ES2396612T3 - Tetrahidrociclopenta[b]indoles como moduladores del receptor de andrógenos - Google Patents
Tetrahidrociclopenta[b]indoles como moduladores del receptor de andrógenos Download PDFInfo
- Publication number
- ES2396612T3 ES2396612T3 ES09747531T ES09747531T ES2396612T3 ES 2396612 T3 ES2396612 T3 ES 2396612T3 ES 09747531 T ES09747531 T ES 09747531T ES 09747531 T ES09747531 T ES 09747531T ES 2396612 T3 ES2396612 T3 ES 2396612T3
- Authority
- ES
- Spain
- Prior art keywords
- formula
- mmol
- compound
- indole
- cyano
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- IAZKTAKWBHQCGF-UHFFFAOYSA-N 1,2,3,3a-tetrahydrocyclopenta[b]indole Chemical class N1=C2C=CC=CC2=C2C1CCC2 IAZKTAKWBHQCGF-UHFFFAOYSA-N 0.000 title description 9
- 239000000849 selective androgen receptor modulator Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- -1 (2R, 3S) -3-hydroxy-1-methyl-pyrrolidin-2-ylmethyl Chemical group 0.000 claims description 80
- 239000000203 mixture Substances 0.000 claims description 45
- 210000003205 muscle Anatomy 0.000 claims description 34
- 230000009467 reduction Effects 0.000 claims description 18
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 16
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 16
- 206010049088 Osteopenia Diseases 0.000 claims description 16
- 201000001881 impotence Diseases 0.000 claims description 16
- 210000000988 bone and bone Anatomy 0.000 claims description 14
- 208000001132 Osteoporosis Diseases 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- FBCDRHDULQYRTB-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one;trihydrate;hydrochloride Chemical compound O.O.O.Cl.CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 FBCDRHDULQYRTB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229960002639 sildenafil citrate Drugs 0.000 claims description 4
- 229960000835 tadalafil Drugs 0.000 claims description 4
- 229960001540 vardenafil hydrochloride Drugs 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 100
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 95
- 239000007787 solid Substances 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 238000000034 method Methods 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 238000012360 testing method Methods 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000003098 androgen Substances 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
- 102000001307 androgen receptors Human genes 0.000 description 23
- 108010080146 androgen receptors Proteins 0.000 description 23
- 230000000694 effects Effects 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000009739 binding Methods 0.000 description 16
- 238000006722 reduction reaction Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 230000027455 binding Effects 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 12
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 12
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 210000002307 prostate Anatomy 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 102000003998 progesterone receptors Human genes 0.000 description 11
- 108090000468 progesterone receptors Proteins 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- CCCIJQPRIXGQOE-XWSJACJDSA-N 17beta-hydroxy-17-methylestra-4,9,11-trien-3-one Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C=C2 CCCIJQPRIXGQOE-XWSJACJDSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- 229940030486 androgens Drugs 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 150000003431 steroids Chemical class 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 6
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 6
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 208000014674 injury Diseases 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 102000005969 steroid hormone receptors Human genes 0.000 description 6
- 230000008733 trauma Effects 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000004296 chiral HPLC Methods 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- 230000003637 steroidlike Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- UGVXXDSOHKIRJX-QMMMGPOBSA-N (2s)-2-amino-1,2,3,4-tetrahydrocyclopenta[b]indole-7-carbonitrile Chemical compound N1C2=CC=C(C#N)C=C2C2=C1C[C@@H](N)C2 UGVXXDSOHKIRJX-QMMMGPOBSA-N 0.000 description 4
- QMJGQJINYQEOMX-UHFFFAOYSA-N 1,2,3,3a-tetrahydrocyclopenta[b]indol-1-amine Chemical compound C1=CC=CC2=C3C(N)CCC3N=C21 QMJGQJINYQEOMX-UHFFFAOYSA-N 0.000 description 4
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010058359 Hypogonadism Diseases 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 4
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 102000006601 Thymidine Kinase Human genes 0.000 description 4
- 108020004440 Thymidine kinase Proteins 0.000 description 4
- 229960002478 aldosterone Drugs 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 238000009806 oophorectomy Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 108020003113 steroid hormone receptors Proteins 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- ALOAXJBUUCJUNH-UHFFFAOYSA-N 1,2,3,3a-tetrahydrocyclopenta[b]indole-1-carbonitrile Chemical compound C1=CC=CC2=C3C(C#N)CCC3N=C21 ALOAXJBUUCJUNH-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010065687 Bone loss Diseases 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000928259 Homo sapiens NADPH:adrenodoxin oxidoreductase, mitochondrial Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 108091027981 Response element Proteins 0.000 description 3
- 201000001880 Sexual dysfunction Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000001548 androgenic effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000001856 erectile effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 102000046818 human AR Human genes 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 239000002395 mineralocorticoid Substances 0.000 description 3
- 238000011474 orchiectomy Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000005543 phthalimide group Chemical group 0.000 description 3
- QFFCYTLOTYIJMR-XMGTWHOFSA-N promegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)CC)(C)[C@@]1(C)CC2 QFFCYTLOTYIJMR-XMGTWHOFSA-N 0.000 description 3
- 229960001584 promegestone Drugs 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 210000001625 seminal vesicle Anatomy 0.000 description 3
- 231100000872 sexual dysfunction Toxicity 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 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 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 201000010653 vesiculitis Diseases 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- JLDHXHPQMBNKMC-BQBZGAKWSA-N (2s,3s)-3-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(O)=O JLDHXHPQMBNKMC-BQBZGAKWSA-N 0.000 description 2
- QTKGVZYJECZACB-UHFFFAOYSA-N (3-fluoro-2-methoxyphenyl)methanol Chemical compound COC1=C(F)C=CC=C1CO QTKGVZYJECZACB-UHFFFAOYSA-N 0.000 description 2
- RFZNBIJSMKMUDX-UHFFFAOYSA-N (3-prop-2-enoxypyridin-2-yl)methanol Chemical compound OCC1=NC=CC=C1OCC=C RFZNBIJSMKMUDX-UHFFFAOYSA-N 0.000 description 2
- RGGOWBBBHWTTRE-UHFFFAOYSA-N (4-bromophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(Br)C=C1 RGGOWBBBHWTTRE-UHFFFAOYSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- PLTQMIYVUSUELE-UHFFFAOYSA-N 1-(chloromethyl)-3-fluoro-2-methoxybenzene Chemical compound COC1=C(F)C=CC=C1CCl PLTQMIYVUSUELE-UHFFFAOYSA-N 0.000 description 2
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 2
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 2
- CELWKQBFFPBIOF-UHFFFAOYSA-N 2-(chloromethyl)-3-prop-2-enoxypyridine Chemical compound ClCC1=NC=CC=C1OCC=C CELWKQBFFPBIOF-UHFFFAOYSA-N 0.000 description 2
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- KBRSJPHSCOAFDR-UHFFFAOYSA-N 3-chloro-6-methyl-5,5-dioxo-11h-benzo[c][2,1]benzothiazepin-11-ol Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(O)C2=CC=C(Cl)C=C21 KBRSJPHSCOAFDR-UHFFFAOYSA-N 0.000 description 2
- UMLOYMZBAUIGKF-UHFFFAOYSA-N 3-fluoro-2-methoxybenzaldehyde Chemical compound COC1=C(F)C=CC=C1C=O UMLOYMZBAUIGKF-UHFFFAOYSA-N 0.000 description 2
- BJBUEDPLEOHJGE-UHFFFAOYSA-N 3-hydroxyproline Chemical compound OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010002261 Androgen deficiency Diseases 0.000 description 2
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 2
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 229930195212 Fischerindole Natural products 0.000 description 2
- 101000836540 Homo sapiens Aldo-keto reductase family 1 member B1 Proteins 0.000 description 2
- 101000809450 Homo sapiens Amphiregulin Proteins 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000029549 Muscle injury Diseases 0.000 description 2
- 101000783356 Naja sputatrix Cytotoxin Proteins 0.000 description 2
- 206010030247 Oestrogen deficiency Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 108010085012 Steroid Receptors Proteins 0.000 description 2
- 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 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 206010047486 Virilism Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000001195 anabolic effect Effects 0.000 description 2
- 238000009165 androgen replacement therapy Methods 0.000 description 2
- 210000000436 anus Anatomy 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- MNEXJHFEULTAKA-UHFFFAOYSA-N bromo carbamate Chemical compound NC(=O)OBr MNEXJHFEULTAKA-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000002340 cardiotoxin Substances 0.000 description 2
- 231100000677 cardiotoxin Toxicity 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 210000005226 corpus cavernosum Anatomy 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 238000003745 diagnosis Methods 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
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000003821 enantio-separation Methods 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
- 239000000284 extract Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 238000011990 functional testing Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 108010073230 parathyroid hormone (1-38) Proteins 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- JJCKUKPQHMVUFJ-SFHVURJKSA-N propan-2-yl n-[(2s)-7-cyano-4-[(2-methoxyphenyl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound COC1=CC=CC=C1CN1C2=CC=C(C#N)C=C2C2=C1C[C@@H](NC(=O)OC(C)C)C2 JJCKUKPQHMVUFJ-SFHVURJKSA-N 0.000 description 2
- UHOVQQBKBRAWNN-KRWDZBQOSA-N propan-2-yl n-[(2s)-7-cyano-4-[(3-fluoro-2-methoxyphenyl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound COC1=C(F)C=CC=C1CN1C2=CC=C(C#N)C=C2C2=C1C[C@@H](NC(=O)OC(C)C)C2 UHOVQQBKBRAWNN-KRWDZBQOSA-N 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 239000004246 zinc acetate Substances 0.000 description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- QMJGQJINYQEOMX-PEHGTWAWSA-N (1s)-1,2,3,3a-tetrahydrocyclopenta[b]indol-1-amine Chemical compound C1=CC=CC2=C3[C@@H](N)CCC3N=C21 QMJGQJINYQEOMX-PEHGTWAWSA-N 0.000 description 1
- LBCJRZBMFLASCQ-KPOBHBOGSA-N (2R,3S)-2-[[(2S)-7-cyano-2-(propan-2-yloxycarbonylamino)-2,3-dihydro-1H-cyclopenta[b]indol-4-yl]methyl]-3-hydroxypyrrolidine-1-carboxylic acid Chemical compound C(#N)C1=CC=2C3=C(N(C=2C=C1)C[C@H]1N(CC[C@@H]1O)C(=O)O)C[C@H](C3)NC(=O)OC(C)C LBCJRZBMFLASCQ-KPOBHBOGSA-N 0.000 description 1
- CSJCEQXZVMIHRX-QZTJIDSGSA-N (2s,3s)-2,3-dibenzyl-2,3-dihydroxybutanedioic acid Chemical compound C([C@@](O)(C(=O)O)[C@@](O)(CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSJCEQXZVMIHRX-QZTJIDSGSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UAWVMPOAIVZWFQ-UHFFFAOYSA-N 1-(chloromethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1CCl UAWVMPOAIVZWFQ-UHFFFAOYSA-N 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical class N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
- VZKZHXJRVKNPGJ-UHFFFAOYSA-N 2-(chloromethyl)-3-methoxypyridine Chemical compound COC1=CC=CN=C1CCl VZKZHXJRVKNPGJ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- ZIDMZOAQFCFSHA-UHFFFAOYSA-N 3,4-difluoro-2-hydroxybenzaldehyde Chemical compound OC1=C(F)C(F)=CC=C1C=O ZIDMZOAQFCFSHA-UHFFFAOYSA-N 0.000 description 1
- VXINHFGHWYFFSP-UHFFFAOYSA-N 3-bromo-4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC=C1Br VXINHFGHWYFFSP-UHFFFAOYSA-N 0.000 description 1
- NWDHTEIVMDYWQJ-UHFFFAOYSA-N 3-fluoro-2-hydroxybenzaldehyde Chemical compound OC1=C(F)C=CC=C1C=O NWDHTEIVMDYWQJ-UHFFFAOYSA-N 0.000 description 1
- JLDHXHPQMBNKMC-UHFFFAOYSA-N 3-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1C(O)=O JLDHXHPQMBNKMC-UHFFFAOYSA-N 0.000 description 1
- BJBUEDPLEOHJGE-BKLSDQPFSA-N 3-hydroxy-L-proline Chemical compound OC1CCN[C@@H]1C(O)=O BJBUEDPLEOHJGE-BKLSDQPFSA-N 0.000 description 1
- QRCUQLANPHYVEH-UHFFFAOYSA-N 3-methoxy-2-methylpyridine Chemical compound COC1=CC=CN=C1C QRCUQLANPHYVEH-UHFFFAOYSA-N 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
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- KPQDKAMSAVONFC-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3-methoxypyridine Chemical compound COC1=C(Cl)C=CN=C1CCl KPQDKAMSAVONFC-UHFFFAOYSA-N 0.000 description 1
- GKQDDKKGDIVDAG-UHFFFAOYSA-N 4-fluoro-2-methylphenol Chemical compound CC1=CC(F)=CC=C1O GKQDDKKGDIVDAG-UHFFFAOYSA-N 0.000 description 1
- DZUUSHCOMPROCJ-UHFFFAOYSA-N 4-hydrazinylbenzonitrile Chemical compound NNC1=CC=C(C#N)C=C1 DZUUSHCOMPROCJ-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N 5-oxo-D-proline Chemical compound OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WLNWBRRUSXTXME-QMMMGPOBSA-N C(#N)C1=CC=2C3=C(NC2C=C1)C[C@H](C3)NC(O)=O Chemical compound C(#N)C1=CC=2C3=C(NC2C=C1)C[C@H](C3)NC(O)=O WLNWBRRUSXTXME-QMMMGPOBSA-N 0.000 description 1
- YDGCYYJTEYDWRF-IWMITWMQSA-N CC(C)OC(=O)N[C@H]1CC2=C(C1)N(C3=C2C=C(C=C3)C#N)C[C@@H]4[C@@H](CCN4C(=O)O)OC(=O)CCl Chemical compound CC(C)OC(=O)N[C@H]1CC2=C(C1)N(C3=C2C=C(C=C3)C#N)C[C@@H]4[C@@H](CCN4C(=O)O)OC(=O)CCl YDGCYYJTEYDWRF-IWMITWMQSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101710095468 Cyclase Proteins 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 108010065556 Drug Receptors Proteins 0.000 description 1
- 102000013138 Drug Receptors Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 description 1
- 101000926939 Homo sapiens Glucocorticoid receptor Proteins 0.000 description 1
- 101000611202 Homo sapiens Peptidyl-prolyl cis-trans isomerase B Proteins 0.000 description 1
- 101000574060 Homo sapiens Progesterone receptor Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 241000272144 Naja atra Species 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 1
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102100040283 Peptidyl-prolyl cis-trans isomerase B Human genes 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Natural products CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- HJPOKQICBCJGHE-UHFFFAOYSA-J [C+4].[Cl-].[Cl-].[Cl-].[Cl-] Chemical compound [C+4].[Cl-].[Cl-].[Cl-].[Cl-] HJPOKQICBCJGHE-UHFFFAOYSA-J 0.000 description 1
- YVBSAPDHRXHFHV-UHFFFAOYSA-N [chloro(methoxy)methyl]benzene Chemical compound COC(Cl)C1=CC=CC=C1 YVBSAPDHRXHFHV-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 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
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- AXSIIYFPGZWYLL-UHFFFAOYSA-N bis(propan-2-yloxycarbonyl)azaniumylideneazanide Chemical compound CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C AXSIIYFPGZWYLL-UHFFFAOYSA-N 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 229940117229 cialis Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000035252 development of secondary sexual characteristics Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 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
- 238000000605 extraction Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- SKVRYQUMKJQZFN-UHFFFAOYSA-N hydron;2-(hydroxymethyl)pyridin-3-ol;chloride Chemical compound Cl.OCC1=NC=CC=C1O SKVRYQUMKJQZFN-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 229940097443 levitra Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 231100000794 masculinization Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 150000002883 o-cresols Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000018052 penile erection Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108010042121 probasin Proteins 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- YLYGHVAJABBYIC-INIZCTEOSA-N propan-2-yl n-[(2s)-4-[(3-bromopyridin-4-yl)methyl]-7-cyano-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CC=NC=C1Br YLYGHVAJABBYIC-INIZCTEOSA-N 0.000 description 1
- HYVGYJVUOGTCCY-HNNXBMFYSA-N propan-2-yl n-[(2s)-4-[(4-chloro-3-methoxypyridin-2-yl)methyl]-7-cyano-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound COC1=C(Cl)C=CN=C1CN1C2=CC=C(C#N)C=C2C2=C1C[C@@H](NC(=O)OC(C)C)C2 HYVGYJVUOGTCCY-HNNXBMFYSA-N 0.000 description 1
- PHVMCWNVJBLADG-NSHDSACASA-N propan-2-yl n-[(2s)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]carbamate Chemical compound N1C2=CC=C(C#N)C=C2C2=C1C[C@@H](NC(=O)OC(C)C)C2 PHVMCWNVJBLADG-NSHDSACASA-N 0.000 description 1
- HNKVROGLZCBJBV-KRWDZBQOSA-N propan-2-yl n-[(2s)-7-cyano-4-[(2-hydroxyphenyl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=C1O HNKVROGLZCBJBV-KRWDZBQOSA-N 0.000 description 1
- BLFNVVWHAGSYAI-HNNXBMFYSA-N propan-2-yl n-[(2s)-7-cyano-4-[(3-hydroxypyridin-2-yl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=NC=CC=C1O BLFNVVWHAGSYAI-HNNXBMFYSA-N 0.000 description 1
- RIZZCKXDHXXMQI-KRWDZBQOSA-N propan-2-yl n-[(2s)-7-cyano-4-[(5-fluoro-2-hydroxyphenyl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CC(F)=CC=C1O RIZZCKXDHXXMQI-KRWDZBQOSA-N 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- PFYFLKXRXBSBLG-UHFFFAOYSA-N pyrrolidin-1-yl 2-chloroacetate Chemical compound ClCC(=O)ON1CCCC1 PFYFLKXRXBSBLG-UHFFFAOYSA-N 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000004706 scrotum Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- OJRKUNLIXAQXJB-BDAKNGLRSA-N tert-butyl (2r,3s)-3-hydroxy-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1COS(C)(=O)=O OJRKUNLIXAQXJB-BDAKNGLRSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- SKWXBTTYZWGUGQ-UHFFFAOYSA-N tert-butyl-(4-fluoro-2-methylphenoxy)-dimethylsilane Chemical compound CC1=CC(F)=CC=C1O[Si](C)(C)C(C)(C)C SKWXBTTYZWGUGQ-UHFFFAOYSA-N 0.000 description 1
- PFBFNQGTNWUPHQ-UHFFFAOYSA-N tert-butyl-[(4-fluoro-2-methylphenyl)methyl]-dimethylsilane Chemical compound CC1=CC(F)=CC=C1C[Si](C)(C)C(C)(C)C PFBFNQGTNWUPHQ-UHFFFAOYSA-N 0.000 description 1
- 238000004154 testing of material Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- SRWMQSFFRFWREA-UHFFFAOYSA-M zinc formate Chemical compound [Zn+2].[O-]C=O SRWMQSFFRFWREA-UHFFFAOYSA-M 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
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/06—Anabolic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (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)
- Public Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53722 | 1987-05-26 | ||
| US5372208P | 2008-05-16 | 2008-05-16 | |
| PCT/US2009/043875 WO2009140448A1 (en) | 2008-05-16 | 2009-05-14 | Tetrahydrocyclopenta[b]indole androgen receptor modulators |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2396612T3 true ES2396612T3 (es) | 2013-02-22 |
Family
ID=40847864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09747531T Active ES2396612T3 (es) | 2008-05-16 | 2009-05-14 | Tetrahidrociclopenta[b]indoles como moduladores del receptor de andrógenos |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US8486943B2 (OSRAM) |
| EP (1) | EP2297100B1 (OSRAM) |
| JP (1) | JP5603327B2 (OSRAM) |
| KR (1) | KR101278788B1 (OSRAM) |
| CN (1) | CN102026974B (OSRAM) |
| AU (1) | AU2009246348B2 (OSRAM) |
| BR (1) | BRPI0912394A2 (OSRAM) |
| CA (1) | CA2724629C (OSRAM) |
| CY (1) | CY1113341T1 (OSRAM) |
| DK (1) | DK2297100T3 (OSRAM) |
| EA (1) | EA019713B1 (OSRAM) |
| ES (1) | ES2396612T3 (OSRAM) |
| HR (1) | HRP20120917T1 (OSRAM) |
| MX (1) | MX2010012436A (OSRAM) |
| PL (1) | PL2297100T3 (OSRAM) |
| PT (1) | PT2297100E (OSRAM) |
| SI (1) | SI2297100T1 (OSRAM) |
| WO (1) | WO2009140448A1 (OSRAM) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA98777C2 (en) | 2006-11-20 | 2012-06-25 | Эли Лилли Энд Компани | Tetrahydrocyclopenta[b]indole compounds as androgen receptor modulators |
| US8268872B2 (en) | 2008-02-22 | 2012-09-18 | Radius Health, Inc. | Selective androgen receptor modulators |
| MX2010009162A (es) | 2008-02-22 | 2010-12-21 | Radius Health Inc | Moduladores selectivos del receptor de androgeno. |
| EP2531029B1 (en) | 2010-02-04 | 2016-10-19 | Radius Health, Inc. | Selective androgen receptor modulators |
| WO2011143469A1 (en) | 2010-05-12 | 2011-11-17 | Radius Health,Inc | Therapeutic regimens |
| US8642632B2 (en) | 2010-07-02 | 2014-02-04 | Radius Health, Inc. | Selective androgen receptor modulators |
| BR112013007685B1 (pt) | 2010-09-28 | 2021-11-09 | Radius Pharmaceuticals, Inc | Compostos moduladores de receptor andrógeno seletivos, composição farmacêutica compreendendo os referidos compostos, método de identificação de um composto capaz de modular um receptor andrógeno, usos de um composto ou da composição e processo para a preparação de um composto |
| US9421264B2 (en) | 2014-03-28 | 2016-08-23 | Duke University | Method of treating cancer using selective estrogen receptor modulators |
| FI3834824T3 (fi) | 2014-03-28 | 2025-12-05 | Univ Duke | Estrogeenireseptoripositiivisen rintasyövän hoito selektiivisellä estrogeenireseptorin modulaattorilla |
| JOP20180072A1 (ar) * | 2014-09-11 | 2019-01-30 | Lilly Co Eli | علاج الأعراض المرتبطة بالعلاج بالحرمان من الأندروجين |
| JP7221699B2 (ja) | 2016-06-22 | 2023-02-14 | エリプセス ファーマ エルティーディー | Ａｒ＋乳癌の治療方法 |
| US20180185347A1 (en) * | 2016-11-16 | 2018-07-05 | Transition Therapeutics (Ireland 2) Limited | Tetrahydrocyclopenta[b]indole compounds and phosphodiesterase inhibitors for the treatment of the signs and symptoms of bhp |
| KR102881465B1 (ko) | 2017-01-05 | 2025-11-04 | 래디어스 파마슈티컬스, 인코포레이티드 | Rad1901-2hcl의 다형 형태 |
| SG11202013177WA (en) | 2018-07-04 | 2021-01-28 | Radius Pharmaceuticals Inc | Polymorphic forms of rad 1901-2hcl |
| KR20210127961A (ko) | 2019-02-12 | 2021-10-25 | 래디어스 파마슈티컬스, 인코포레이티드 | 방법 및 화합물 |
| US20230096602A1 (en) * | 2020-01-27 | 2023-03-30 | Eirgen Pharma Ltd. | Tetrahydrocyclopenta[b]indole compounds for treatment of renal disease |
| CN116761598A (zh) * | 2020-07-06 | 2023-09-15 | 新月生物科学 | Fabp4调节化合物的抗病毒用途 |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4988820A (en) | 1986-02-21 | 1991-01-29 | Bayer Aktiengesellschaft | Cycloalkano(1,2-B) indole-sulponamides |
| GB8924392D0 (en) | 1989-10-30 | 1989-12-20 | Bayer Ag | Substituted cycloalkano/b/dihydroindole-and-indolesulphonamides |
| GB9008108D0 (en) | 1990-04-10 | 1990-06-06 | Bayer Ag | Cycloalkano(b)dihydroindoles and-indolesulphonamides substituted by heterocycles |
| DE4027278A1 (de) | 1990-08-29 | 1992-03-05 | Bayer Ag | Heterocyclisch substituierte indolsulfonamide |
| DE4131346A1 (de) | 1991-09-20 | 1993-03-25 | Bayer Ag | Indolsulfonamid substituierte dihydropyridine, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
| JP2005527464A (ja) | 2001-08-09 | 2005-09-15 | イーライ・リリー・アンド・カンパニー | ｓＰＬＡ２インヒビターとしてのシクロヘプタＢインドール誘導体 |
| DE10164564B4 (de) | 2001-12-14 | 2007-05-16 | Zentaris Gmbh | Tetrahydrocarbazolderivate als Liganden für G-Protein gekoppelte Rezeptoren (GPCR) |
| US7534897B2 (en) | 2002-05-16 | 2009-05-19 | Shionogi & Co., Ltd. | Indole arylsulfonaimide compounds exhibiting PGD 2 receptor antagonism |
| US20060074124A1 (en) | 2003-09-12 | 2006-04-06 | Andrew Napper | Methods of treating a disorder |
| US7019022B2 (en) | 2003-12-15 | 2006-03-28 | Merck Frosst Canada & Co. | Substituted tetrahydrocarbazole and cyclopentanoindole derivatives |
| ES2414604T3 (es) | 2004-03-03 | 2013-07-22 | Eli Lilly And Company | Moduladores del receptor nuclear de hormonas esteroides de derivados bicíclicos sustituidos con indol |
| US8946444B2 (en) | 2004-11-23 | 2015-02-03 | Ptc Therapeutics, Inc. | Tetrahydrocarbazoles as active agents for inhibiting VEGF production by translational control |
| AR052674A1 (es) | 2005-02-17 | 2007-03-28 | Wyeth Corp | Derivados de indol, benzotiofeno, benzofurano e indeno cicloalquilcondensados |
| MX2007015905A (es) * | 2005-06-24 | 2008-03-06 | Lilly Co Eli | Derivados de tetrahidrocarbazol utiles como moduladores de receptor de androgeno (sarm). |
| WO2007047604A2 (en) | 2005-10-18 | 2007-04-26 | Elixir Pharmaceuticals, Inc. | Sirt1 inhibition |
| WO2008019825A1 (en) | 2006-08-14 | 2008-02-21 | Santhera Pharmaceuticals (Schweiz) Ag | Use of tricyclic indole derivatives for the treatment of muscular diseases |
| UA98777C2 (en) * | 2006-11-20 | 2012-06-25 | Эли Лилли Энд Компани | Tetrahydrocyclopenta[b]indole compounds as androgen receptor modulators |
-
2009
- 2009-05-14 BR BRPI0912394A patent/BRPI0912394A2/pt not_active IP Right Cessation
- 2009-05-14 JP JP2011509679A patent/JP5603327B2/ja active Active
- 2009-05-14 DK DK09747531.3T patent/DK2297100T3/da active
- 2009-05-14 EP EP09747531A patent/EP2297100B1/en active Active
- 2009-05-14 HR HRP20120917AT patent/HRP20120917T1/hr unknown
- 2009-05-14 PL PL09747531T patent/PL2297100T3/pl unknown
- 2009-05-14 PT PT97475313T patent/PT2297100E/pt unknown
- 2009-05-14 ES ES09747531T patent/ES2396612T3/es active Active
- 2009-05-14 EA EA201071317A patent/EA019713B1/ru not_active IP Right Cessation
- 2009-05-14 CA CA2724629A patent/CA2724629C/en not_active Expired - Fee Related
- 2009-05-14 AU AU2009246348A patent/AU2009246348B2/en not_active Ceased
- 2009-05-14 WO PCT/US2009/043875 patent/WO2009140448A1/en not_active Ceased
- 2009-05-14 KR KR1020107025588A patent/KR101278788B1/ko not_active Expired - Fee Related
- 2009-05-14 US US12/989,959 patent/US8486943B2/en active Active
- 2009-05-14 CN CN200980117076XA patent/CN102026974B/zh active Active
- 2009-05-14 MX MX2010012436A patent/MX2010012436A/es active IP Right Grant
- 2009-05-14 SI SI200930447T patent/SI2297100T1/sl unknown
-
2012
- 2012-11-14 CY CY20121101095T patent/CY1113341T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100132551A (ko) | 2010-12-17 |
| US8486943B2 (en) | 2013-07-16 |
| EA201071317A1 (ru) | 2011-06-30 |
| CN102026974B (zh) | 2013-08-28 |
| AU2009246348B2 (en) | 2012-04-12 |
| DK2297100T3 (da) | 2012-12-17 |
| JP5603327B2 (ja) | 2014-10-08 |
| CN102026974A (zh) | 2011-04-20 |
| WO2009140448A1 (en) | 2009-11-19 |
| CA2724629C (en) | 2014-08-19 |
| MX2010012436A (es) | 2010-12-06 |
| KR101278788B1 (ko) | 2013-06-25 |
| AU2009246348A8 (en) | 2010-12-16 |
| PL2297100T3 (pl) | 2013-03-29 |
| WO2009140448A8 (en) | 2010-01-07 |
| CA2724629A1 (en) | 2009-11-19 |
| SI2297100T1 (sl) | 2013-02-28 |
| CY1113341T1 (el) | 2016-06-22 |
| EP2297100B1 (en) | 2012-10-31 |
| HRP20120917T1 (hr) | 2012-12-31 |
| JP2011520903A (ja) | 2011-07-21 |
| AU2009246348A1 (en) | 2009-11-19 |
| EA019713B1 (ru) | 2014-05-30 |
| BRPI0912394A2 (pt) | 2016-07-26 |
| US20110039855A1 (en) | 2011-02-17 |
| EP2297100A1 (en) | 2011-03-23 |
| PT2297100E (pt) | 2013-01-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2396612T3 (es) | Tetrahidrociclopenta[b]indoles como moduladores del receptor de andrógenos | |
| ES2376048T3 (es) | Compuestos tetrahidrociclopenta[b]indol como moduladores del receptor de andrógenos. | |
| ES2972491T3 (es) | Piridinil-(aza)indolsulfonamidas | |
| KR101528617B1 (ko) | 신규한 선택적인 히스톤탈아세틸화 효소 억제제로서의 하이드록사메이트 유도체 및 이를 포함하는 약제학적 조성물 | |
| CA2468673C (en) | Compounds specific to adenosine a1 and a3 receptors and uses thereof | |
| JP5089578B2 (ja) | 選択的なアンドロゲン受容体調節物質としての置換型ｎ−アリールピロリジン | |
| ES2258631T3 (es) | Piranoindazoles y su uso para el tratamiento de glaucoma. | |
| CN112375077A (zh) | 四氢-吡啶并[3,4-b]吲哚雌激素受体调节剂及其用途 | |
| KR20160086404A (ko) | Mknk1 및 mknk2 억제제로서의 티에노피리미딘 | |
| TW202045499A (zh) | 用於治療ｈｂｖ感染或ｈｂｖ誘發疾病之醯胺衍生物 | |
| AU2017300841B2 (en) | Imidazolyl-substituted indole derivatives binding 5-HT7 serotonin receptor and pharmaceutical compositions thereof | |
| ES2887674T3 (es) | 1-Arilnaftiridin-3-carboxamidas 7-sustituidas y su uso | |
| ES2461520T3 (es) | Modulador de receptores de andrógenos y sus usos | |
| HK40029219A (en) | Compounds as neurokinin-1 receptor antagonists and uses thereof |