EA008166B1 - Производные азобициклооктанов и нонанов, обладающие активностью в ингибировании dpp-iv - Google Patents
Производные азобициклооктанов и нонанов, обладающие активностью в ингибировании dpp-iv Download PDFInfo
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- EA008166B1 EA008166B1 EA200500017A EA200500017A EA008166B1 EA 008166 B1 EA008166 B1 EA 008166B1 EA 200500017 A EA200500017 A EA 200500017A EA 200500017 A EA200500017 A EA 200500017A EA 008166 B1 EA008166 B1 EA 008166B1
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- Eurasian Patent Office
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- formula
- azabicyclo
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- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 6
- QUIJMHDIAFOPRK-UHFFFAOYSA-N 1-cyclooctylazocane Chemical compound C1CCCCCCC1N1CCCCCCC1 QUIJMHDIAFOPRK-UHFFFAOYSA-N 0.000 title 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical class CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- -1 phenylethenyl Chemical group 0.000 claims description 61
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 102000004190 Enzymes Human genes 0.000 claims description 15
- 108090000790 Enzymes Proteins 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- PRSDPVKGJUBIAA-UHFFFAOYSA-N 1,3-thiazolidine-4-carbonitrile Chemical compound N#CC1CSCN1 PRSDPVKGJUBIAA-UHFFFAOYSA-N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 6
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000012634 fragment Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 abstract 1
- 229930004006 tropane Natural products 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
- 239000000243 solution Substances 0.000 description 55
- 239000013078 crystal Substances 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000725 suspension Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- CSTBBLHIGMTEAZ-UHFFFAOYSA-N chloroform;ethyl acetate;hexane Chemical compound ClC(Cl)Cl.CCCCCC.CCOC(C)=O CSTBBLHIGMTEAZ-UHFFFAOYSA-N 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 210000004027 cell Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- 229910052740 iodine Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- OOAHXPHXLDYFAR-UHFFFAOYSA-N 1,3-thiazolidine-4-carbonitrile dihydrochloride Chemical compound Cl.Cl.N#CC1CSCN1 OOAHXPHXLDYFAR-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 1
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FHNCCAGEZMNIHZ-UHFFFAOYSA-N 3,4,5,5a,6,7,8,9-octahydro-2h-1,2-benzodiazepine Chemical compound N1CCCC2CCCCC2=N1 FHNCCAGEZMNIHZ-UHFFFAOYSA-N 0.000 description 1
- 102100027123 55 kDa erythrocyte membrane protein Human genes 0.000 description 1
- ORIQLMBUPMABDV-UHFFFAOYSA-N 6-chloropyridine-3-carbonitrile Chemical compound ClC1=CC=C(C#N)C=N1 ORIQLMBUPMABDV-UHFFFAOYSA-N 0.000 description 1
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Virology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Transplantation (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0202001A HUP0202001A2 (hu) | 2002-06-14 | 2002-06-14 | DDP-IV gátló hatású azabiciklooktán- és nonánszármazékok |
| PCT/HU2003/000041 WO2003106456A2 (en) | 2002-06-14 | 2003-06-11 | New compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200500017A1 EA200500017A1 (ru) | 2005-06-30 |
| EA008166B1 true EA008166B1 (ru) | 2007-04-27 |
Family
ID=90001551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200500017A EA008166B1 (ru) | 2002-06-14 | 2003-06-11 | Производные азобициклооктанов и нонанов, обладающие активностью в ингибировании dpp-iv |
Country Status (21)
Families Citing this family (77)
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| CA2557275C (en) * | 2004-02-27 | 2012-06-05 | Kyorin Pharmaceutical Co., Ltd. | Bicyclo derivative |
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| TW200624427A (en) | 2004-09-20 | 2006-07-16 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
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| US8541457B2 (en) | 2005-06-03 | 2013-09-24 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors |
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| KR101368988B1 (ko) | 2005-09-16 | 2014-02-28 | 다케다 야쿠힌 고교 가부시키가이샤 | 디펩티딜 펩티다제 억제제 |
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| PE20080344A1 (es) * | 2006-06-27 | 2008-06-09 | Sanofi Aventis | Compuestos 8-azabiciclo[3.2.1]oct-8-il-1,2,3,4-tetrahidroquinolina sustituidos como inhibidores 11b-hsd1 |
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| FR2902791B1 (fr) * | 2006-06-27 | 2008-08-22 | Sanofi Aventis Sa | Derives d'urees de tropane,leur preparation et leur application en therapeutique |
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| GB0713602D0 (en) * | 2007-07-12 | 2007-08-22 | Syngenta Participations Ag | Chemical compounds |
| EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| SI2074120T1 (sl) * | 2007-10-25 | 2010-06-30 | Exelixis Inc | Tropan spojine |
| EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
| WO2010003624A2 (en) | 2008-07-09 | 2010-01-14 | Sanofi-Aventis | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
| JP5476305B2 (ja) * | 2008-08-07 | 2014-04-23 | 杏林製薬株式会社 | ビシクロ［２．２．２］オクチルアミン誘導体の製造方法 |
| RU2011108420A (ru) * | 2008-08-14 | 2012-09-20 | Киорин Фармасьютикал Ко., Лтд. (Jp) | Стабилизированный фармацевтический состав |
| WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
| AR077642A1 (es) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo |
| US8785608B2 (en) | 2009-08-26 | 2014-07-22 | Sanofi | Crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
| WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
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| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
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| WO2012120056A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
| US8846666B2 (en) | 2011-03-08 | 2014-09-30 | Sanofi | Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
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| WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
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| EP3273981B1 (en) | 2015-03-24 | 2020-04-29 | INSERM - Institut National de la Santé et de la Recherche Médicale | Method and pharmaceutical composition for use in the treatment of diabetes |
| CN110996951A (zh) | 2017-04-03 | 2020-04-10 | 科赫罗斯生物科学股份有限公司 | 治疗进行性核上性麻痹的PPARγ激动剂 |
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|---|---|---|---|---|
| US4273778A (en) * | 1978-12-30 | 1981-06-16 | Beecham Group, Limited | Pharmaceutically active aza-bicyclo-benzamide derivatives |
| WO1998019998A2 (en) * | 1996-11-07 | 1998-05-14 | Novartis Ag | N-substituted 2-cyanopyrrolidines |
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| EP1323710A1 (en) * | 2000-10-06 | 2003-07-02 | Tanabe Seiyaku Co., Ltd. | Nitrogenous five-membered ring compounds |
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| EP1254113A1 (en) | 2000-01-24 | 2002-11-06 | Novo Nordisk A/S | N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv |
| HUP0200849A2 (hu) * | 2002-03-06 | 2004-08-30 | Sanofi-Synthelabo | N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra |
-
2002
- 2002-06-14 HU HU0202001A patent/HUP0202001A2/hu unknown
-
2003
- 2003-06-11 PL PL03372799A patent/PL372799A1/xx not_active Application Discontinuation
- 2003-06-11 WO PCT/HU2003/000041 patent/WO2003106456A2/en active Application Filing
- 2003-06-11 HR HR20050027A patent/HRP20050027A2/hr not_active Application Discontinuation
- 2003-06-11 JP JP2004513288A patent/JP4502804B2/ja not_active Expired - Fee Related
- 2003-06-11 CN CNB038138581A patent/CN100347170C/zh not_active Expired - Fee Related
- 2003-06-11 US US10/518,114 patent/US7781455B2/en not_active Expired - Fee Related
- 2003-06-11 RS YUP-1091/04A patent/RS109104A/sr unknown
- 2003-06-11 BR BR0311771-5A patent/BR0311771A/pt not_active IP Right Cessation
- 2003-06-11 AT AT03738355T patent/ATE495162T1/de not_active IP Right Cessation
- 2003-06-11 NZ NZ537633A patent/NZ537633A/en unknown
- 2003-06-11 EA EA200500017A patent/EA008166B1/ru not_active IP Right Cessation
- 2003-06-11 DE DE60335717T patent/DE60335717D1/de not_active Expired - Lifetime
- 2003-06-11 KR KR1020047020277A patent/KR100756761B1/ko not_active Expired - Fee Related
- 2003-06-11 AU AU2003244880A patent/AU2003244880B2/en not_active Ceased
- 2003-06-11 MX MXPA04012691A patent/MXPA04012691A/es active IP Right Grant
- 2003-06-11 EP EP03738355A patent/EP1517907B1/en not_active Expired - Lifetime
-
2004
- 2004-11-29 IL IL16543404A patent/IL165434A0/xx not_active IP Right Cessation
- 2004-12-07 ZA ZA200409907A patent/ZA200409907B/en unknown
-
2005
- 2005-01-12 IS IS7638A patent/IS7638A/is unknown
- 2005-01-13 NO NO20050199A patent/NO20050199L/no not_active Application Discontinuation
-
2010
- 2010-07-07 US US12/831,771 patent/US20110118305A1/en not_active Abandoned
Patent Citations (6)
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|---|---|---|---|---|
| US4273778A (en) * | 1978-12-30 | 1981-06-16 | Beecham Group, Limited | Pharmaceutically active aza-bicyclo-benzamide derivatives |
| WO1998019998A2 (en) * | 1996-11-07 | 1998-05-14 | Novartis Ag | N-substituted 2-cyanopyrrolidines |
| WO2001034594A1 (en) * | 1999-11-12 | 2001-05-17 | Guilford Pharmaceuticals, Inc. | Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors |
| WO2001096295A2 (en) * | 2000-06-13 | 2001-12-20 | Novartis Ag | 2-cyanopyrrolidine derivatives and their use as medicaments |
| EP1323710A1 (en) * | 2000-10-06 | 2003-07-02 | Tanabe Seiyaku Co., Ltd. | Nitrogenous five-membered ring compounds |
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Also Published As
| Publication number | Publication date |
|---|---|
| IL165434A0 (en) | 2006-01-15 |
| EP1517907A2 (en) | 2005-03-30 |
| MXPA04012691A (es) | 2005-08-15 |
| US20110118305A1 (en) | 2011-05-19 |
| EP1517907B1 (en) | 2011-01-12 |
| DE60335717D1 (de) | 2011-02-24 |
| WO2003106456A2 (en) | 2003-12-24 |
| JP2005532369A (ja) | 2005-10-27 |
| NZ537633A (en) | 2006-08-31 |
| PL372799A1 (en) | 2005-08-08 |
| ATE495162T1 (de) | 2011-01-15 |
| NO20050199L (no) | 2005-03-04 |
| EA200500017A1 (ru) | 2005-06-30 |
| AU2003244880A1 (en) | 2003-12-31 |
| US7781455B2 (en) | 2010-08-24 |
| HUP0202001A2 (hu) | 2005-08-29 |
| AU2003244880B2 (en) | 2009-05-28 |
| CN100347170C (zh) | 2007-11-07 |
| JP4502804B2 (ja) | 2010-07-14 |
| WO2003106456A3 (en) | 2004-03-04 |
| ZA200409907B (en) | 2006-08-30 |
| IS7638A (is) | 2005-01-12 |
| KR100756761B1 (ko) | 2007-09-07 |
| HRP20050027A2 (en) | 2006-02-28 |
| KR20050016551A (ko) | 2005-02-21 |
| US20050153973A1 (en) | 2005-07-14 |
| HUP0202001D0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 2002-08-28 |
| RS109104A (en) | 2007-02-05 |
| BR0311771A (pt) | 2005-03-29 |
| CN1662530A (zh) | 2005-08-31 |
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