CA2712352C - Dicycloazaalkane derivates, preparation processes and medical uses thereof - Google Patents
Dicycloazaalkane derivates, preparation processes and medical uses thereof Download PDFInfo
- Publication number
- CA2712352C CA2712352C CA2712352A CA2712352A CA2712352C CA 2712352 C CA2712352 C CA 2712352C CA 2712352 A CA2712352 A CA 2712352A CA 2712352 A CA2712352 A CA 2712352A CA 2712352 C CA2712352 C CA 2712352C
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- CA
- Canada
- Prior art keywords
- compound
- azabicyclo
- alkyl
- cyano
- formula
- 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.)
- Expired - Fee Related
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- 238000002360 preparation method Methods 0.000 title claims abstract description 101
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 claims abstract description 7
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 229940122344 Peptidase inhibitor Drugs 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 246
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 177
- -1 cycloalkoxyl Chemical group 0.000 claims description 165
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N Minaline Natural products OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims description 144
- 239000000203 mixture Substances 0.000 claims description 125
- 125000000217 alkyl group Chemical group 0.000 claims description 107
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims description 75
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 73
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 65
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 65
- 125000003545 alkoxy group Chemical group 0.000 claims description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000004104 aryloxy group Chemical group 0.000 claims description 36
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 29
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- ZILVXVYEINTQJF-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-5-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1NCC2CC(=O)CC21 ZILVXVYEINTQJF-UHFFFAOYSA-N 0.000 claims description 15
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 15
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000005543 phthalimide group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- XSEMARCLUCFBCO-UHFFFAOYSA-N 3-tert-butyl-5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid Chemical compound C1C(=O)CC2CN(C(O)=O)C(C(C)(C)C)C21 XSEMARCLUCFBCO-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 9
- 150000001735 carboxylic acids Chemical class 0.000 claims 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 2
- 150000003892 tartrate salts Chemical class 0.000 claims 2
- 159000000021 acetate salts Chemical class 0.000 claims 1
- 150000001860 citric acid derivatives Chemical class 0.000 claims 1
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims 1
- 125000005553 heteroaryloxy group Chemical group 0.000 claims 1
- 150000003893 lactate salts Chemical class 0.000 claims 1
- 150000004701 malic acid derivatives Chemical class 0.000 claims 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract description 31
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract 1
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- 230000002829 reductive effect Effects 0.000 description 81
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- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 71
- 239000000243 solution Substances 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 238000004949 mass spectrometry Methods 0.000 description 61
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 55
- 239000008103 glucose Substances 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 50
- 238000010898 silica gel chromatography Methods 0.000 description 50
- 229910001868 water Inorganic materials 0.000 description 49
- 239000000284 extract Substances 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 47
- 239000005457 ice water Substances 0.000 description 47
- 238000001816 cooling Methods 0.000 description 45
- 238000003304 gavage Methods 0.000 description 45
- 238000003756 stirring Methods 0.000 description 43
- 238000012360 testing method Methods 0.000 description 41
- 238000004809 thin layer chromatography Methods 0.000 description 41
- 239000007858 starting material Substances 0.000 description 40
- 230000008034 disappearance Effects 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- 210000004369 blood Anatomy 0.000 description 29
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- RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical compound NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 235000001727 glucose Nutrition 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000012230 colorless oil Substances 0.000 description 20
- 239000012154 double-distilled water Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 239000012299 nitrogen atmosphere Substances 0.000 description 17
- 239000000758 substrate Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 102100036968 Dipeptidyl peptidase 8 Human genes 0.000 description 15
- 101710087011 Dipeptidyl peptidase 8 Proteins 0.000 description 15
- 239000007983 Tris buffer Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 15
- 102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 14
- 101710087005 Dipeptidyl peptidase 9 Proteins 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 239000011877 solvent mixture Substances 0.000 description 14
- WJGUFWWOWFGZGF-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;n-methylmethanamine Chemical compound CNC.OC(=O)C(O)C(O)C(O)=O WJGUFWWOWFGZGF-UHFFFAOYSA-N 0.000 description 13
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 12
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 12
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 12
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- 229910052799 carbon Inorganic materials 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
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- 238000001914 filtration Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 9
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- PTNHUPJANGKQAM-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;n-methylmethanamine Chemical compound CNC.CC1=CC=C(S(O)(=O)=O)C=C1 PTNHUPJANGKQAM-UHFFFAOYSA-N 0.000 description 8
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
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- 125000000623 heterocyclic group Chemical group 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
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- KNVDCIPZIYQYAO-UHFFFAOYSA-N 5-amino-n,n,5-trimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(C)(N)CC2CN(C(=O)N(C)C)CC21 KNVDCIPZIYQYAO-UHFFFAOYSA-N 0.000 description 5
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- 239000012300 argon atmosphere Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
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- 230000002218 hypoglycaemic effect Effects 0.000 description 5
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000004385 trihaloalkyl group Chemical group 0.000 description 5
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000004103 aminoalkyl group Chemical group 0.000 description 4
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 4
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—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
- C07D209/52—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 condensed with a ring other than six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (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)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
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| CN 200810004727 CN101230059B (zh) | 2007-01-23 | 2008-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
| CN200810004727.1 | 2008-01-23 | ||
| PCT/CN2008/071014 WO2009094866A1 (en) | 2008-01-23 | 2008-05-20 | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
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| MX (1) | MX2010008049A (OSRAM) |
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| WO (1) | WO2009094866A1 (OSRAM) |
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| CN102174007B (zh) * | 2011-03-11 | 2013-06-12 | 成都博天化工有限责任公司 | [2-(2-氰基-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁基酯的工业化制备方法 |
| RU2618673C2 (ru) | 2011-12-21 | 2017-05-10 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Производные пирролопиримидина, полезные в качестве ингибиторов jak-киназы |
| US9567300B2 (en) | 2012-06-25 | 2017-02-14 | Sunshine Lake Pharma Co., Ltd. | Hexahydropentaleno derivatives, preparation method and use in medicine thereof |
| CN104030967B (zh) * | 2013-03-05 | 2018-01-02 | 连云港恒运药业有限公司 | 一种dpp‑iv抑制剂的中间体、其制备方法和通过其制备dpp‑iv抑制剂的方法 |
| EP3461827B1 (en) | 2013-09-26 | 2022-02-23 | Cadent Therapeutics, Inc. | Selective octahydro-cyclopenta[c]pyrrole negative modulators of nr2b |
| JO3579B1 (ar) * | 2014-09-26 | 2020-07-05 | Luc Therapeutics Inc | مُعدِلات تفاغرية سالبة لمستقبل nr2b من المركب n-ألكيل أريل-5-أوكسي أريل-ثامن هيدرو-خماسي الحلقة [c] بيرول |
| US20170301620A1 (en) * | 2016-04-15 | 2017-10-19 | International Business Machines Corporation | Structure and process for metal cap integration |
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| US5280028A (en) * | 1992-06-24 | 1994-01-18 | G. D. Searle & Co. | Benzimidazole compounds |
| CA2189963A1 (en) * | 1994-05-18 | 1995-11-23 | Haruhiko Kikuchi | Novel pyrimidine derivative |
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| US6110949A (en) * | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US7183290B2 (en) | 2001-06-27 | 2007-02-27 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
| US6861440B2 (en) * | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
| HUP0200849A2 (hu) | 2002-03-06 | 2004-08-30 | Sanofi-Synthelabo | N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra |
| TW200401635A (en) * | 2002-07-23 | 2004-02-01 | Yamanouchi Pharma Co Ltd | 2-Cyano-4-fluoropyrrolidine derivative or salt thereof |
| GB0307856D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
| AU2004226824B2 (en) * | 2003-04-04 | 2008-05-01 | Novartis Ag | Quinoline-2-one-derivatives for the treatment of airways diseases |
| US7514571B2 (en) * | 2004-02-27 | 2009-04-07 | Kyorin Pharmaceutical Co., Ltd. | Bicyclo derivative |
| FR2870538B1 (fr) * | 2004-05-19 | 2006-07-14 | Servier Lab | Nouveaux derives de pyrrolidines et de thiazolidines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| EP1778688A1 (en) * | 2004-07-22 | 2007-05-02 | Glaxo Group Limited | Antibacterial agents |
| DK1796663T3 (da) * | 2004-09-03 | 2011-08-15 | Athersys Inc | Tricykliske heteroaryl-piperaziner, pyrrolidiner og azetidiner som serotonin-receptor-modulatorer |
| US20080300251A1 (en) * | 2005-09-05 | 2008-12-04 | Sattigeri Jitendra A | Derivatives of 3-Azabicyclo[3.1.0] Hexane as Dipeptidyl Peptidase-IV Inhibitors |
| CN101050194B (zh) | 2006-04-05 | 2013-08-21 | 上海恒瑞医药有限公司 | 双环辛烷类衍生物、其制备方法及其在医药上的用途 |
| CN101230058A (zh) * | 2007-01-23 | 2008-07-30 | 上海恒瑞医药有限公司 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
| CN101230059B (zh) | 2007-01-23 | 2011-08-17 | 上海恒瑞医药有限公司 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
-
2008
- 2008-05-20 US US12/863,964 patent/US8304411B2/en not_active Expired - Fee Related
- 2008-05-20 CA CA2712352A patent/CA2712352C/en not_active Expired - Fee Related
- 2008-05-20 KR KR1020107018542A patent/KR101469306B1/ko not_active Expired - Fee Related
- 2008-05-20 EP EP08748620.5A patent/EP2246347B1/en not_active Not-in-force
- 2008-05-20 WO PCT/CN2008/071014 patent/WO2009094866A1/zh not_active Ceased
- 2008-05-20 RU RU2010128972/04A patent/RU2487866C2/ru not_active IP Right Cessation
- 2008-05-20 BR BRPI0822143A patent/BRPI0822143A2/pt not_active IP Right Cessation
- 2008-05-20 JP JP2010543359A patent/JP5438028B2/ja not_active Expired - Fee Related
- 2008-05-20 MX MX2010008049A patent/MX2010008049A/es active IP Right Grant
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2012
- 2012-09-14 US US13/619,138 patent/US8415349B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| RU2010128972A (ru) | 2012-02-27 |
| MX2010008049A (es) | 2010-11-12 |
| AU2008349110A1 (en) | 2009-08-06 |
| US20130012705A1 (en) | 2013-01-10 |
| US8415349B2 (en) | 2013-04-09 |
| EP2246347A4 (en) | 2012-01-11 |
| US20100311747A1 (en) | 2010-12-09 |
| JP2011510026A (ja) | 2011-03-31 |
| RU2487866C2 (ru) | 2013-07-20 |
| US8304411B2 (en) | 2012-11-06 |
| BRPI0822143A2 (pt) | 2019-09-24 |
| JP5438028B2 (ja) | 2014-03-12 |
| EP2246347A1 (en) | 2010-11-03 |
| KR101469306B1 (ko) | 2014-12-04 |
| CA2712352A1 (en) | 2009-08-06 |
| WO2009094866A1 (en) | 2009-08-06 |
| EP2246347B1 (en) | 2016-09-28 |
| KR20100103881A (ko) | 2010-09-28 |
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