, and
W3 is acid residue, or a salt thereof, with a compound of the formula : H-X^Y-R3 wherein R3 , X1 and Y are each as def ined above, or a sal t thereof , to give a compound of the formula :
wherein R1 , R2 , R3 , A, X1 and Y are each as defined above, or a salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in associa¬ tion with a pharmaceutically acceptable, substantially non- toxic carrier or excipient.
6. A method for treating or preventing testosteron 5a- reductase-mediated diseases, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animals.
7. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament.
8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a testosteron δa-reductase inhibitor. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5514691A JPH07503969A (en) | 1992-02-25 | 1993-02-18 | Indole derivatives as testosterone 5α-reductase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9204024.5 | 1992-02-25 | ||
GB929204024A GB9204024D0 (en) | 1992-02-25 | 1992-02-25 | Indole derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993016996A1 true WO1993016996A1 (en) | 1993-09-02 |
Family
ID=10711023
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1993/000201 WO1993016996A1 (en) | 1992-02-25 | 1993-02-18 | Indole derivatives as testosterone-5-alpha-reductase inhibitors |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPH07503969A (en) |
GB (1) | GB9204024D0 (en) |
WO (1) | WO1993016996A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994018168A1 (en) * | 1993-02-10 | 1994-08-18 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives as 5-alpha-reductase inhibitors |
WO1995023143A1 (en) * | 1994-02-24 | 1995-08-31 | Pfizer Limited | Indole derivatives as testosterone-5-alpha-reductase inhibitors |
WO1995026955A1 (en) * | 1994-03-30 | 1995-10-12 | Zeria Pharmaceutical Co., Ltd. | Indole derivative and medicine containing the same |
US5543417A (en) * | 1994-10-21 | 1996-08-06 | Merck & Co., Inc. | Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents |
WO2012110768A1 (en) | 2011-02-18 | 2012-08-23 | The University Of Birmingham | Therapeutic uses of diarylalkanes such as mitotane |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3557142A (en) * | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
US3856967A (en) * | 1968-01-11 | 1974-12-24 | Roussel Uclaf | Novel indoles in the treatment of pain |
EP0458207A2 (en) * | 1990-05-21 | 1991-11-27 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives |
WO1993002050A1 (en) * | 1991-07-24 | 1993-02-04 | Pfizer Limited | Indoles |
-
1992
- 1992-02-25 GB GB929204024A patent/GB9204024D0/en active Pending
-
1993
- 1993-02-18 JP JP5514691A patent/JPH07503969A/en active Pending
- 1993-02-18 WO PCT/JP1993/000201 patent/WO1993016996A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3856967A (en) * | 1968-01-11 | 1974-12-24 | Roussel Uclaf | Novel indoles in the treatment of pain |
US3557142A (en) * | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
US3843683A (en) * | 1968-02-20 | 1974-10-22 | Sterling Drug Inc | Alpha-(3-(4-chlorobenzoyl)-2-methyl-6-methoxy-1-ndole)-acetic acid |
EP0458207A2 (en) * | 1990-05-21 | 1991-11-27 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives |
WO1993002050A1 (en) * | 1991-07-24 | 1993-02-04 | Pfizer Limited | Indoles |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994018168A1 (en) * | 1993-02-10 | 1994-08-18 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives as 5-alpha-reductase inhibitors |
WO1995023143A1 (en) * | 1994-02-24 | 1995-08-31 | Pfizer Limited | Indole derivatives as testosterone-5-alpha-reductase inhibitors |
WO1995026955A1 (en) * | 1994-03-30 | 1995-10-12 | Zeria Pharmaceutical Co., Ltd. | Indole derivative and medicine containing the same |
US5543417A (en) * | 1994-10-21 | 1996-08-06 | Merck & Co., Inc. | Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents |
WO2012110768A1 (en) | 2011-02-18 | 2012-08-23 | The University Of Birmingham | Therapeutic uses of diarylalkanes such as mitotane |
Also Published As
Publication number | Publication date |
---|---|
JPH07503969A (en) | 1995-04-27 |
GB9204024D0 (en) | 1992-04-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5530019A (en) | Indole derivatives useful as testosterone 5α-reductase inhibitors | |
EP0458207B1 (en) | Indole derivatives | |
NO179748B (en) | Analogous Process for Preparation of Therapeutically Active Bis- (1H-Indol-3-yl) -maleinimide Derivatives | |
NZ332640A (en) | Optionally fused phenyl methyl substituted indole derivatives useful as endothelin receptor antagonists | |
AU3210799A (en) | Antagonists of gonadotropin releasing hormone | |
EP0620818A1 (en) | ARYL KETONES AS TESTOSTERONE 5$g(a)-REDUCTASE INHIBITORS | |
AU3367999A (en) | Antagonists of gonadotropin releasing hormone | |
US5981550A (en) | Antagonists of gonadotropin releasing hormone | |
AU1197299A (en) | Antagonists of gonadotropin releasing hormone | |
AU3210899A (en) | Antagonists of gonadotropin releasing hormone | |
JP2004307487A (en) | Indolylmaleimides | |
JP2002538205A (en) | 6-azaindole compounds as gonadotropin-releasing hormone antagonists | |
WO1993016996A1 (en) | Indole derivatives as testosterone-5-alpha-reductase inhibitors | |
KR100244879B1 (en) | Heterocyclic derivatives | |
WO1993005019A1 (en) | Indole derivatives as 5-alpha-reductase inhibitor | |
US5312829A (en) | Indole derivatives | |
EP0717742B1 (en) | Process for the preparation of indolizine derivatives | |
GB2287706A (en) | Indolizine derivatives | |
WO1994018168A1 (en) | Indole derivatives as 5-alpha-reductase inhibitors | |
US5212320A (en) | Indole derivatives and their use for testosterone 5-alpha-reductase-mediated diseases | |
WO1994026710A1 (en) | INDOLE DERIVATIVES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS | |
RU2120942C1 (en) | INDOLIZINE DERIVATIVES, METHOD OF THEIR SYNTHESIS, PHARMACEUTICAL COMPOSITION, METHOD OF INHIBITION OF ACTIVITY OF TESTOSTERONE-5α-REDUCTASE | |
MXPA98004819A (en) | Gonadotrop liberating hormone antagonists | |
MXPA97008032A (en) | Derivatives of indol-3-carbonyl and indol 3-sulfonyl as antagonists of the plaqu activator factor | |
MXPA98004765A (en) | Gonadotrop liberating hormone antagonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP KR US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |
|
122 | Ep: pct application non-entry in european phase |