WO2011069298A1 - Novel cyclopropane indolinone derivatives - Google Patents
Novel cyclopropane indolinone derivatives Download PDFInfo
- Publication number
- WO2011069298A1 WO2011069298A1 PCT/CN2009/075500 CN2009075500W WO2011069298A1 WO 2011069298 A1 WO2011069298 A1 WO 2011069298A1 CN 2009075500 W CN2009075500 W CN 2009075500W WO 2011069298 A1 WO2011069298 A1 WO 2011069298A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclopropane
- indoline
- oxospiro
- methyl
- chlorophenyl
- Prior art date
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- XJZXHATWISBMLI-UHFFFAOYSA-N C1CC1.C1=CC=C2NC(=O)CC2=C1 Chemical class C1CC1.C1=CC=C2NC(=O)CC2=C1 XJZXHATWISBMLI-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 243
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 687
- 239000005711 Benzoic acid Substances 0.000 claims description 351
- 235000010233 benzoic acid Nutrition 0.000 claims description 351
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 264
- 125000003003 spiro group Chemical group 0.000 claims description 158
- -1 alkylsulfonylphenyl Chemical group 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 59
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- LBBWIBWOPGDMAJ-UHFFFAOYSA-N spiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound O=C1NC2=CC=CC=C2C11CC1 LBBWIBWOPGDMAJ-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 229910052757 nitrogen Chemical group 0.000 claims description 15
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 10
- LYVUCYIXDIUONJ-HYBUGGRVSA-N 3-[[(1s,2r)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 LYVUCYIXDIUONJ-HYBUGGRVSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 238000011321 prophylaxis Methods 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- XFYSLZKVJWVHFD-UHFFFAOYSA-N 2'-(3-chloro-4-fluorophenyl)spiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C1=C(Cl)C(F)=CC=C1C1C2(C3=CC=CC=C3NC2=O)C1 XFYSLZKVJWVHFD-UHFFFAOYSA-N 0.000 claims description 8
- FMPYBWCZQOAMLS-RDPSFJRHSA-N 4-[[(1r,2s)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1C2=CC=CC=C2[C@@]2([C@@H](C2)C=2C=CC(F)=CC=2)C1=O FMPYBWCZQOAMLS-RDPSFJRHSA-N 0.000 claims description 8
- 208000008589 Obesity Diseases 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- UQKPZNDCQQQWCM-UHFFFAOYSA-N 5-bromo-2'-(4-chlorophenyl)spiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C1=CC(Cl)=CC=C1C1C2(C3=CC(Br)=CC=C3NC2=O)C1 UQKPZNDCQQQWCM-UHFFFAOYSA-N 0.000 claims description 7
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 7
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 7
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 7
- 201000001421 hyperglycemia Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- YCXDQINPHSJNBJ-UHFFFAOYSA-N 2'-(4-chlorophenyl)-5-fluorospiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C12=CC(F)=CC=C2NC(=O)C21CC2C1=CC=C(Cl)C=C1 YCXDQINPHSJNBJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000005059 halophenyl group Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 229940081066 picolinic acid Drugs 0.000 claims description 6
- QGBMVTHYTCNCSW-UHFFFAOYSA-N 2'-(4-fluorophenyl)spiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C1=CC(F)=CC=C1C1C2(C3=CC=CC=C3NC2=O)C1 QGBMVTHYTCNCSW-UHFFFAOYSA-N 0.000 claims description 5
- DMCVACZMODEWSA-DQEYMECFSA-N 3-[[(1s,2s)-2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound O=C([C@@]1(C2=CC=CC=C22)C[C@@]1(C)C=1C=CC(Cl)=CC=1)N2CC1=CC=CC(C(O)=O)=C1 DMCVACZMODEWSA-DQEYMECFSA-N 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 5
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- OHLHQMUOTLRPOZ-DENIHFKCSA-N (1s,2r)-2-(4-chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-indole]-2'-one Chemical compound C1=CC(Cl)=CC=C1[C@@H]1[C@]2(C3=CC=CC=C3N(CC=3C=NC=CC=3)C2=O)C1 OHLHQMUOTLRPOZ-DENIHFKCSA-N 0.000 claims description 4
- YELFDUKVBNDMIH-HYBUGGRVSA-N (1s,2r)-2-(4-fluorophenyl)-1'-[(3-fluorophenyl)methyl]-2'-oxospiro[cyclopropane-1,3'-indole]-5'-carboxylic acid Chemical compound C1([C@]2([C@H](C2)C=2C=CC(F)=CC=2)C2=O)=CC(C(=O)O)=CC=C1N2CC1=CC=CC(F)=C1 YELFDUKVBNDMIH-HYBUGGRVSA-N 0.000 claims description 4
- BURNPSJAHSFLIM-SUMWQHHRSA-N (2's,3s)-2'-(4-fluorophenyl)-2-oxospiro[1h-indole-3,1'-cyclopropane]-5-carboxylic acid Chemical compound C1([C@@H]2C[C@]22C(=O)NC3=CC=C(C=C32)C(=O)O)=CC=C(F)C=C1 BURNPSJAHSFLIM-SUMWQHHRSA-N 0.000 claims description 4
- AUMZILDOCNKKDG-UHFFFAOYSA-N 2'-(3-fluorophenyl)-2'-propan-2-ylspiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C1C2(C3=CC=CC=C3NC2=O)C1(C(C)C)C1=CC=CC(F)=C1 AUMZILDOCNKKDG-UHFFFAOYSA-N 0.000 claims description 4
- QRRASXPVPNYPLC-UHFFFAOYSA-N 2'-(4-chlorophenyl)-2'-methylspiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C1C2(C3=CC=CC=C3NC2=O)C1(C)C1=CC=C(Cl)C=C1 QRRASXPVPNYPLC-UHFFFAOYSA-N 0.000 claims description 4
- FQYBTAHRACYCEV-UHFFFAOYSA-N 2'-(4-methylsulfonylphenyl)spiro[1h-indole-3,1'-cyclopropane]-2-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1C2(C3=CC=CC=C3NC2=O)C1 FQYBTAHRACYCEV-UHFFFAOYSA-N 0.000 claims description 4
- RPZQJEJPPUDNJU-UHFFFAOYSA-N 2'-[2-(trifluoromethyl)phenyl]spiro[1H-indole-3,1'-cyclopropane]-2-one Chemical compound O=C1NC2=CC=CC=C2C12C(C2)C2=C(C=CC=C2)C(F)(F)F RPZQJEJPPUDNJU-UHFFFAOYSA-N 0.000 claims description 4
- UPPMWJLXCGOQBK-IIBYNOLFSA-N 2-[4-[(1s,2r)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]imidazol-1-yl]acetic acid Chemical compound OC(=O)CN1C=NC(N2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 UPPMWJLXCGOQBK-IIBYNOLFSA-N 0.000 claims description 4
- NPVJQQPYVZMCJB-HYBUGGRVSA-N 2-[[(1s,2r)-5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CN1C2=CC=C(Cl)C=C2[C@]2([C@H](C2)C=2C=CC(Cl)=CC=2)C1=O NPVJQQPYVZMCJB-HYBUGGRVSA-N 0.000 claims description 4
- UTOKZZMMFILFLW-RLWLMLJZSA-N 3-[(1r,2r)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]-5-(2-oxo-1,3-oxazolidin-3-yl)benzoic acid Chemical compound C1([C@H]2C[C@@]22C(=O)N(C3=CC=CC=C32)C=2C=C(C=C(C=2)C(=O)O)N2C(OCC2)=O)=CC=C(Cl)C=C1 UTOKZZMMFILFLW-RLWLMLJZSA-N 0.000 claims description 4
- MCQLRHMFTOKJDX-XXBNENTESA-N 3-[(1r,2r)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(N2C3=CC=CC=C3[C@@]3([C@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 MCQLRHMFTOKJDX-XXBNENTESA-N 0.000 claims description 4
- MCQLRHMFTOKJDX-CVDCTZTESA-N 3-[(1r,2s)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(N2C3=CC=CC=C3[C@@]3([C@@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 MCQLRHMFTOKJDX-CVDCTZTESA-N 0.000 claims description 4
- MCQLRHMFTOKJDX-AUSIDOKSSA-N 3-[(1s,2r)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(N2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 MCQLRHMFTOKJDX-AUSIDOKSSA-N 0.000 claims description 4
- UTOKZZMMFILFLW-HFZDXXHNSA-N 3-[(1s,2s)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]-5-(2-oxo-1,3-oxazolidin-3-yl)benzoic acid Chemical compound C1([C@@H]2C[C@]22C(=O)N(C3=CC=CC=C32)C=2C=C(C=C(C=2)C(=O)O)N2C(OCC2)=O)=CC=C(Cl)C=C1 UTOKZZMMFILFLW-HFZDXXHNSA-N 0.000 claims description 4
- MCQLRHMFTOKJDX-WMZHIEFXSA-N 3-[(1s,2s)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(N2C3=CC=CC=C3[C@]3([C@@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 MCQLRHMFTOKJDX-WMZHIEFXSA-N 0.000 claims description 4
- CWIHAYDGQPNJPJ-AUSIDOKSSA-N 3-[[(1s,2r)-2'-oxo-2-pyridin-3-ylspiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=NC=CC=3)C2=O)=C1 CWIHAYDGQPNJPJ-AUSIDOKSSA-N 0.000 claims description 4
- DLPZTOPBGLSDJZ-YADARESESA-N 3-[[(1s,2r)-2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@@H](C3)C=3C(=CC=CC=3)F)C2=O)=C1 DLPZTOPBGLSDJZ-YADARESESA-N 0.000 claims description 4
- CRAMOQUWHSJJQT-HYBUGGRVSA-N 3-[[(1s,2r)-2-(3-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=C(Cl)C=CC=3)C2=O)=C1 CRAMOQUWHSJJQT-HYBUGGRVSA-N 0.000 claims description 4
- VLYXNXKAHYPPTQ-HYBUGGRVSA-N 3-[[(1s,2r)-2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=C(F)C=CC=3)C2=O)=C1 VLYXNXKAHYPPTQ-HYBUGGRVSA-N 0.000 claims description 4
- ZQNYAKRRRXZVJA-PXDATVDWSA-N 3-[[(1s,2r)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]-n-methylsulfonylbenzamide Chemical compound CS(=O)(=O)NC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 ZQNYAKRRRXZVJA-PXDATVDWSA-N 0.000 claims description 4
- VPVYQEAQFMHOFT-PXDATVDWSA-N 3-[[(1s,2r)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(=CC=3)C#N)C2=O)=C1 VPVYQEAQFMHOFT-PXDATVDWSA-N 0.000 claims description 4
- DLPZTOPBGLSDJZ-NTKDMRAZSA-N 3-[[(1s,2s)-2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C(=CC=CC=3)F)C2=O)=C1 DLPZTOPBGLSDJZ-NTKDMRAZSA-N 0.000 claims description 4
- ZDPLODINMBZEAQ-GBXCKJPGSA-N 3-[[(1s,2s)-2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=C(F)C=C3[C@]3([C@@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=C1 ZDPLODINMBZEAQ-GBXCKJPGSA-N 0.000 claims description 4
- ARPBCPJWZSDCIU-UHFFFAOYSA-N 4-(2-oxo-1'-propan-2-ylspiro[1h-indole-3,2'-cyclopropane]-1'-yl)benzonitrile Chemical compound C1C2(C3=CC=CC=C3NC2=O)C1(C(C)C)C1=CC=C(C#N)C=C1 ARPBCPJWZSDCIU-UHFFFAOYSA-N 0.000 claims description 4
- ZKGVGKSRZZKAFQ-CUBQBAPOSA-N 4-[[(1r,2s)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]-n-cyclopropylsulfonylbenzamide Chemical compound C=1C=C(CN2C3=CC=CC=C3[C@@]3([C@@H](C3)C=3C=CC(=CC=3)C#N)C2=O)C=CC=1C(=O)NS(=O)(=O)C1CC1 ZKGVGKSRZZKAFQ-CUBQBAPOSA-N 0.000 claims description 4
- POWGXXOOCJYBQQ-OFVILXPXSA-N 4-[[(1r,2s)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1C2=CC=CC=C2[C@@]2([C@@H](C2)C=2C=CC(=CC=2)C#N)C1=O POWGXXOOCJYBQQ-OFVILXPXSA-N 0.000 claims description 4
- FRZCOVHZLVKFCO-AUSIDOKSSA-N 4-[[(1s,2r)-2'-oxo-2-pyridin-3-ylspiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1C2=CC=CC=C2[C@]2([C@H](C2)C=2C=NC=CC=2)C1=O FRZCOVHZLVKFCO-AUSIDOKSSA-N 0.000 claims description 4
- ZKGVGKSRZZKAFQ-UFHPHHKVSA-N 4-[[(1s,2r)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]-n-cyclopropylsulfonylbenzamide Chemical compound C=1C=C(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(=CC=3)C#N)C2=O)C=CC=1C(=O)NS(=O)(=O)C1CC1 ZKGVGKSRZZKAFQ-UFHPHHKVSA-N 0.000 claims description 4
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- OOPJMCFHPVYNQA-MBSDFSHPSA-N 6-[[(1r,2s)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@@]3([C@@H](C3)C=3C=CC(Cl)=CC=3)C2=O)=N1 OOPJMCFHPVYNQA-MBSDFSHPSA-N 0.000 claims description 4
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- FGIBQDRKXAGWNT-WZONZLPQSA-N 6-[[(1s,2r)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(CN2C3=CC=CC=C3[C@]3([C@H](C3)C=3C=CC(F)=CC=3)C2=O)=N1 FGIBQDRKXAGWNT-WZONZLPQSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- ALXXZNBELHRZOC-HOFKKMOUSA-N n-cyclopropylsulfonyl-3-[[(1r,2s)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indole]-1'-yl]methyl]benzamide Chemical compound C1=CC(F)=CC=C1[C@H]1[C@@]2(C3=CC=CC=C3N(CC=3C=C(C=CC=3)C(=O)NS(=O)(=O)C3CC3)C2=O)C1 ALXXZNBELHRZOC-HOFKKMOUSA-N 0.000 claims description 4
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- LGDNSGSJKBIVFG-UHFFFAOYSA-N n,n-dimethyl-2-piperazin-1-ylethanamine Chemical compound CN(C)CCN1CCNCC1 LGDNSGSJKBIVFG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102220305863 rs1015663503 Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
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Classifications
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- 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
- C07D209/96—Spiro-condensed ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- 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
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- 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
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- 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
- C07D401/10—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 aromatic rings
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- 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
- C07D401/12—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 chain containing hetero atoms as chain links
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- C07D401/14—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 three or more hetero rings
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- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
- C07D403/10—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 aromatic rings
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- 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
- C07D403/12—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 chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Definitions
- the invention relates to compounds which are activators of AMP-activated protein kinase (AMPK) and which are useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
- AMPK AMP-activated protein kinase
- the invention relates in particular to a compound of formula (I)
- R 1 and R 2 are independently selected from hydrogen, alkyl, pyridinyl, phenyl,
- R 3 is hydrogen, pyridinyl, piperidinyl, carboxypyridinyl, tetrahydropyranyl,
- alkylsulfonylpiperazinylcarbonyl alkylpyrrolidinylalkylaminocarbonyl, alkyl- 1H- pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl, cycloalkyl- lH-pyrazolylaminocarbonyl and cycloalkylsulfonylaminocarbonyl;
- R 4 is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof.
- the invention also relates to a process for the manufacture of these novel compounds and medicaments containing them.
- the compounds of the invention have activation effect on AMP (adenosine monophosphate)-activated protein kinase, which results in lowered blood glucose.
- AMP adenosine monophosphate
- the invention thus also concerns the use of such compounds for the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
- Obesity and type 2 diabetes, hypertension, cancer, and cardiovascular disease are diseases that feature serious disturbances in glucose or lipid metabolism that severely affect the health and quality of life of affected individuals. The increasing prevalence of these diseases makes finding new drug targets for treating these syndromes an urgent task.
- AMP-activated protein kinase acts as a cellular energy sensor and regulator. It is activated by an increase in the cellular AMP: ATP ratio induced by metabolic stress, hormone and nuturient signals. Once activated, AMPK switches on catabolic pathways that generate ATP and switches off ATP-consuming anabolic pathways by acute regulation of the activity of key enzymes in metabolism and chronic regulation of the expression of pivotal transcription factors (Hardie, DG. Nature reviews 8 (2007b), 774-785; Woods, A et al. Molecular and cellular biology 20 (2000), 6704-6711). The growing evidence of AMPK regulatory effects on glucose and lipid metabolism makes it a potential drug target for treatment of diabetes and metabolic syndrome (Carling, D. Trends Biochem Sci
- Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activation of AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing PEPCK and G6Pase expression, whereas the administration of dominant negative l adenovirus reverses the effect in vivo (Yamauchi, T et al. Nature medicine 8 (2002), 1288-1295).
- AMPK AMPK as a potential target for treating metabolic syndrome
- thiazolidinediones Rosiglitazone, troglitazone and pioglitazone
- biguanides metalformin and phenformin
- Rosiglitazone is traditionally considered to be a PPARy agonist and exerts its antidiabetic effects through differentiation of adipocytes (Semple, RK et al. The Journal of clinical investigation 116 (2006), 581-589).
- alkyl signifies a saturated, linear- or branched chain alkyl group containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like.
- Preferred “alkyl” groups are methyl, ethyl, isopropyl, tert-butyl.
- alkoxy signifies a group alkyl-O-, wherein the "alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy and the like.
- Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.
- cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- Preferred cycloalkyl groups are cyclopropyl and cyclopentyl, cyclopropyl being particularly preferred.
- halogen or "halo”, alone or in combination, means fluorine, chlorine, bromine or iodine.
- Halogen is preferably fluorine, chlorine or bromine.
- halophenyl means phenyl substituted by halogen.
- carboxy alone or in combination, refers to the group -COOH.
- carbonyl alone or in combination, refers to the group -C(O)-.
- amino alone or in combination, refers to primary (- H 2 -), secondary (- H-) or tertiary amino (-N-).
- hydroxy alone or in combination, refers to the group -OH.
- sulfonyl alone or in combination, refers to the group -S(0) 2 -
- pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
- Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
- Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
- the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J. et al, Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H. et al, In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).
- “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any
- physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
- Preferred are the methyl and ethyl esters of the compounds of formula (I).
- R 1 and R 2 are independently selected from hydrogen, alkyl, pyridinyl, phenyl,
- R 3 is pyridinyl, carboxypyridinyl, tetrahydropyranyl, dialkylamino, morpholinyl,
- alkylsulfonylpiperazinylcarbonyl alkylpyrrolidinylalkylaminocarbonyl, alkyl- 1H- pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl and oxo- imidazolidinyl;
- R 4 is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof.
- R 1 and R 2 are selected from hydrogen and alkyl and the other one is selected from pyridinyl, halophenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl, or R 1 and R 2 , together with the carbon atom to which they are attached form cycloalkyl or tetrahydropyranyl;
- R 1 and R 2 are selected from hydrogen and isopropyl and the other one is selected from pyridinyl, fluorophenyl, chlorophenyl, cyanophenyl, methylsulfonylphenyl and trifluoromethylphenyl.
- Preferred is a compound according of formula (I) wherein R 3 is pyridinyl
- alkylpiperazinylcarbonyl alkylsulfonylpiperazinylcarbonyl
- alkylpyrrolidinylalkylaminocarbonyl alkyl- lH-pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl and oxo-imidazolidinyl.
- R 3 is carboxypyridinyl, carboxyalkyl- lH-imidazolyl, carboxyphenyl or phenyl substituted with carboxy and oxo- oxazolidinyl.
- R 4 is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl is also preferred.
- a compound of formula (I) wherein R 4 is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl is also preferred.
- R 4 is hydrogen, halogen or carboxy.
- R 4 is hydrogen, fluoro or chloro.
- a compound of formula (I) wherein n is 0 or 1 is preferred.
- R 5 is hydrogen, halogen, oxo-oxazolidinyl, oxo-imidazolidinyl.
- R 6 and R 7 are independently selected from hydrogen, alkyl, cycloalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl.
- R 1 , R 2 , R 3 , R 4 and n are as defined above unless otherwise indicated.
- the compounds of formula la and lb can be prepared according to Scheme 1.
- Intermediate III is prepared as by the condensation reaction between II and different aldehydes or ketones. Cyclopropanation of III affords the intermediate IV. Alkylation between IV and bromide V affords the ester VI.
- Ester VII can be obtained by introducing R 5 to the intermediate VI under copper salts catalysts. Hydrolysis of the methyl ester VII gives the corresponding acid la.
- Amide lb can be prepared by the coupling reaction between the acid la and amine VIII.
- the condensation reaction between II and different aldehydes is carried out in refluxing toluene or refluxing alcohol overnight when using base such as piperidine or pyrrolidine as catalyst.
- Cyclopropanation of III is carried out in organic solvents such as DMSO at 50°C for several hours by treating trimethylsulfoxoniumiodide with sodium hydride to generate sulfurylide in situation.
- introduction of R 5 to the methyl ester VI can be carried out in the presence of a copper source such as copper(I) iodide (Cul), in combination with a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
- a copper source such as copper(I) iodide (Cul)
- a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol
- a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxid
- the reaction can be carried out in a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone at a temperature between 100°C and 180°C for 15 to 60 minutes under microwave irradiation.
- a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone
- a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone
- Hydrolysis of the methyl esters VII can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours to give the stereoisomers of la.
- an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide
- a solvent such as methanol, 1,4-dioxane or tetrahydrofuran
- the reaction is typically carried out in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), o- (lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or 1- ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt) or N,N-dimethylaminopyridine (DMAP), in the presence of a base such as trie
- the reaction can be carried out in a solvent such as dichloromethane or N,N-dimethylformamide at room temperature for several hours (Montalbetti, C. A. G. N. et a/., Tetrahedron 61 (2005) 10827).
- a solvent such as dichloromethane or N,N-dimethylformamide
- the compounds of formula Ic and Id can be prepared according to Scheme 2.
- the diazo compound X can be obtained by treating the isatin IX with /?-toluenesulfonyl hydrazide under basic conditions. Cyclopropanation of alkene XI with diazo compound X by Rh catalyst affords the intermediate XII. Alkylation or arylation of XII with the bromide V afforded the methyl ester XIII. Introduction of R 5 to XIII by using copper salts as catalyst gave intermediate XIV. Hydrolysis of the methyl ester gives the corresponding acids Ic.
- the hydrolysis can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours. Conversion of the acids Ic to the corresponding amides Id with suitable amines VIII can be easily accomplished using methods well known to someone skilled in the art.
- the reaction is typically carried out in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC), benzotriazol- 1 -yl-oxy-tris-pyrrolidinophosphonium
- hexafluorophosphate PyBop
- HATU o-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- HBTU o-(lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- EDCI l-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt
- HABt hydroxybenzotriazole
- DMAP N,N- dimethylaminopyridine
- a base such as triethylamine or N,N- diisopropyl ethylamine.
- the reaction can be carried out in a solvent such as
- the compounds of formula Ie can be prepared according to Scheme 3. Alkylation of IV with the alkyl halide XV by using a base such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvent such as THF or DMF at room temperature for several hours affords the formula of Ie.
- the compounds of formula If can be prepared according to Scheme 4. Alkylation of IV with the bromide XVI by using a base such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvent such as THF or DMF at room temperature for several hours affords the bromide XVII. If can be obtained by treating XVII with amine VIII under basic condition such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvent such as THF or DMF at room temperature.
- alkylation between IV and the iodide XVIII can be carried out by using bases such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvents such as THF, DMF at room temperature for several hours.
- Reductive amination of XX with different amines VIII can be carried out in organic solvents such as DCM, THF by using reducing reagents such as NaBH 4 or NaHB(OAc) 3 at room temperature to afford formula Ig.
- the compounds of formula Ih and Ii can be prepared according to Scheme 6.
- Ih and Ii can be obtained by alkylation of IV with XXI by using bases such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvents such as THF or DMF at room temperature for several hours.
- the compounds of formula Ij and Ik can be prepared according to Scheme 7.
- the coupling between IV and idoimidazole XXII followed by deprotection in the presence of TFA affords Ij.
- Subsequent alkylation with XXIII affords formula XXIV.
- hydrolysis of the methyl esters XXIV provides the corresponding acids Ik.
- the coupling reaction can be carried out in the presence of a copper source such as copper(I) iodide (Cul), in combination with a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
- a copper source such as copper(I) iodide (Cul)
- a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol
- a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert
- the reaction can be carried out in a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone at a temperature between 100°C and 180°C for 15 to 60 minutes under microwave irradiation.
- a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
- the reactions can be carried out without the use of a microwave at a raised temperature such as 80°C for a longer reaction time (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
- Deprotection can be carried out in organic solvent such as DCM or THF with TFA at room temperature to afford stereoisomers Ij .
- organic solvent such as DCM or THF with TFA at room temperature to afford stereoisomers Ij .
- the alkylation of Ij with bromide XXIII is carried out by using bases such as NaH, K 2 C0 3 or CS2CO 3 in organic solvents such as THF or DMF at room temperature for several hours.
- hydrolysis of the methyl ester gives the compounds Ik.
- the hydrolysis can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours.
- Scheme 8 The compounds of formula IL can be prepared according to Scheme 8. The alkylation between IV and ethylene dibromide XXV affords the bromides XXVI.
- nucleophilic substitution reaction between the ester XXVII and the bromide XXVI gives the methyl esters XXVIII. Hydrolysis of the methyl esters furnishes the corresponding acids IL.
- the condensation between IV and ethylene dibromide can be carried out in organic solvents (THF or DMF) by using bases such as NaH, K 2 CO 3 or Cs 2 C0 3 at room temperature for several hours .
- the substitution reaction between the imidazole XXVII and XXVI can be carried out in organic solvents such as THF or DMF by using bases such as NaH, K 2 C0 3 or Cs 2 C0 3 at room temperature for several hours.
- hydrolysis of the methyl ester XXVII can afford the compounds IL.
- the reaction can be carried out in the presence of an aqueous inorganic bases such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4- dioxane or tetrahydrofuran at room temperature for several hours.
- an aqueous inorganic bases such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4- dioxane or tetrahydrofuran at room temperature for several hours.
- the invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps: a) the reaction of a compound of formula (A)
- R 1 , R 2 , R 3 , R 4 and n are defined as in any one of claims 1 to 8; wherein R 5 is hydrogen, halogen, oxo-oxazolidinyl or oxo-imidazolidinyl; wherein R 6 and R 7 are independently selected from hydrogen, alkyl, cycloalkyl, alkylsulfonyl,
- cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl wherein X is carbon or nitrogen; wherein Y is Br, I, or OTs; wherein Q is Br or I; and wherein R is alkyl.
- the coupling reagent is for example dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), o- (lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or 1- ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI).
- DCC dicyclohexyl carbodiimide
- PyBop benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
- Step (a) can be carried out in the presence or absence of hydroxybenzotriazole (HOBt) or N,N- dimethylaminopyridine (DMAP), in the presence of a base such as triethylamine or N,N- diisopropyl ethylamine.
- the reaction of step (a) can be carried out in a solvent such as dichloromethane or N,N-dimethylformamide. The reaction can be carried out at room temperature for several hours.
- the base can be for example NaH, K 2 C0 3 or Cs 2 C0 3 .
- Step (b) can be carried out in an organic solvent such as THF or DMF. This reaction can proceed at room temperature for several hours.
- the base can be for example NaH, K 2 C0 3 or Cs 2 C0 3 .
- Step (c) can be done in an organic solvent such as THF or DMF. The reaction can proceed at room temperature.
- step (d) can be carried out in an organic solvent such as DCM or THF.
- the reducing agent of step (d) can be for example NaBH 4 or NaHB(OAc) 3 .
- the reaction can proceed at room temperature.
- the base in step (e), can be for example NaH, K 2 C0 3 or Cs 2 C0 3 .
- the solvent can be an organic solvent such as THF or DMF. The reaction can be carried out at room temperature for several hours.
- the base in step (f), can be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
- the solvent of step (f) can be for example methanol, 1,4-dioxane or tetrahydrofuran. The reaction can proceed at room temperature for several hours.
- the base in step (g), can be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
- the solvent of step (g) can be for example methanol, 1,4-dioxane or tetrahydrofuran. The reaction can proceed at room temperature for several hours.
- the invention also relates to a compound of formula (I) for use as therapeutically active substance.
- the invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
- the use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to AMPK regulation is an object of the invention.
- the invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, in particular type 2 diabetes.
- Said medicaments e.g. in the form of pharmaceutical preparations, can be
- administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
- the above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers.
- Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
- Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- the pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
- the doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several administrations.
- a compound of formula (I) when manufactured according to the above process is also an object of the invention.
- the invention also relates to a method for the treatment or prophylaxis of diseases that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I).
- the invention further relates to a method for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, in particular type 2 diabetes, which method comprises administering an effective amount of a compound of formula (I).
- the invention also relates to a compound of formula (I) for the preparation of medicaments useful in the treatment of cancer that are related to AMPK regulation and provides a method for the treatment of cancer that are related to AMPK regulation.
- Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
- Basic condition A: 0.01% NH 3 H 2 0 in H 2 0; B: acetonitrile;
- Oxindole (0.13 g, 1 mmol), 4-chlorobenzaldehyde (0.17 g, 1.2 mmol) were mixed in alcohol; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture was refluxed for 3 hours. The formed precipitates was collected by filtration and washed with alcohol twice to give the title compound as yellow powder (0.24 g, 92 %).
- CisHioClNO 255 observed(M+H) + : 256.1.
- a solution of dimethylsulfoxoniummethylide was prepared as under argon from a 60% NaH mineral oil dispersion (88 mg, 2.2 mmol), trimethylsulfoxoniumiodide (484 mg, 2.2 mmol), and DMSO (10 mL). After 20 min, a solution of (Z)-3-(4-chloro-benzylidene)-l, 3-dihydro- indol-2-one (510 mg, 2 mmol) in THF (5 mL) was added dropwise over 20 min. After stirring for 1 hour at room temperature and another 1 hour at 50°C, the solution was poured into ice-cold water (20 mL) and extracted with ether (3 x 20 mL).
- the tosylhydrazone (38.1 mmol) was treated with a solution of NaOH (76.1 mmol) in water 375 mL.
- the reaction mixture was stirred for 15 hours in a water bath at 50 "C and then allowed to cool to room temperature.
- the reaction mixture was neutralized by addition of dry ice whereupon diazo compound was precipitated. (5.94 g, 88%).
- the tile compounds were obtained by separation of the stereoisomers of (I S, 2S) and (1R, 2R)-3 -((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 32) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
- tile compounds were obtained by separation of the stereoisomers of (I S, 2S) and (1R, 2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopropane-l,3'-indoline]- l'-yl)methyl)benzoic acid (Example 35) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol. (+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[[(irans)-cyclo
- Example 40 and Example 41 (-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(irans)-cyclopropane-l,3'-indoline]- l'-yl)methyl)benzoic acid and (+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'- oxospirol ⁇ ran ⁇ -cyclopropane-l ⁇ '-indolinel-l'-y ⁇ methy ⁇ benzoic acid
- the tile compounds were obtained by separation of the stereoisomers of (I S, 2S) and (IR, 2R)-3 -((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 27) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
- the tile compounds were obtained by separation of the stereoisomers of (1R, 2S) and (I S, 2R)-3 -((2-(4-chlorophenyl)-2-methyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 42) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
- Example 46 and Example 47 (+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-l,3 , -indoline]-l'- yl)methyl)benzoic acid and (-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(ciV)- cyclopropane-l,3'-indoline]-l'-yl)methyl)benzoic acid
- the tile compounds were obtained by separation of the stereoisomers of (1R, 2R) and (I S, 2 S)-3 -((2-(4-chlorophenyl)-2-methyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 45) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
- the tile compounds were obtained by separation of the stereoisomers of (1R, 2S) and (I S, 2R)- 3 -((2-(4-cyanophenyl)-5 '-fluoro-2-methyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl) benzoic acid (Example 48) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
- Racemic (I S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-l,3'-indolin]-2'-one and (1R, 2S)- 2-(4-chlorophenyl)spiro[cyclopropane-l,3'-indolin]-2'-one 270 mg, 1.0 mmol, 1.0 equiv.
- a stirred solution of sodium hydride 60 %, 60 mg, 1.5 mmol
- Example 72 (IS, 2R) and (1R, 2S)-2-(4-chlorophenyl)-l'-(2-morpholinoethyl)spiro[cyclopropane- l,3'-indolin]-2'-one
- Example 77 (IS, 2R)-2-(4-chlorophenyl)-l'-(2-((R)-3-(dimethylamino)pyrrolidin-l- yl)ethyl)spiro[cyclopropane-l,3'-indolin]-2'-one and (IR, 2S)-2-(4-chlorophenyl)-l'- (2-((R)-3-(dimethylamino)pyrrolidin-l-yl)ethyl)spiro[cyclopropane-l,3'-indolin]-2'- one
- Example 80 (IS, 2R) and (1R, 2S)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-l,3'- indoline] - 1 '-yl)- lH-imidazol- l-yl)acetic acid
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US12/959,408 US8354443B2 (en) | 2009-12-11 | 2010-12-03 | Cyclopropane indolinone derivatives |
BR112012013847A BR112012013847A2 (pt) | 2009-12-11 | 2010-12-08 | novos derivados de indolinona ciclopropano |
CA2781839A CA2781839A1 (en) | 2009-12-11 | 2010-12-08 | Spiro indole - cyclopropane indolinones useful as ampk modulators |
CN2010800558075A CN102656147A (zh) | 2009-12-11 | 2010-12-08 | 可用作ampk调节剂的螺吲哚-环丙烷二氢吲哚酮 |
ES10790751.1T ES2464044T3 (es) | 2009-12-11 | 2010-12-08 | Espirol indol-ciclopropano indolinonas útiles como moduladores de AMPK |
RU2012126987/04A RU2012126987A (ru) | 2009-12-11 | 2010-12-08 | Спироиндолциклопропаниндолиноны в качестве модуляторов амрк |
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US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
WO2014202580A1 (en) * | 2013-06-20 | 2014-12-24 | Boehringer Ingelheim International Gmbh | Spiro-substituted oxindole derivatives having ampk activity |
US9394285B2 (en) | 2013-03-15 | 2016-07-19 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
ES2646993A1 (es) * | 2016-06-17 | 2017-12-18 | Consejo Superior De Investigaciones Científicas (Csic) | Derivados de indolin-2-ona y su uso terapéutico |
US11279702B2 (en) | 2020-05-19 | 2022-03-22 | Kallyope, Inc. | AMPK activators |
US11407768B2 (en) | 2020-06-26 | 2022-08-09 | Kallyope, Inc. | AMPK activators |
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CA2756568C (en) | 2009-04-06 | 2018-02-13 | University Health Network | Kinase inhibitors and method of treating cancer with same |
CN102892766B (zh) | 2010-04-06 | 2015-05-20 | 大学健康网络 | 激酶抑制剂和用其治疗癌症的方法 |
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US11279702B2 (en) | 2020-05-19 | 2022-03-22 | Kallyope, Inc. | AMPK activators |
US11851429B2 (en) | 2020-05-19 | 2023-12-26 | Kallyope, Inc. | AMPK activators |
US11407768B2 (en) | 2020-06-26 | 2022-08-09 | Kallyope, Inc. | AMPK activators |
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US8354443B2 (en) | 2013-01-15 |
EP2509946A1 (en) | 2012-10-17 |
US20130102604A1 (en) | 2013-04-25 |
RU2012126987A (ru) | 2014-01-20 |
BR112012013847A2 (pt) | 2016-05-10 |
WO2011070039A1 (en) | 2011-06-16 |
CA2781839A1 (en) | 2011-06-16 |
KR20120114297A (ko) | 2012-10-16 |
EP2509946B1 (en) | 2014-04-16 |
US20110144106A1 (en) | 2011-06-16 |
JP2013513569A (ja) | 2013-04-22 |
ES2464044T3 (es) | 2014-05-30 |
MX2012006180A (es) | 2012-06-19 |
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