JP2015522602A - 糖尿病の治療に有用なイミダゾピリジン誘導体 - Google Patents
糖尿病の治療に有用なイミダゾピリジン誘導体 Download PDFInfo
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- JP2015522602A JP2015522602A JP2015522149A JP2015522149A JP2015522602A JP 2015522602 A JP2015522602 A JP 2015522602A JP 2015522149 A JP2015522149 A JP 2015522149A JP 2015522149 A JP2015522149 A JP 2015522149A JP 2015522602 A JP2015522602 A JP 2015522602A
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- JP
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- Prior art keywords
- imidazo
- pyridin
- ethynyl
- group
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 38
- 238000011282 treatment Methods 0.000 title claims abstract description 19
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 title abstract 3
- 239000003814 drug Substances 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 99
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 56
- -1 substituted Chemical class 0.000 claims description 53
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 41
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 27
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 25
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 22
- 150000005232 imidazopyridines Chemical class 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 201000001421 hyperglycemia Diseases 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 6
- WGWKFCHYCKINFX-UHFFFAOYSA-N 2-[[3-[2-(4-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=C(F)C=C1 WGWKFCHYCKINFX-UHFFFAOYSA-N 0.000 claims description 5
- AZIBVKNCYJJKNC-UHFFFAOYSA-N 2-[[3-[2-(4-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCC1=C(C#CC=2C=CC(F)=CC=2)N2C=CC=CC2=N1 AZIBVKNCYJJKNC-UHFFFAOYSA-N 0.000 claims description 5
- QRCQMXKZSPNIND-UHFFFAOYSA-N 2-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylamino]acetic acid Chemical compound FC(C=1C=C(C=CC1)C#CC1=C(N=C2N1C=CC=C2)CNCC(=O)O)(F)F QRCQMXKZSPNIND-UHFFFAOYSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- DEVDIJAGKGFGQK-UHFFFAOYSA-N 2-[[3-[2-(3-cyanophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(C#N)=C1 DEVDIJAGKGFGQK-UHFFFAOYSA-N 0.000 claims description 4
- FNVXIDVTNVUYRL-UHFFFAOYSA-N 2-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]acetic acid Chemical compound OC(=O)CSCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 FNVXIDVTNVUYRL-UHFFFAOYSA-N 0.000 claims description 4
- XROZSWFVMLLPLB-UHFFFAOYSA-N 2-[[6-chloro-3-[2-[3-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfonyl]acetic acid Chemical compound OC(=O)CS(=O)(=O)CC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=CC(OC(F)(F)F)=C1 XROZSWFVMLLPLB-UHFFFAOYSA-N 0.000 claims description 4
- HYOMEUYVKAWGDH-UHFFFAOYSA-N 2-[[6-chloro-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]acetic acid Chemical compound OC(=O)CSCC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 HYOMEUYVKAWGDH-UHFFFAOYSA-N 0.000 claims description 4
- IXFMLNMXLGLLDT-UHFFFAOYSA-N 3-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylcarbamoylamino]benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)NCC2=C(N3C=CC=CC3=N2)C#CC=2C=C(C=CC=2)C(F)(F)F)=C1 IXFMLNMXLGLLDT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- SHFDOCZNZPKJMT-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-2-[[3-[2-(4-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]benzamide Chemical compound CN(C)CCNC(=O)C1=CC=CC=C1OCC1=C(C#CC=2C=CC(F)=CC=2)N2C=CC=CC2=N1 SHFDOCZNZPKJMT-UHFFFAOYSA-N 0.000 claims description 4
- UGAYJTDEXCGIHZ-UHFFFAOYSA-N 2-[methyl-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methyl]amino]acetic acid Chemical compound OC(=O)CN(C)CC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 UGAYJTDEXCGIHZ-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003472 antidiabetic agent Substances 0.000 claims description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 3
- 229960003105 metformin Drugs 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 229940125708 antidiabetic agent Drugs 0.000 claims description 2
- 125000000686 lactone group Chemical group 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 13
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 5
- VFDGSYFSSFIMFQ-UHFFFAOYSA-N 2-[[3-[2-(2-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC=C1F VFDGSYFSSFIMFQ-UHFFFAOYSA-N 0.000 claims 2
- QKEBMOZXNFEFER-UHFFFAOYSA-N 2-[[3-[2-(3,4-difluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=C(F)C(F)=C1 QKEBMOZXNFEFER-UHFFFAOYSA-N 0.000 claims 2
- YIGGUJJCLMVYAL-UHFFFAOYSA-N 2-[[3-[2-(3-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(F)=C1 YIGGUJJCLMVYAL-UHFFFAOYSA-N 0.000 claims 2
- CSFHLACQWNPYTH-UHFFFAOYSA-N 2-[[3-[2-(3-methoxyphenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound COC1=CC=CC(C#CC=2N3C=CC=CC3=NC=2COCC(O)=O)=C1 CSFHLACQWNPYTH-UHFFFAOYSA-N 0.000 claims 2
- SHVPMVAGPWXFGF-UHFFFAOYSA-N 2-[[3-[2-(4-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]-n-hydroxyacetamide Chemical compound ONC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=C(F)C=C1 SHVPMVAGPWXFGF-UHFFFAOYSA-N 0.000 claims 2
- JOCZKVMYIAGZJI-UHFFFAOYSA-N 2-[[3-[2-(4-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=CC=C1OCC1=C(C#CC=2C=CC(F)=CC=2)N2C=CC=CC2=N1 JOCZKVMYIAGZJI-UHFFFAOYSA-N 0.000 claims 2
- LUCKAOYJWZSCAI-UHFFFAOYSA-N 2-[[3-[2-[3-(difluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(OC(F)F)=C1 LUCKAOYJWZSCAI-UHFFFAOYSA-N 0.000 claims 2
- CMYLAWNFRQHKPF-UHFFFAOYSA-N 2-[[3-[2-[3-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(OC(F)(F)F)=C1 CMYLAWNFRQHKPF-UHFFFAOYSA-N 0.000 claims 2
- FAGCKBWJPQBLCY-UHFFFAOYSA-N 2-[[3-[2-[3-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]acetic acid Chemical compound OC(=O)CSCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(OC(F)(F)F)=C1 FAGCKBWJPQBLCY-UHFFFAOYSA-N 0.000 claims 2
- JRLOTYIRGAIZBB-UHFFFAOYSA-N 2-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCC1=C(C#CC=2C=C(C=CC=2)C(F)(F)F)N2C=CC=CC2=N1 JRLOTYIRGAIZBB-UHFFFAOYSA-N 0.000 claims 2
- LXNFXJXJXSQMEE-UHFFFAOYSA-N 2-[[3-[2-[3-fluoro-4-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=C(OC(F)(F)F)C(F)=C1 LXNFXJXJXSQMEE-UHFFFAOYSA-N 0.000 claims 2
- RTMVBSDFRMCWIL-UHFFFAOYSA-N 2-[[3-[2-[4-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC=1N=C2C=CC=CN2C=1C#CC1=CC=C(OC(F)(F)F)C=C1 RTMVBSDFRMCWIL-UHFFFAOYSA-N 0.000 claims 2
- CQSTZEGHTVSCOA-UHFFFAOYSA-N 2-[[6-chloro-3-[2-(4-fluorophenyl)ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]acetic acid Chemical compound OC(=O)CSCC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=C(F)C=C1 CQSTZEGHTVSCOA-UHFFFAOYSA-N 0.000 claims 2
- HYCZSTAFTALBGN-UHFFFAOYSA-N 2-[[6-chloro-3-[2-[3-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methyl-methylamino]acetic acid Chemical compound OC(=O)CN(C)CC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=CC(OC(F)(F)F)=C1 HYCZSTAFTALBGN-UHFFFAOYSA-N 0.000 claims 2
- DFLCMGPGMNEKSF-UHFFFAOYSA-N 2-[[6-chloro-3-[2-[3-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]acetic acid Chemical compound OC(=O)CSCC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=CC(OC(F)(F)F)=C1 DFLCMGPGMNEKSF-UHFFFAOYSA-N 0.000 claims 2
- HVFROFZGLWKBJG-UHFFFAOYSA-N 2-[[6-chloro-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methyl-methylamino]acetic acid Chemical compound OC(=O)CN(C)CC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 HVFROFZGLWKBJG-UHFFFAOYSA-N 0.000 claims 2
- RRKSKXSEOBREHY-UHFFFAOYSA-N 2-[[6-chloro-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]ethanol Chemical compound OCCSCC=1N=C2C=CC(Cl)=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 RRKSKXSEOBREHY-UHFFFAOYSA-N 0.000 claims 2
- YPJNBUNQPBFASA-UHFFFAOYSA-N 2-[[8-methoxy-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]acetic acid Chemical compound OC(=O)CSCC=1N=C2C(OC)=CC=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 YPJNBUNQPBFASA-UHFFFAOYSA-N 0.000 claims 2
- LHMSNVGRJDVNPT-UHFFFAOYSA-N 2-[[8-methoxy-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methylsulfanyl]ethanol Chemical compound OCCSCC=1N=C2C(OC)=CC=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 LHMSNVGRJDVNPT-UHFFFAOYSA-N 0.000 claims 2
- BFOXDYBPLYJSJJ-UHFFFAOYSA-N 2-[methyl-[[3-[2-[3-(trifluoromethoxy)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methyl]amino]acetic acid Chemical compound OC(=O)CN(C)CC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(OC(F)(F)F)=C1 BFOXDYBPLYJSJJ-UHFFFAOYSA-N 0.000 claims 2
- CNSXPEGYNCYWTR-UHFFFAOYSA-N 3-[[3-(2-phenylethynyl)imidazo[1,2-a]pyridin-2-yl]methoxy]benzoic acid Chemical compound OC(=O)C1=CC=CC(OCC2=C(N3C=CC=CC3=N2)C#CC=2C=CC=CC=2)=C1 CNSXPEGYNCYWTR-UHFFFAOYSA-N 0.000 claims 2
- NKIYKRCCBRHCIM-UHFFFAOYSA-N 4-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OCC1=C(C#CC=2C=C(C=CC=2)C(F)(F)F)N2C=CC=CC2=N1 NKIYKRCCBRHCIM-UHFFFAOYSA-N 0.000 claims 2
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 claims 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 2
- BSCVUGXZDCXGSE-UHFFFAOYSA-N 4-hydroxy-3,3-dimethyl-2-[[3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methoxy]butanoic acid Chemical compound OCC(C)(C)C(C(O)=O)OCC=1N=C2C=CC=CN2C=1C#CC1=CC=CC(C(F)(F)F)=C1 BSCVUGXZDCXGSE-UHFFFAOYSA-N 0.000 claims 1
- DCQWUZQCWRSYAU-UHFFFAOYSA-N [[6-chloro-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]imidazo[1,2-a]pyridin-2-yl]methyl-methylamino] acetate Chemical compound C(C)(=O)ON(C)CC=1N=C2N(C=C(C=C2)Cl)C=1C#CC1=CC(=CC=C1)C(F)(F)F DCQWUZQCWRSYAU-UHFFFAOYSA-N 0.000 claims 1
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 230000007170 pathology Effects 0.000 abstract description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Description
・世界中で2億2000万人超が糖尿病である。
・糖尿病は、脳卒中のリスクを3倍にする。
・糖尿病は、西側世界における失明及び腎不全の第一原因である。
・推定によれば、糖尿病により2005年に110万人が死亡している。
・WHOの予測によれば、糖尿病による死亡者数は、2005年から2030年の間に倍増する。
Yは、酸素若しくは硫黄原子、SO基、SO2基若しくは−NR19基(式中、R19は水素原子若しくはC1〜C6アルキル基、有利にはメチル(Me)を表す)を表し、有利には、Yは、酸素、硫黄原子又は−NR19基、特に酸素原子又は−NR19基を表し、
R1、Ra、Rb、及びRcは、互いに独立して、水素原子;ハロゲン原子、有利にはCl;C1〜C6アルキル基、有利にはメチルであって、該アルキル基が−OH基で置換されていてもよいC1〜C6アルキル基;−OH基;−OMe基などの−O(C1〜C6アルキル)基、−O(C1〜C6アルキル)O(C1〜C6アルキル)基;−CN基;−NR4R5基(式中、R4及びR5は、互いに独立して、水素原子若しくはC1〜C6アルキル基を表す);又は−(C1〜C6アルキル)NR6R7基(式中、R6及びR7は、互いに独立して、水素原子若しくはC1〜C6アルキル基を表す)を表し;
R2は、
・水素原子;
・−OH基で置換されたC1〜C6アルキル基、特に−(CH2)2OH;
・−(C1〜C6アルキル)COOR8基、有利には−CH2COOR8(式中、R8は水素原子又はC1〜C6アルキル基、特にメチル(Me)、エチル(Et)、若しくはイソプロピル(iPr)を表し、アルキル基は−NH2基又は−OH基で置換されていてもよく(有利には、アルキル基は置換されていない)、−(C1〜C6アルキル)COOR8基の例は、−CH2COOH、−CH2COOMe、−CH2COOEt、CH2CH(NH2)COOEt及び−CH2COOiPrである);
・−(C1〜C6アルキル)CONHR9基、有利には−CH2CONHR9(式中、R9は、−OH基;C1〜C6アルキル基、有利にはエチル;−O(C1〜C6アルキル)基、有利には−OEt;アリール基、有利にはフェニル;ヘテロアリール基、有利にはピリジル;−(C=NH)NHCOO(C1〜C6アルキル)基、有利には−(C=NH)NHCOOt−ブチル;−(C=NH)NH2基;又は−(C1〜C6アルキル)NR10R11基、有利には−(CH2)2NR10R11(式中、R10及びR11は、互いに独立して、C1〜C6アルキル基、有利にはメチルを表す)を表し;−(C1〜C6アルキル)CONHR9基の例は、−CH2CONHOH、−CH2CONHOEt及び−CH2CONH(CH2)2NMe2である);
・−(C1〜C6アルキル)COモルホリン基、有利には−CH2COモルホリン;
・−C(=O)R12基(式中、R12は、−O(C1〜C6アルキル)基、有利には−Oイソブチル(OiBu)を表す);C1〜C6アルキル基、有利にはエチル又はイソプロピルであって、−(CH2)2OHのように、−OH基で置換されていてもよいC1〜C6アルキル基;モルホリン基;NH−アリール基、有利には−NHフェニルであって、アリール基が−COOH若しくは−COO(C1〜C6アルキル)基、有利には−COOMeで置換されていてもよいNH−アリール基;又は−NR13R14基(式中、R13及びR14は、互いに独立して、C1〜C6アルキル基、有利にはエチルを表す)であって、−C(=O)R12基の例は、−C(=O)OiBu、−C(=O)(CH2)2OH、−C(=O)NEt2、−C(=O)モルホリン、−C(=O)iPr、−C(=O)NH−3−HO2C−Ph及び−C(=O)NH−3−MeO2C−Phであり;
・(C1〜C6アルキル)アリール基、有利にはベンジルであって、アリール基が−CN、−COOH若しくは−COO(C1〜C6アルキル)基で置換されていてもよい(C1〜C6アルキル)アリール基;置換された(C1〜C6アルキル)アリール基の例は、CH2−3−NC−Phであり;
・(C1〜C6アルキル)ヘテロアリール基、有利には(C1〜C6アルキル)チオフェン、特にメチルチオフェン基;
・アリール基、有利にはフェニルであって、該アリール基が−COOH、−COO(C1〜C6アルキル)、有利には−COOMe、−OH基で置換されたC1〜C6アルキル、有利には−CH2OH、−CN、−CONHOH、−NHSO2(C1〜C6アルキル)、有利には−NHSO2Me、若しくは−CONH−(C1〜C6アルキル)NR15R16、有利には−CONH−(エチル)NR15R16(式中、R15及びR16は、互いに独立して、C1〜C6アルキル基、有利にはメチルを表す)から選択される1つ若しくは複数の基で置換されていてもよいアリール基であり、置換されていてもよいアリール基の例は、−Ph;−2−MeO2C−Ph、−2−HO2C−Ph、−3−MeO2C−Ph、−3−HO2C−Ph、−4−MeO2C−Ph、−4−HO2C−Ph;−2−HO2HC−Ph、−3−MeSO2HN−Ph、−3−NC−Ph、−2−HONHOC−Ph及び−2−Me2N(CH2)2HNOC−Phであり;
・ヘテロアリール基、有利にはピリジル;
・複素環基、有利にはテトラヒドロフランであって、特に1つ又は2つのヘテロ原子、有利にはN、S及びOから選択されるヘテロ原子を含み、必要であれば不飽和を含んでいてもよい、チアゾリンなどの複素環基;
・3〜6員のラクトン基、特にテトラヒドロフラノンであって、1つ若しくは複数のC1〜C6アルキル基、特に2つのメチル基など2つの基で置換されていてもよいラクトン基;
・又は−SO2(C1〜C6アルキル)基、有利には−SO2(イソプロピル)
を表し;
R3は、アリール基、有利にはフェニル、又はヘテロアリール基、有利にはピリジル若しくはチエニルを表し、該アリール基が、以下に示す1つ又は複数の基で置換されていてもよい:−(C1〜C6アルキル)、有利にはメチルであって、該アルキル基が、例えば−CF3のように1つ若しくは複数のハロゲン原子、有利にはFで置換されていてもよく、又は例えば−CH2CNのように、−CN基によって置換されていてもよい−(C1〜C6アルキル);ハロゲン原子、有利にはF;−O(C1〜C6アルキル)、有利には−OMeであって、例えば、−OCF3若しくは−OCH2Fのように、該アルキル基が、1つ若しくは複数のハロゲン原子、有利にはFで置換されていてもよい−O(C1〜C6アルキル)、;−CN;−OH;−NO2;−COOH;−NR17R18(式中、R17及びR18は、互いに独立して、C1〜C6アルキル基、有利にはメチルを表す);又は−NHCO−(C1〜C6アルキル)、有利には−NHCOMe;置換されていてもよいアリール基の例は、−Ph、−2−F3C−Ph、−3−F3C−Ph、−4−F3C−Ph、−2−F−Ph、−3−F−Ph、−4−F−Ph、−3,4−(F)2−Ph、−3−F−4−F3CO−Ph、−3−F3CO−Ph、−4−F3CO−Ph、−3−F2HCO−Ph、−3−NC−Ph、−3−HO−Ph、−2−MeO−Ph、−3−MeO−Ph、−4−MeO−Ph、−3,4−(MeO)2−Ph、−4−Me−Ph、−4−Me2N−Ph、−4−O2N−Ph、−3−HO2C−Ph、−3−MeCOHN−Ph、及び−4−NCH2C−Phである。
・−(C1〜C6アルキル)COOR8基、有利には−CH2COOR8(式中、R8は水素原子又はC1〜C6アルキル基、特にメチル(Me)、エチル(Et)、又はイソプロピル(iPr)を表し、−(C1〜C6アルキル)COOR8基の例は、−CH2COOH、−CH2COOMe、−CH2COOEt、及びCH2COOiPrである);
・(C1〜C6アルキル)CONHR9基、有利には−CH2CONHR9(式中、R9は、−OH基;−O(C1〜C6アルキル)基、有利には−OEt、又は−(C1〜C6アルキル)NR10R11基(式中、R10及びR11は、互いに独立して、C1〜C6アルキル基、有利にはメチルを表す)を表し、−(C1〜C6アルキル)CONHR9基の例は、−CH2CONHOH、−CH2CONHOEt、及び−CH2CONH(CH2)2NMe2である);
・アリール基、有利にはフェニルであって、該アリール基が−COOH、−COO(C1〜C6アルキル)、有利には−COOMe、−CONHOH又は−CONH−(C1〜C6アルキル)NR15R16、有利には−CONH−(エチル)NR15R16(式中、R15及びR16は、互いに独立して、C1〜C6アルキル基、有利にはメチルを表す)から選択される1つ若しくは複数の基で置換されていてもよいアリール基であって、置換されていてもよいアリール基の例は、−Ph;2−MeO2C−Ph、−2−HO2C−Ph、−3−MeO2C−Ph、−3−HO2C−Ph、−4−MeO2C−Ph、−4−HO2C−Ph;−2−HONHOC−Ph及び−2−Me2N(CH2)2HNOC−Phである;又は
・−CONHアリール基、有利には−CONHフェニルであって、−COOH又は−COO(C1〜C6アルキル)基、有利には−COOMeで置換されていてもよい−CONHアリール基
を表す。
(1)酸付加塩であって、塩酸、臭化水素酸、硫酸、硝酸、リン酸などの鉱酸と形成される;若しくは、酢酸、ベンゼンスルホン酸、安息香酸、カンファースルホン酸、クエン酸、エタンスルホン酸、フマル酸、グルコヘプトン酸、グルコン酸、グルタミン酸、グリコール酸、ヒドロキシナフトエ酸、2−ヒドロキシエタンスルホン酸、乳酸、マレイン酸、リンゴ酸、マンデル酸、メタンスルホン酸、ムコン酸、2−ナフタレンスルホン酸、プロピオン酸、サリチル酸、コハク酸、ジベンゾイル−L−酒石酸、酒石酸、p−トルエンスルホン酸、トリメチル酢酸、トリフルオロ酢酸などの有機酸と形成される酸付加塩;又は
(2)塩であって、親化合物中に存在する酸性プロトンが金属イオン、例えば、アルカリ金属イオン、アルカリ土類金属イオン若しくはアルミニウムイオンによって置換されるか、又は有機若しくは無機塩基に配位するとき形成される塩を含む。許容される有機塩基としては、ジエタノールアミン、エタノールアミン、N−メチルグルカミン、トリエタノールアミン、トロメタミンなどが挙げられる。許容される無機塩基としては、水酸化アルミニウム、水酸化カルシウム、水酸化カリウム、炭酸ナトリウム、及び水酸化ナトリウムが挙げられる。
一般式(I)の化合物は、当業者にそれ自体公知の、及び/又は当業者にとって実現可能な任意の方法、特に、LarockによってComprehensive Organic Transformations、VCH Pub.、1989年に記載されている方法を適用する若しくは適合させる、又は以下の手順に記載されている方法を適用する若しくは適合させることによって調製することができる。
プロトン(1H)の核磁気共鳴(NMR)スペクトルの取得は、Bruker Avance DPX300装置(300.16MHz)で行われる。化学シフト(δ)は百万分率(ppm)で測定される。スペクトルは、使用される重水素化溶媒の化学シフトに基づき較正する。結合定数(J)は、ヘルツ(Hz)で表され、多重度は、次のように、一重線(s)、二重線(d)、二重線の二重線(dd)、三重線(t)、二重線の三重線(td)、四重線(q)、多重線(m)で表される。質量スペクトル(MS)は、分光計Agilent Technologies MSD、G1946A型で得られ、試料は、「大気圧化学イオン化」(APCI)供給源によってイオン化される。
AIBN アゾイソブチロニトリル
dba ジベンジリデンアセトン
DIAD ジイソプロピルアゾジカルボキシレート
DME 1,2−ジメトキシエタン
EDC N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド
HOBt 1−ヒドロキシベンゾトリアゾール
LAH 水素化アルミニウムリチウム
RED−Al ナトリウムジヒドロビス(2−メトキシエトキシ)アルミネート
TIPS トリイソプロピルシリル
CDCl3 重水素化クロロホルム
DMSO 重水素化ジメチルスルホキシド
PyBOP (ベンゾトリアゾール−1−イル−オキシトリピロリジノホスホニウムヘキサフルオロホスフェート)
DMPU 1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H)−ピリミジノン
DMF ジメチルホルムアミド
Boc tert−ブトキシカルボニル
mmol ミリモル
μM マイクロモル
ml ミリリットル
g グラム
M モル/リットル
N 規定度
nm ナノメートル
min 分
h 時間
d 日
r.t. 室温
UV 紫外線
ctrl 対照
HGP 肝グルコース産生
工程1:2−(クロロメチル)イミダゾ[1,2−a]ピリジンの調製
LC−MS:m/z=307(MH+);254nmでのUV純度=99%.1H NMR(300MHz,DMSO) δ 8.62(d,J=6.7Hz,1H),7.79−7.58(m,3H),7.45(dd,J=8.8,7.2Hz,4H),7.13(t,J=6.5Hz,1H),4.74(s,2H),3.70(s,2H)
LC−MS:m/z=367(MH+);254nmでのUV純度=98%.1H NMR(300MHz,DMSO) δ 8.62(d,J=6.8Hz,1H),7.74(dd,J=8.7,5.5Hz,2H),7.67(d,J=9.0Hz,1H),7.45(d,J=7.0Hz,1H),7.33(t,J=8.9Hz,2H),7.12(t,J=6.5Hz,1H),4.93(dt,J=12.5,6.3Hz,1H),4.78(s,2H),4.19(s,2H),1.15(d,J=6.3Hz,6H).
工程1:2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセチルクロリドの調製
工程1:2−(((トリイソプロピルシリル)オキシ)メチル)イミダゾ[1,2−a]ピリジンの調製
LC−MS:m/z=249(MH+);254nmでのUV純度=99%.1H NMR(300MHz,DMSO) δ 8.59(dt,J=6.7,1.1Hz,1H),7.77−7.56(m,3H),7.56−7.32(m,4H),7.11(td,J=6.8,1.1Hz,1H),5.33(t,J=5.9Hz,1H),4.67(d,J=5.9Hz,2H)
工程1:2−(クロロメチル)−3−ヨードイミダゾ[1,2−a]ピリジンの調製
工程1:2−(イミダゾ[1,2−a]ピリジン−2−イルメチル)イソインドリン−1,3−ジオンの調製
工程1:メチル=2−((イミダゾ[1,2−a]ピリジン−2−イルメチル)(メチル)アミノ)アセテートの調製
工程1:メチル=2−((3−ヨードイミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエートの調製
工程1:エチル=イミダゾ[1,2−a]ピリジン−2−カルボキシレートの調製
工程1:2−((3−((4−フルオロフェニル)エチニル)イミダゾ−[1,2−a]ピリジン−2−イル)メトキシ)ベンゾイルクロリドの調製
工程1:2−(クロロメチル)−3−(フェニルエチニル)イミダゾ[1,2−a]ピリジンの調製
LC−MS:m/z=267(MH+);254nmでのUV純度=98%.
工程1:エチル=2−((6−クロロイミダゾ[1,2−a]ピリジン−2−イル)メチルチオ)アセテートの調製
異なる化合物を、INS−1β膵臓系について試験し、グルコースに反応してインスリン分泌を増強する能力を評価した。非常に簡単に述べると、細胞は、Asfariら[9]によって説明されているように、ピルビン酸ナトリウム1mM、2−メルカプトエタノール50μM、グルタミン2mM、HEPES10mM、ペニシリン100IU/ml、ストレプトマイシン100μg/ml及び10%の不活性化ウシ胎児血清を含有し、グルコース10mMを有するRPMI1640培地中で培養する。インスリン分泌試験については、INS−1細胞を96ウェルプレートに播種し、培養する。湿潤雰囲気中、37℃で3日間培養した後(95%空気/5%CO2)、培地を除去し、細胞をグルコース5mM及び不活性化ウシ胎児血清1%を含有する培地中で16時間インキュベートする。試験日に、細胞を、ウシアルブミン0.1%を含有するクレブス緩衝液(pH7.4)で洗浄し、次いで、2.8mMのグルコースを含有するこの同じ緩衝液中、37℃で30分間プレインキュベートする。最後に、細胞をクレブス緩衝液で再度洗浄し、次いで、分泌試験の緩衝液中で1時間インキュベートする(ウシアルブミン0.1%及びグルコース3.5mM及び評価される分子を含有するクレブス、pH7.4)。試験の終了時に、細胞上清を回収し、ラット抗インスリン抗体を用いるELISAキット(ELISA Alpco Cat no.80−INSRTH−E10)によってインスリン分泌を測定する。各条件を3通り試験する。3.5mMのグルコース、10−7MのGLP−1及びForskoline10−7/IBMX10−5M混合物を試験の陽性対照として使用する。この因子が、所与のグルコースの投与量の対照の130%以上である場合、化合物はインスリンの分泌を刺激している。
機器及び方法
肝細胞を、門脈にコラゲナーゼを潅流した後24時間絶食したウィスターラットの肝臓から単離する。1)新たに単離した肝細胞をコラーゲンでコーティングされ、接着培地(ウィリアム培地)を含有する6ウェルプレートに播種する。接着後、培地は、グルコースを含まず16〜18時間ヒドロコルチゾン(7×10−5M)を含有するRPMI1640培地と交換する。翌日、グルコースの肝臓産生試験をクレブス培地中で3時間行う。基底条件はクレブスのみでインキュベートした細胞であり、刺激された条件はクレブス+ラクテート+ピルビン酸中に配置された細胞であり、生産条件はクレブス/ラクテート/ピルビン酸培地中で化学物質に曝露された細胞である。化合物がDMSOに溶解している場合、試験条件は全て最終濃度が0.1%のDMSO溶液の状態で満たされる。試験の陽性対照は、ホスホエノールピルビン酸カルボキシキナーゼを経由したグルコースの肝臓産生に対する抑制作用が公知のメルカプトピコリネートである。短期処置については、化合物は3時間インキュベートする。長期処置については、化合物は、肝細胞をRPMI中で培養する時に20時間インキュベートし、次いで、肝臓産生試験の間に3時間追加する。3時間のインキュベーションの終了時に、上清を、グルコースオキシダーゼを用いた比色法でグルコースを測定するために回収する。ローリー法でタンパク質の量を測定するために、細胞を0.1%NaOH水溶液で溶解する。結果は、タンパク質1mg当たりのグルコースのミリモルで表されている。この因子が、対照の75%以下である場合、化合物はグルコースの肝臓産生を抑制している。
機器及び方法
出生日にストレプトゾトシンを注射することによって糖尿病にされ[10]、ペントバルビタールで麻酔した(Nembutal(C):45mg/kg;腹腔内経路)ラットから膵臓を採取した。これらのラットは、2型糖尿病のヒトにおいて観察されるように、グルコースに対するインスリン反応の特異的な欠陥を有する[11]。膵臓の単離及び潅流は、Sussmanら[13]によって記載された手順の変更[12]に従って達成した。化合物又は参照物質の効果について、クレブス緩衝液中で35分間(t=20分からt=55分)、次いで、グルコース16.5mMの存在下で20分間(t=55分からt=75分)試験する。培地中に分泌されるインスリンの濃度は、Elisaアッセイ(ELISA Alpco Cat no.80−INSRTH−E10)によって測定する。結果は、数回の実験の平均値+/−SEM(平均の標準誤差)として表される。
化合物118の抗糖尿病活性を2型糖尿病の非肥満モデルであるGKラットで評価した。このモデルは、グルコースに対するわずかな不耐性[14]に基づいて選択されたウィスターラットの交雑育種によって得た。これらのラットは、ヒトの2型糖尿病において観察される機能障害(高血糖、グルコースに対する不耐性、インスリン抵抗性及びグルコースに対するインスリン反応の劣化など)の大多数を有する[15]。これらの動物は、Metabrainで繁殖させ、12時間昼/夜サイクル(7時間〜19時間の光)で一定の湿度(50±20%)の下で調整された温度(22±2℃)で動物飼育施設において飼育され、食べ物や飲み物へのアクセスは自由にした。飼育及び実験条件は、実験その他科学的目的に使用される脊椎動物の保護のための欧州協定(ETS123)に準拠する。この検討において、使用されるラットは、検討を開始する前に2時間絶食させた雄の16週齢のGKラットである(吸収後条件)。血糖のモニタリングは、ラットの2つの群:50mg/kgの単回投与で化合物118で経口的に処置した1つの群及び担体で経口的に処置した対照群に対して行われる。血液サンプルは、化合物118又は担体の投与直前のT0、並びに投与後T1h、T2h、T4h及びT6hに取った。血糖は、血糖計Accu−Check Performaで測定される尾から採血される血液1滴から決定される。以下に示す結果では、化合物118で処置された群のT1h、T2h、T4h及びT6hにおける血糖減少率は対照群と比較したときの割合(%)として表されている。
[1]国際公開第2010/089292号
[2]国際公開第2010/070008号
[3]国際公開第2010/034500号
[4]欧州特許出願公開第2168965号明細書
[5]国際公開第2009080291;
[6]国際公開第2009023179;
[7]Helvetica Chimica Acta (2007),90(12),2349−2367;
[8]Letters in Organic Chemistry(2005),2(2),184−187;
[9]Asfari et al., Endocrinology 130:167−178,1992
[10]Portha et al., Diabetes,23,(1974),889−895
[11]Giroix et al., Diabetes,32,(1983),445−451
[12]Assan et al., Nature,239,(1972),125−126
[13]Sussman et al., Diabetes,15,(1966),466−472
[14]Goto et al., Proc.Jpn.Acad.51,80−85,1975
[15]Portha et al., Mol.Cell.Endocrinol.,297:73−85,2009
Claims (12)
- 以下の一般式Iのイミダゾピリジン誘導体
Yは、酸素原子、硫黄原子、SO基、SO2基、又は−NR19基(式中、R19は水素原子又はC1〜C6アルキル基を表す)を表し;
R1、Ra、Rb及びRcは、互いに独立して、水素原子;ハロゲン原子;−OH基で置換されていてもよいC1〜C6アルキル基;−OH基;−O(C1〜C6アルキル)基;−O(C1〜C6アルキル)O(C1〜C6アルキル)基;−CN基;−NR4R5基(式中、R4及びR5は、互いに独立して、水素原子若しくはC1〜C6アルキル基を表す);又は−(C1〜C6アルキル)NR6R7基(式中、R6及びR7は、互いに独立して、水素原子若しくはC1〜C6アルキル基を表す)を表し;
R2は、
水素原子;
−OH基で置換されたC1〜C6アルキル基;
(C1〜C6アルキル)COOR8基(式中、R8は水素原子又はC1〜C6アルキル基を表し、アルキル基は−NH2又は−OH基で置換されていてもよい);
(C1〜C6アルキル)CONHR9基(式中、R9は、−OH基;C1〜C6アルキル基;−O(C1〜C6アルキル)基;アリール基;ヘテロアリール基;−(C=NH)NHCOO(C1〜C6アルキル)基;−(C=NH)NH2基、又は−(C1〜C6アルキル)NR10R11基(式中、R10及びR11は、互いに独立して、C1〜C6アルキル基を表す)を表す);
(C1〜C6アルキル)COモルホリン基;
C(=O)R12基(式中、R12は、−O(C1〜C6アルキル)基;−OH基で置換されていてもよいC1〜C6アルキル基;モルホリン基;NH−アリール基であって、該アリール基が−COOH若しくは−COO(C1〜C6アルキル)基で置換されていてもよいNH−アリール基;又は−NR13R14基(式中、R13及びR14は、互いに独立して、C1〜C6アルキル基を表す)を表す);
(C1〜C6アルキル)アリール基であって、該アリール基が−CN、−COOH若しくは−COO(C1〜C6アルキル)基で置換されていてもよい(C1〜C6アルキル)アリール基;
(C1〜C6アルキル)ヘテロアリール基;
アリール基、有利にはフェニルであって、該アリール基が、−COOH;−COO(C1〜C6アルキル);−OH、−CN、−CONHOH、−NHSO2(C1〜C6アルキル)、又はC1〜C6アルキルであって−CONH−(C1〜C6アルキル)NR15R16基(式中、R15及びR16は、互いに独立して、C1〜C6アルキル基を表す)で置換されたC1〜C6アルキルから選択される1つ又は複数の基で置換されていてもよいアリール基、有利にはフェニル;
ヘテロアリール基;
不飽和を含んでいてもよい複素環基;
1つ又は複数のC1〜C6アルキル基で置換されていてもよい3〜6員を有するラクトン基;又は、
−SO2(C1〜C6アルキル)基
を表し;
R3は、アリール基、有利にはフェニル基、又はヘテロアリール基を表し、ここで、該アリール基は、−C1〜C6アルキルであって該アルキル基が1つ又は複数のハロゲン原子、有利にはFで、又は−CN基で置換されていてもよい−C1〜C6アルキル;ハロゲン原子、有利にはF;−O(C1〜C6アルキル)であって、該アルキル基が、1つ又は複数のハロゲン原子、有利にはFで置換されていてもよい−O(C1〜C6アルキル);−CN;−OH;−NO2;−COOH;NR17R18(式中、R17及びR18は、互いに独立して、C1〜C6アルキル基を表す);又は−NHCO−(C1〜C6アルキル)から選択される1つ又は複数の基で置換されていてもよい)
又はそのエナンチオマー、ジアステレオ異性体、水和物、溶媒和物、互変異性体、ラセミ混合物若しくは薬学的に許容される塩。 - Yが、酸素原子、硫黄原子、−NH基、又は−Nme基、有利には酸素原子を表すことを特徴とする、請求項1に記載のイミダゾピリジン誘導体。
- R1、Ra、Rb及びRcが水素原子を表すことを特徴とする、請求項1又は2に記載のイミダゾピリジン誘導体。
- R2が、
(C1〜C6アルキル)COOR8基(式中、R8は水素原子又はC1〜C6アルキル基を表す);
(C1〜C6アルキル)CONHR9基(式中、R9は、−OH基;−O(C1〜C6アルキル)基;又は−(C1〜C6アルキル)NR10R11基(式中、R10及びR11は、互いに独立して、C1〜C6アルキル基を表す)を表す);
アリール基、有利にはフェニルであって、該アリール基が、−COOH、−COO(C1〜C6アルキル)、−CONHOH、又は−CONH−(C1〜C6アルキル)NR15R16(式中、R15及びR16は、互いに独立して、C1〜C6アルキル基を表す)から選択される1つ又は複数の基で置換されていてもよいアリール基;又は
−CONHアリール基であって、−COOH若しくは−COO(C1〜C6アルキル)基で置換されていてもよい−CONHアリール基
を表すことを特徴とする、請求項1〜3のいずれか一項に記載のイミダゾピリジン誘導体。 - R2が、−(C1〜C6アルキル)COOH基、有利には−CH2COOHを表すことを特徴とする、請求項4に記載のイミダゾピリジン誘導体。
- R3が、アリール基、有利にはフェニルであって、該アリール基が、−(C1〜C6アルキル)であって該アルキル基が1つ又は複数のハロゲン原子、有利にはFで置換されていてもよい−(C1〜C6アルキル);ハロゲン原子、有利にはF;−O(C1〜C6アルキル)であって、該アルキル基が、1つ又は複数のハロゲン原子、有利にはFで置換されていてもよい−O(C1〜C6アルキル);−CN;又は−NO2から選択される1つ又は複数の基で置換されていてもよいアリール基を表すことを特徴とする、請求項1〜5のいずれか一項に記載のイミダゾピリジン誘導体。
- R3が、1つ若しくは複数のハロゲン原子、有利にはFで置換された−(C1〜C6アルキル);ハロゲン原子、有利にはF;アルキル基が、1つ若しくは複数のハロゲン原子、有利にはFで置換された−O(C1〜C6アルキル);又は−CNから選択される1つ若しくは複数の基で置換されたフェニル基を表すことを特徴とする、請求項6に記載のイミダゾピリジン誘導体。
- 以下の化合物から選択されることを特徴とする、請求項1〜7のいずれか一項に記載のイミダゾピリジン誘導体。
2−(((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)アミノ)酢酸(68);
2−((3−((2−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(42);
2−((3−((3−(ジフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(35);
2−((3−((3−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(29);
2−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)安息香酸(89);
2−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸ナトリウム(51);
2−((3−((3,4−ジフルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(38);
2−((3−((3−シアノフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(27);
2−((3−((3−フルオロ−4−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(39);
2−((3−((3−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(40);
2−((3−((3−メトキシフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(30);
2−((3−((4−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(32);
2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸(44);
2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)安息香酸(88);
2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)−N−ヒドロキシアセトアミド(59);
2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)−N−ヒドロキシベンズアミド(96);
2−((3−((4−ニトロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸ナトリウム(48);
2−((3−(フェニルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸ナトリウム(45);
2−((3−(フェニルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)安息香酸ナトリウム(92);
2−((3−(p−トリルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸ナトリウム(47);
2−(メチル((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)アミノ)酢酸(73);
3−((3−(フェニルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)安息香酸(93);
3−(3−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)ウレイド)安息香酸(75);
4−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)安息香酸(90);
エチル=2−((3−((2−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(26);
エチル=2−((3−((2−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(25);
エチル=2−((3−((3−(ジフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(20);
エチル=2−((3−((3−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(18);
エチル2−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(7);
エチル=2−((3−((3,4−ジフルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(10);
エチル=2−((3−((3−シアノフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(14);
エチル2−((3−((3−フルオロ−4−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(11);
エチル=2−((3−((3−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(23);
エチル=2−((3−((3−メトキシフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(12);
エチル=2−((3−((4−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(17);
エチル=2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(3);
エチル2−((3−((4−ニトロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(5);
エチル=2−((3−(フェニルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(1);
エチル=2−((3−(p−トリルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(2);
イソプロピル=2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセテート(54);
メチル=2−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(77);
メチル=2−((3−((3−シアノフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(79);
メチル=2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(76);
メチル=2−((3−(フェニルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(78);
エチル=2−(メチル((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)アミノ)アセテート(72);
メチル=3−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(81);
メチル=3−((3−(フェニルエチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(87);
メチル=3−(3−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)ウレイド)ベンゾエート(74);
メチル=4−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンゾエート(83);
N−(2−(ジメチルアミノ)エチル)−2−((3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセトアミド(55);
N−(2−(ジメチルアミノ)エチル)−2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセトアミド(57);
N−(2−(ジメチルアミノ)エチル)−2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンズアミド(95);
N−エトキシ−2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)アセトアミド(58);
2−((3−((4−フルオロフェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メトキシ)酢酸ナトリウム(46);
エチル=2−[メチル−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチル]アミノ]アセテート塩酸塩(101);
エチル=2−[[6−クロロ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチル−メチル−アミノ]アセテート(102);
エチル=2−(メチル((3−((3−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)アミノ)アセテート(103);
エチル=2−(((6−クロロ−3−((3−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)(メチル)アミノ)アセテート塩酸塩(104);
2−(((6−クロロ−3−((3−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)(メチル)アミノ)酢酸(105);
2−(メチル((3−((3−(トリフルオロメトキシ)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)アミノ)酢酸(106);
2−(((6−クロロ−3−((3−(トリフルオロメチル)フェニル)エチニル)イミダゾ[1,2−a]ピリジン−2−イル)メチル)(メチル)アミノ)酢酸(107);
エチル=2−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセテート(108);
エチル=2−[[3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセテート(109);
エチル=2−[[6−クロロ−3−[2−[4−(フルオロ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセテート(110);
エチル=2−[[6−クロロ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセテート(111);
エチル=2−[[6−クロロ−3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセテート(112);
エチル=(2R)−2−アミノ−3−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]プロパノエート(113);
エチル=2−[[8−メトキシ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセテート(114);
2−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]酢酸(115);
2−[[3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]酢酸(116);
2−[[6−クロロ−3−[2−(4−フルオロフェニル)エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]酢酸(117);
2−[[6−クロロ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]酢酸(118);
2−[[6−クロロ−3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]酢酸(119);
2−[[8−メトキシ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]酢酸(120);
エチル=2−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルホニル]アセテート(121);
エチル=2−[[6−クロロ−3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルホニル]アセテート(122);
2−[[6−クロロ−3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルホニル]酢酸(123);
N−(3−ピリジル)−2−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセトアミド(124);
N−(3−ピリジル)−2−[[3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メトキシ]アセトアミド(125);
N−(3−ピリジル)−2−[[3−[2−[3−(トリフルオロメトキシ)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセトアミド(126);
4−ヒドロキシ−3,3−ジメチル−2−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メトキシ]ブタン酸(129);
2−[[8−メトキシ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]エタノール(130);
2−[[6−クロロ−3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]エタノール(131);
N−カルバムイミドイル−2−[[3−[2−[3−(トリフルオロメチル)フェニル]エチニル]イミダゾ[1,2−a]ピリジン−2−イル]メチルスルファニル]アセトアミド塩酸塩(135) - 請求項1〜8のいずれか一項に記載の誘導体及び薬学的に許容される賦形剤を含む医薬組成物。
- 別の抗糖尿病薬、特にメトホルミンをさらに含む、請求項9に記載の医薬組成物。
- 薬剤として使用するための請求項1〜8のいずれか一項に記載の誘導体。
- 糖尿病、その合併症及び/又は関連病状、有利には、2型糖尿病若しくは高血糖の治療及び/又は予防を目的とした薬剤として使用するための請求項1〜8のいずれか一項に記載の誘導体。
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PCT/FR2013/051703 WO2014013182A1 (fr) | 2012-07-20 | 2013-07-16 | Derive d'imidazopyridine utiles dans le traitement du diabete |
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FR2925905B1 (fr) * | 2008-01-02 | 2010-11-05 | Sanofi Aventis | DERIVES DE 2-BENZOYL-IMIDAZO°1,2-a!PYRIDINE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE |
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KR102132744B1 (ko) | 2020-07-10 |
EP2875026A1 (fr) | 2015-05-27 |
AU2013291866B2 (en) | 2017-08-10 |
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AU2013291866A1 (en) | 2015-02-26 |
CN104662020A (zh) | 2015-05-27 |
CA2879054A1 (fr) | 2014-01-23 |
ES2602056T3 (es) | 2017-02-17 |
CA2879054C (fr) | 2021-02-09 |
EP2875026B1 (fr) | 2016-09-21 |
PT2875026T (pt) | 2016-12-13 |
RU2648242C2 (ru) | 2018-03-23 |
JP6154007B2 (ja) | 2017-06-28 |
FR2993564B1 (fr) | 2014-08-22 |
US9381191B2 (en) | 2016-07-05 |
DK2875026T3 (en) | 2017-01-09 |
US20150182507A1 (en) | 2015-07-02 |
PL2875026T3 (pl) | 2017-02-28 |
WO2014013182A1 (fr) | 2014-01-23 |
FR2993564A1 (fr) | 2014-01-24 |
RU2015101211A (ru) | 2016-09-10 |
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