CA2228997C - Benzothiophene compounds - Google Patents

Benzothiophene compounds Download PDF

Info

Publication number: CA2228997C
Authority: CA; Canada
Prior art keywords: alkyl; compounds; compound; estrogen; formula
Prior art date: 1995-08-17
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.): Expired - Fee Related

Application number

CA002228997A

Other languages

English (en)

French (fr)

Other versions

CA2228997A1 (en

Inventor

Henry Uhlman Bryant

Stephen Sung Yong Cho

Timothy Alan Grese

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Eli Lilly and Co

Original Assignee

Eli Lilly and Co

Priority date (The priority date 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 date listed.)

1995-08-17

Filing date

1996-08-13

Publication date

2002-07-30

1996-08-13 Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co

1997-02-27 Publication of CA2228997A1 publication Critical patent/CA2228997A1/en

2002-07-30 Application granted granted Critical

2002-07-30 Publication of CA2228997C publication Critical patent/CA2228997C/en

2016-08-13 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims abstract description 145
239000000262 estrogen Substances 0.000 claims abstract description 50
229940011871 estrogen Drugs 0.000 claims abstract description 49
-1 1-thienyl Chemical group 0.000 claims abstract description 38
150000003839 salts Chemical class 0.000 claims abstract description 30
239000000583 progesterone congener Substances 0.000 claims abstract description 19
RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class 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 claims abstract description 16
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
208000037803 restenosis Diseases 0.000 claims abstract description 15
201000010260 leiomyoma Diseases 0.000 claims abstract description 14
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 12
206010027304 Menopausal symptoms Diseases 0.000 claims abstract description 12
201000009273 Endometriosis Diseases 0.000 claims abstract description 11
206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 10
210000000329 smooth muscle myocyte Anatomy 0.000 claims abstract description 10
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 9
230000004663 cell proliferation Effects 0.000 claims abstract description 9
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
125000001424 substituent group Chemical group 0.000 claims abstract description 9
208000024891 symptom Diseases 0.000 claims abstract description 8
208000010579 uterine corpus leiomyoma Diseases 0.000 claims abstract description 8
201000007954 uterine fibroid Diseases 0.000 claims abstract description 8
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 6
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 6
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 5
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 4
230000002401 inhibitory effect Effects 0.000 claims abstract description 3
XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims abstract 4
125000001475 halogen functional group Chemical group 0.000 claims abstract 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
239000003085 diluting agent Substances 0.000 claims description 8
239000000546 pharmaceutical excipient Substances 0.000 claims description 7
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 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
125000003386 piperidinyl group Chemical group 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims 1
206010028980 Neoplasm Diseases 0.000 abstract description 22
208000001132 Osteoporosis Diseases 0.000 abstract description 11
230000001419 dependent effect Effects 0.000 abstract description 7
230000001575 pathological effect Effects 0.000 abstract description 6
201000011510 cancer Diseases 0.000 abstract description 4
230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
238000000034 method Methods 0.000 description 43
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
238000011282 treatment Methods 0.000 description 39
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
239000000203 mixture Substances 0.000 description 31
210000004027 cell Anatomy 0.000 description 28
238000006243 chemical reaction Methods 0.000 description 28
210000001519 tissue Anatomy 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
241001465754 Metazoa Species 0.000 description 25
239000000243 solution Substances 0.000 description 23
238000012360 testing method Methods 0.000 description 22
230000000694 effects Effects 0.000 description 21
238000009472 formulation Methods 0.000 description 21
239000002904 solvent Substances 0.000 description 19
210000004291 uterus Anatomy 0.000 description 18
239000004480 active ingredient Substances 0.000 description 17
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 17
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
230000012010 growth Effects 0.000 description 15
239000002253 acid Substances 0.000 description 14
239000004615 ingredient Substances 0.000 description 14
239000003795 chemical substances by application Substances 0.000 description 13
238000004587 chromatography analysis Methods 0.000 description 13
230000002357 endometrial effect Effects 0.000 description 13
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
241000700159 Rattus Species 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
210000000988 bone and bone Anatomy 0.000 description 12
239000000047 product Substances 0.000 description 12
238000005160 1H NMR spectroscopy Methods 0.000 description 11
230000004044 response Effects 0.000 description 11
210000002966 serum Anatomy 0.000 description 11
238000002560 therapeutic procedure Methods 0.000 description 11
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
239000003826 tablet Substances 0.000 description 10
201000010099 disease Diseases 0.000 description 9
239000000741 silica gel Substances 0.000 description 9
229910002027 silica gel Inorganic materials 0.000 description 9
238000001356 surgical procedure Methods 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 8
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
239000006260 foam Substances 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
229920002472 Starch Polymers 0.000 description 7
206010067269 Uterine fibrosis Diseases 0.000 description 7
239000003638 chemical reducing agent Substances 0.000 description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
230000008569 process Effects 0.000 description 7
239000008107 starch Substances 0.000 description 7
235000019698 starch Nutrition 0.000 description 7
DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 6
101150041968 CDC13 gene Proteins 0.000 description 6
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
235000012000 cholesterol Nutrition 0.000 description 6
230000001076 estrogenic effect Effects 0.000 description 6
DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 6
229960002568 ethinylestradiol Drugs 0.000 description 6
239000012091 fetal bovine serum Substances 0.000 description 6
238000000338 in vitro Methods 0.000 description 6
150000002632 lipids Chemical class 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
230000035755 proliferation Effects 0.000 description 6
238000006722 reduction reaction Methods 0.000 description 6
UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
230000002792 vascular Effects 0.000 description 6
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
108091003079 Bovine Serum Albumin Proteins 0.000 description 5
125000000217 alkyl group Chemical group 0.000 description 5
150000008064 anhydrides Chemical class 0.000 description 5
239000012911 assay medium Substances 0.000 description 5
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
229910002092 carbon dioxide Inorganic materials 0.000 description 5
239000001768 carboxy methyl cellulose Substances 0.000 description 5
JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 5
125000005843 halogen group Chemical group 0.000 description 5
239000012442 inert solvent Substances 0.000 description 5
239000007928 intraperitoneal injection Substances 0.000 description 5
239000002609 medium Substances 0.000 description 5
208000001685 postmenopausal osteoporosis Diseases 0.000 description 5
229940063238 premarin Drugs 0.000 description 5
239000003981 vehicle Substances 0.000 description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
206010006187 Breast cancer Diseases 0.000 description 4
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
239000006144 Dulbecco’s modiﬁed Eagle's medium Substances 0.000 description 4
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
229930182816 L-glutamine Natural products 0.000 description 4
241000699660 Mus musculus Species 0.000 description 4
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
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239000000908 ammonium hydroxide Substances 0.000 description 4
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235000019359 magnesium stearate Nutrition 0.000 description 4
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ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 4
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VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 3
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 3
ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
229930182555 Penicillin Natural products 0.000 description 3
JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
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PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
TZAVGZOZSPFAEO-UHFFFAOYSA-N [2-(dimethylamino)-6-methoxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound CN(C)C=1SC2=CC(OC)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 TZAVGZOZSPFAEO-UHFFFAOYSA-N 0.000 description 3
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 3
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SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
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PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
150000002790 naphthalenes Chemical class 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
235000001968 nicotinic acid Nutrition 0.000 description 1
239000011664 nicotinic acid Substances 0.000 description 1
RBXVOQPAMPBADW-UHFFFAOYSA-N nitrous acid;phenol Chemical class ON=O.OC1=CC=CC=C1 RBXVOQPAMPBADW-UHFFFAOYSA-N 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
230000000474 nursing effect Effects 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
230000011164 ossification Effects 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
239000012188 paraffin wax Substances 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
108040007629 peroxidase activity proteins Proteins 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
229940049953 phenylacetate Drugs 0.000 description 1
WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
229950009215 phenylbutanoic acid Drugs 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
229920000137 polyphosphoric acid Polymers 0.000 description 1
229920001296 polysiloxane Polymers 0.000 description 1
235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
229940069328 povidone Drugs 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
230000001072 progestational effect Effects 0.000 description 1
239000000186 progesterone Substances 0.000 description 1
229960003387 progesterone Drugs 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
HNDXKIMMSFCCFW-UHFFFAOYSA-M propane-2-sulfonate Chemical compound CC(C)S([O-])(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-M 0.000 description 1
239000003380 propellant Substances 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
229940063222 provera Drugs 0.000 description 1
239000008213 purified water Substances 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
239000001008 quinone-imine dye Substances 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
108020003175 receptors Proteins 0.000 description 1
102000005962 receptors Human genes 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
230000000306 recurrent effect Effects 0.000 description 1
238000011946 reduction process Methods 0.000 description 1
230000000979 retarding effect Effects 0.000 description 1
229960001860 salicylate Drugs 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
238000003345 scintillation counting Methods 0.000 description 1
229940116351 sebacate Drugs 0.000 description 1
CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
238000013207 serial dilution Methods 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229940054269 sodium pyruvate Drugs 0.000 description 1
QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
239000012453 solvate Substances 0.000 description 1
229910001220 stainless steel Inorganic materials 0.000 description 1
239000010935 stainless steel Substances 0.000 description 1
230000003637 steroidlike Effects 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
239000000126 substance Substances 0.000 description 1
229940086735 succinate Drugs 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
150000003871 sulfonates Chemical class 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
230000001629 suppression Effects 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
238000011477 surgical intervention Methods 0.000 description 1
230000004083 survival effect Effects 0.000 description 1
238000013268 sustained release Methods 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
239000007916 tablet composition Substances 0.000 description 1
229960001603 tamoxifen Drugs 0.000 description 1
KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
238000010257 thawing Methods 0.000 description 1
210000002303 tibia Anatomy 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
230000002110 toxicologic effect Effects 0.000 description 1
231100000027 toxicology Toxicity 0.000 description 1
WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
238000012546 transfer Methods 0.000 description 1
IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
206010046766 uterine cancer Diseases 0.000 description 1
239000001993 wax Substances 0.000 description 1
BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
229960001600 xylazine Drugs 0.000 description 1
229940071104 xylenesulfonate Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
- 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
- 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
- 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
- A61P35/00—Antineoplastic 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system

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)
Public Health (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Physical Education & Sports Medicine (AREA)
Endocrinology (AREA)
Orthopedic Medicine & Surgery (AREA)
Rheumatology (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Diabetes (AREA)
Reproductive Health (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA002228997A 1995-08-17 1996-08-13 Benzothiophene compounds Expired - Fee Related CA2228997C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US238595P	1995-08-17	1995-08-17
US60/002,385		1995-08-17
PCT/US1996/013162 WO1997006796A1 (en)	1995-08-17	1996-08-13	Benzothiophene compounds

Publications (2)

Publication Number	Publication Date
CA2228997A1 CA2228997A1 (en)	1997-02-27
CA2228997C true CA2228997C (en)	2002-07-30

Family

ID=21700526

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002228997A Expired - Fee Related CA2228997C (en)	1995-08-17	1996-08-13	Benzothiophene compounds

Country Status (6)

Country	Link
US (1)	US5728724A (2)
EP (1)	EP0759434A1 (2)
JP (1)	JPH11511169A (2)
AU (1)	AU6774096A (2)
CA (1)	CA2228997C (2)
WO (1)	WO1997006796A1 (2)

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CA2214072C (en) *	1996-08-29	2006-11-14	Eli Lilly And Company	Benzo [b] thiophene compounds, intermediates, processes, compositions, and methods
JP2001517664A (ja) *	1997-09-23	2001-10-09	イーライ・リリー・アンド・カンパニー	ベンゾチオフェン類
US6060488A (en) *	1998-09-22	2000-05-09	Eli Lilly And Company	Benzothiophenes for treating estrogen deficiency
ES2236536T3 (es) *	2001-05-22	2005-07-16	Eli Lilly And Company	Derivados tetrahidroquinolino para la inhibicion de enfermedades asociadas con la privacion de estrogenos o con una respuesta fisiologica aberrante a estrogenos endogenos.
ATE321754T1 (de) *	2001-05-22	2006-04-15	Lilly Co Eli	2-substituierte 1,2,3,4-tetrahydrochinoline und derivate davon, zusammensetzungen und verfahren
DE60221391T2 (de)	2001-06-20	2008-04-17	Wyeth	Substituierte indolsäurederivate als inhibitoren von plasminogen-aktivator-inhibitor-1 (pai-1)
TWI224101B (en)	2001-06-20	2004-11-21	Wyeth Corp	Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
CN1684958A (zh) *	2002-09-25	2005-10-19	伊莱利利公司	二氢－二苯并[a]蒽及相关化合物,组合物和方法
JP2004128195A (ja) *	2002-10-02	2004-04-22	Oki Electric Ind Co Ltd	保護膜の製造方法
UA80453C2 (en)	2002-12-10	2007-09-25		Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1)
BR0316583A (pt)	2002-12-10	2005-10-04	Wyeth Corp	Derivados de ácido acético 3-alquil e 3-arilalquil 1h-indol-1-il substituìdo como inibidores do inibidor-1 do ativador do plasminogênio (pai-1)
MXPA05006288A (es)	2002-12-10	2005-08-19	Wyeth Corp	Derivados del acido 3-carbonil-1h-indol-1-ilacetico sustituidos como inhibidores del inhibidor del activador de plasminogeno 1 (pai-1).
AU2003296324A1 (en)	2002-12-10	2004-06-30	Wyeth	Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US7332521B2 (en)	2003-09-25	2008-02-19	Wyeth	Substituted indoles
US7420083B2 (en)	2003-09-25	2008-09-02	Wyeth	Substituted aryloximes
US7582773B2 (en)	2003-09-25	2009-09-01	Wyeth	Substituted phenyl indoles
US7265148B2 (en)	2003-09-25	2007-09-04	Wyeth	Substituted pyrrole-indoles
US7163954B2 (en)	2003-09-25	2007-01-16	Wyeth	Substituted naphthyl benzothiophene acids
US7141592B2 (en)	2003-09-25	2006-11-28	Wyeth	Substituted oxadiazolidinediones
US7411083B2 (en)	2003-09-25	2008-08-12	Wyeth	Substituted acetic acid derivatives
US7534894B2 (en)	2003-09-25	2009-05-19	Wyeth	Biphenyloxy-acids
US7446201B2 (en)	2003-09-25	2008-11-04	Wyeth	Substituted heteroaryl benzofuran acids
US7268159B2 (en)	2003-09-25	2007-09-11	Wyeth	Substituted indoles
US7342039B2 (en)	2003-09-25	2008-03-11	Wyeth	Substituted indole oximes
US7351726B2 (en)	2003-09-25	2008-04-01	Wyeth	Substituted oxadiazolidinediones
US7442805B2 (en)	2003-09-25	2008-10-28	Wyeth	Substituted sulfonamide-indoles
EP1794138A2 (en)	2004-08-23	2007-06-13	Wyeth	Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1
JP2008510814A (ja)	2004-08-23	2008-04-10	ワイス	Ｐａｉ−１阻害剤としてのピロロ−ナフチル酸
MX2007002178A (es)	2004-08-23	2007-04-02	Wyeth Corp	Acidos de oxazolo-naftilo como moduladores del inhibidor del activador de plasminogeno tipo 1 (pai-1) util en el tratamiento de trombosis y enfermedades cardiovasculares.
US8278290B2 (en)	2005-02-14	2012-10-02	Biononics Limited	Tubulin polymerisation inhibitors
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EP3749654B1 (en) *	2018-02-06	2025-04-23	The Board of Trustees of the University of Illinois	Substituted benzothiophene analogs as selective estrogen receptor degraders

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AU555658B2 (en) *	1981-04-03	1986-10-02	Eli Lilly And Company	Benzothiophene compounds
US4358593A (en) *	1981-04-03	1982-11-09	Eli Lilly And Company	Process for preparing 3-(4-aminoethoxybenzoyl)benzo[b]thiophenes
US4418068A (en) *	1981-04-03	1983-11-29	Eli Lilly And Company	Antiestrogenic and antiandrugenic benzothiophenes
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US5395842A (en) *	1988-10-31	1995-03-07	Endorecherche Inc.	Anti-estrogenic compounds and compositions
DE4117512A1 (de) *	1991-05-25	1992-11-26	Schering Ag	2-phenylbenzo(b)furane und -thiophene, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate
US5210211A (en) *	1991-06-21	1993-05-11	Warner-Lambert Company	4-(1h-pyrrol-1-yl) imidazoles with angiotension ii antagonist activity
JP3157882B2 (ja) *	1991-11-15	2001-04-16	帝国臓器製薬株式会社	新規なベンゾチオフエン誘導体
US5482949A (en) *	1993-03-19	1996-01-09	Eli Lilly And Company	Sulfonate derivatives of 3-aroylbenzo[b]thiophenes
US6756388B1 (en) *	1993-10-12	2004-06-29	Pfizer Inc.	Benzothiophenes and related compounds as estrogen agonists
US6399634B1 (en) *	1994-09-20	2002-06-04	Eli Lilly And Company	Benzothiophene compounds, compositions, and methods

1996
- 1996-08-06 US US08/692,666 patent/US5728724A/en not_active Expired - Fee Related
- 1996-08-13 JP JP9509444A patent/JPH11511169A/ja not_active Ceased
- 1996-08-13 AU AU67740/96A patent/AU6774096A/en not_active Abandoned
- 1996-08-13 CA CA002228997A patent/CA2228997C/en not_active Expired - Fee Related
- 1996-08-13 WO PCT/US1996/013162 patent/WO1997006796A1/en not_active Ceased
- 1996-08-14 EP EP96305934A patent/EP0759434A1/en not_active Withdrawn

Also Published As

Publication number	Publication date
US5728724A (en)	1998-03-17
JPH11511169A (ja)	1999-09-28
WO1997006796A1 (en)	1997-02-27
CA2228997A1 (en)	1997-02-27
AU6774096A (en)	1997-03-12
EP0759434A1 (en)	1997-02-26

Legal Events

Date	Code	Title	Description
1998-07-06	EEER	Examination request
2008-08-13	MKLA	Lapsed

Publication	Publication Date	Title
CA2228997C (en)	2002-07-30	Benzothiophene compounds
EP0703228B1 (en)	2002-03-06	Naphthyl compounds, intermediates, processes, compositions involving them
US6399634B1 (en)	2002-06-04	Benzothiophene compounds, compositions, and methods
US5492922A (en)	1996-02-20	Benzothiophene compounds intermediate compositions and methods for inhibiting aortal smooth muscle proliferation
EP0729951B1 (en)	1999-06-02	Naphthyl compounds, intermediates, compositions, and methods
EP0806420B1 (en)	2002-08-07	Benzothiophenes, formulations containing same, and methods
EP0761659B1 (en)	2003-05-21	Naphthyl and dihydronaphthyl compounds as medicaments
US5622974A (en)	1997-04-22	α-substituted-3-benzyl-benzofurans
EP0774966B1 (en)	2003-11-05	Benzofuran compounds, compositions, and methods
EP0733620B1 (en)	1999-08-25	Alpha-substituted-1-benzyl-naphthyls
EP0953568B1 (en)	2003-08-13	Benzothiophene pharmaceutical compounds
US5688796A (en)	1997-11-18	Heterocyclic substituted benzothiophenes, compositions, and methods
EP0731101B1 (en)	2003-06-11	3-Benzyl-benzothiophenes
EP0731098B1 (en)	2003-06-18	Alpha-substituted-3-benzyl-benzofurans
EP0791590B1 (en)	2003-05-02	Benzothiophenes, and formulations and methods using same
US6608090B1 (en)	2003-08-19	Benzothiophenes with novel basic side chains
US6384053B1 (en)	2002-05-07	α-substituted-1-benzyl-napthyls
US6653328B1 (en)	2003-11-25	3-benzyl-benzothiophenes