CN1990486A - N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 - Google Patents
N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 Download PDFInfo
- Publication number
- CN1990486A CN1990486A CNA2006101640208A CN200610164020A CN1990486A CN 1990486 A CN1990486 A CN 1990486A CN A2006101640208 A CNA2006101640208 A CN A2006101640208A CN 200610164020 A CN200610164020 A CN 200610164020A CN 1990486 A CN1990486 A CN 1990486A
- Authority
- CN
- China
- Prior art keywords
- group
- base
- formula
- different
- general 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.)
- Pending
Links
- 239000002532 enzyme inhibitor Substances 0.000 title abstract 2
- 229940125532 enzyme inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 38
- 150000003851 azoles Chemical class 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- -1 benzimidazolyl- Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 18
- 125000005504 styryl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 9
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 9
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 9
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 9
- 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 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000005493 quinolyl group Chemical group 0.000 claims description 9
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 9
- 241000790917 Dioxys <bee> Species 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012453 solvate Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000011737 fluorine Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003513 alkali Substances 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
- 238000010992 reflux Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- XPZWAPFROPIRGN-UHFFFAOYSA-N butyl pyrrolidine-1-carboxylate Chemical class CCCCOC(=O)N1CCCC1 XPZWAPFROPIRGN-UHFFFAOYSA-N 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000005336 cracking Methods 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 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
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- OTWVFHZMWFGHSJ-UHFFFAOYSA-N 1-fluoropyrrolidine Chemical compound FN1CCCC1 OTWVFHZMWFGHSJ-UHFFFAOYSA-N 0.000 description 1
- KZMRGTASBWZPFC-UHFFFAOYSA-N 1-fluoropyrrolidine-2-carboxylic acid Chemical class OC(=O)C1CCCN1F KZMRGTASBWZPFC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical group C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000034493 Mucous membrane disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- FVVODWCAJZDYQH-UHFFFAOYSA-N P1=CC=CC=C1.[P] Chemical compound P1=CC=CC=C1.[P] FVVODWCAJZDYQH-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- TZLOABAMYQPANY-WCCKRBBISA-N [F].OC(=O)[C@@H]1CCCN1 Chemical class [F].OC(=O)[C@@H]1CCCN1 TZLOABAMYQPANY-WCCKRBBISA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- BWVPLMNECWEEAF-UHFFFAOYSA-N butyl 1-aminopiperidine-4-carboxylate Chemical compound CCCCOC(=O)C1CCN(N)CC1 BWVPLMNECWEEAF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Images
Classifications
-
- 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
- C07D451/02—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 not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—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 not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Abstract
本发明涉及包含氟原子的通式(I)的DPP-IV酶抑制剂的中间体化合物(V)、(VII)、(VIII)和(IX)。
Description
本申请为申请号为03805263.6的专利申请的分案申请。
本发明涉及具有二肽基-肽酶-IV酶抑制活性的通式(I)的新型化合物以及其盐、溶剂化物和异构体,涉及通式(I)的化合物的治疗应用,涉及包含通式(I)的化合物的药物组合物,涉及其制备方法以及通式(II)、(III)、(V)、(VII)、(VIII)和(IX)的新中间体。
与淋巴细胞表面糖蛋白CD26,一种摩尔质量为110k道尔顿的多肽相同的酶二肽基-肽酶-IV(DPP-IV)是在哺乳动物的组织和器官中形成的。例如,可以在肝、胰岛、肾皮质、肺、和前列腺以及小肠的某些组织中发现这种酶。此外,在体液(例如在血浆、血清和尿)中可以观测到显著的DPP-IV活性。
DPP-IV是丝氨酸蛋白酶型酶,其特异性地将二肽从其中倒数第二个氨基酸主要是脯氨酸、丙氨酸或羟脯氨酸的肽的N-末端上裂解下来。
DPP-IV酶对体内高血糖素样肽,肽-1(GLP-1)和肽-2(GLP-2)的分解负责。酶GLP-1强烈刺激胰腺产生胰岛素,从而其对葡萄糖内环境稳定具有直接的有利作用,所以DPP-IV抑制剂可用于治疗和预防非-胰岛素依赖性糖尿病(NIDDM)和与DPP-IV酶活性有关的其它疾病,其非限制性地包括糖尿病、肥胖、高血脂症、皮肤或粘膜病症、银屑病(poriasis)、肠窘迫、便秘、自身免疫性疾病如脑脊髓炎(enchephalomyelitis)、补体介导的病症如肾小球肾炎(glomerulonepritis)、脂肪代谢障碍、和组织损害、身心失调性、抑郁性、和精神神经性疾病如焦虑、抑郁、失眠、精神分裂症、癫痫症、痉挛、和慢性疼痛、HIV感染、过敏、炎症、关节炎、移植排斥、高血压、充血性心衰、肿瘤、和压力诱导的流产。
我们的目的是要制备有效、稳定、和安全的新DPP-IV抑制剂。
我们已经发现其中R1代表:
-包含氮的由一个或两个芳族环所组成的芳族部分,优选地是吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基(pirazolyl)、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、四唑基或三嗪基环;其可任选地被彼此独立地选自下面基团中的一个或两个的取代基所单-或二-取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基、氨基或苯基;或
-噻吩基或呋喃基或苯甲基;或
-对-甲苯磺酰基;或
-式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个C1-4烷基和/或C1-4烷氧基或硝基或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基取代的苯乙烯基、或苯基乙基;哌啶-1-基、4-甲基-哌嗪-1-基、或吡咯烷-1-基;
B代表式(1)或(2)或(3)或(4)或(5)或(6)或(7)的基团;
R2代表氢原子或氟原子;
R3代表氟原子-
的通式(I)的化合物以及这些化合物的盐、异构体和溶剂化物,就其活性、作用的持续时间、稳定性和毒性而言显著优于其现有技术。
与可接受的术语相一致,氟吡咯烷基中2位碳原子的构型有利地为S,而4位碳原子的构型有利地为S或R。
本发明的一个实施方案包括其中R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,优选吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基环;其在给定的情况中被一或两个彼此独立的选自下面基团的基团所单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基;或
-噻吩基或呋喃基;或
-对-甲苯磺酰基;或
-式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基-或硝基或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表-
式(1)或(2)或(3)或(4)或(5)或(6)或(7)的基团;
R2代表氢原子或氟原子;
R3代表氟原子
的通式(I)的化合物以及其盐、异构体、互变异构体、溶剂化物和水合物。
本发明的另一个实施方案包括其中R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,优选吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基环;在给定的情况中,其可以被一个或两个彼此独立地选自下面基团的基团所单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基;或
噻吩基或呋喃基;或
对-甲苯磺酰基;或
式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基-或硝基或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表-
式(1)的基团;
R2代表氢原子或氟原子;
R3代表氟原子-
的通式(I)的化合物以及其盐、异构体、互变异构体溶剂化物和水合物。
本发明的另一个实施方案包括其中R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,优选吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基环;在给定的情况中,其可以被一个或两个彼此独立地选自下面基团的基团所单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基;或
噻吩基或呋喃基;或
对-甲苯磺酰基;或
式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基-或硝基或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表-
式(2)的基团;
R2代表氢原子或氟原子;
R3代表氟原子-
的通式(I)的化合物以及其盐、异构体、互变异构体、溶剂化物和水合物。
本发明的另一个实施方案包括其中R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,优选吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基环;在给定的情况中,其可以被一个或两个彼此独立地选自下面基团的基团所单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基;或
噻吩基或呋喃基;或
对-甲苯磺酰基;或
式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基-或硝基-或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表
-式(3)的基团;
R2代表氢原子或氟原子;
R3代表氟原子-
的通式(I)的化合物以及其盐、异构体、互变异构体溶剂化物和水合物。
本发明的另一个实施方案包括其中R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,优选吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基环;在给定的情况中,其可以被一个或两个下面的基团独立地单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基;或
噻吩基或呋喃基;或
对-甲苯磺酰基;或
式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基-或硝基-或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表
-式(4)或(5)的基团;
R2代表氢原子或氟原子;
R3代表氟原子-
的通式(I)的化合物以及其盐、异构体、互变异构体、溶剂化物和水合物。
本发明的另一个实施方案包括其中R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,优选吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基环;在给定的情况中,其可以被一个或两个下面的基团独立地单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基;或
噻吩基或呋喃基;或
对-甲苯磺酰基;或
式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基-或硝基-或卤素原子所取代的苯基、吡啶基或苯乙烯基;被亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表-
式(6)或(7)的基团;
R2代表氢原子或氟原子;
R3代表氟原子-
的通式(I)的化合物及其盐、异构体、互变异构体、溶剂化物和水合物。
优选的通式(I)的化合物是其中R1、B或R2和R3是包括其任何组合在内的表1至3中所列基团的这些基团,例如(2S)-4,4-二氟-1-(2-{[8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基]外-氨基}乙酰基)-2-吡咯烷腈;(2S,4S)-4-氟-1-(2-{[8-(2-吡嗪基)-8-氮杂二环-[3.2.1]-辛-3-基]外-氨基}乙酰基)-2-吡咯烷腈;(2S)-4,4-二氟-1-(2-{[1-(2-吡嗪基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈;(2S)-4,4-二氟-1-(2-{[1-(5-氰基吡啶-2-基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈;(2S)-4,4-二氟-1-(2-{[1-(6-氯哒嗪-3-基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈;(2S)-4,4-二氟-1-(2-{[1-(6-氰基哒嗪-3-基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈;
术语“包含氮的由一个或两个芳环所组成的芳族部分”包括在本专利申请优先权日时公知的所有该类环系。
术语“卤素原子”指的是氟、氯、溴、或碘原子。“C1-4烷基”和“C1-4烷氧基”指的是包含1-4个碳原子的直链或支链的脂族烃基。
本发明通式(I)的化合物可以通过其中R1和B的含义与上面所给出的含义相同的通式(II)的伯胺与其中R2和R3的含义与上面给出的含义相同的通式(III)的氯乙酰基衍生物的烷基化来进行制备,如果需要的话,可以将所得的化合物转化成其盐或溶剂化物中的一种(流程图1)。
在烷基化过程中,通式(III)的氯乙酰基衍生物是被过量应用的,并且用各种酸结合剂与所得的氯化氢进行结合,所说的酸结合剂优选地为碱,如例如三乙胺、碳酸钾、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)或已知可作为超碱的2-叔-丁基亚氨基-2-二乙基氨基-1,3-二甲基-全氢化-1,3,2-二氮杂phosphorine-结合的树脂(PBEMP)。该反应优选地是在25至70℃的温度下进行的。
通式(II)的伯胺是用一种两步合成来进行制备的(流程图2)。在第一步中,将起始的通式(IV)的环状仲胺——其中Y的含义是氢原子、乙酰基、或叔-丁氧基羰基——芳化,优选地用其中R1具有上面给出的相同含义并且X代表卤素原子的通式(X)的芳基卤化物来进行芳化。根据R1的含义,该芳化反应可以使用酸结合剂,例如过量的胺或DBU在极性、质子或质子惰性溶剂中在25至150℃下进行,优选地在醇类(乙醇、正-丁醇、正-戊醇)中进行,或者可以在没有溶剂的情况下在微波炉中进行。
对于起始材料而言,可以使用可以从文献中获知的通式(IV)的游离胺或被保护的仲胺,因此,可以使用4-乙酰氨基哌啶(B=式(1),Y=COCH3)(US-3225037);4-叔-丁氧基羰基氨基哌啶(B=式(1),Y=COOC(CH3)3)(J.Med.Chem.1999,42,2706);3-(S)-叔-丁氧基羰基氨基哌啶(B=式(2))和3-(S)-叔-丁氧基羰基氨基吡咯烷(B=式(3))(Synth.Comm.1998,28,3919)在最后两种情况中Y=COOC(CH3)3;叔-丁基8-氮杂二环[3.2.1]-辛-3-基-外-氨基甲酸酯(B=式(4),叔-丁基8-氮杂二环[3.2.1]-辛-3-基-内-氨基甲酸酯(B=式(5))(J.Med.Chem1991,34,656),叔-丁基-9-氮杂二环[3.3.1]-壬-3-基-外-氨基甲酸酯(B=式(6))和叔-丁基-9-氮杂二环-[3.3.1]-壬-3-基-内-氨基甲酸酯(B=式(7)),(J.Med.Chem 1993,36,3720))(Y=COOC(CH3)3)。
在第二步中,通过酸水解将保护基团Y从该芳化的通式(V)的胺——其中R1和B的含义与上面所定义的含义相同——上除去。该反应是在盐酸水溶液或乙醇性氯化氢溶液中在25至78℃的温度下进行的,得到其中R1和B的含义与上面所定义的含义相同的通式(II)的脂族或环状伯胺。
如果R1代表式R1a-CO的酰基,则通过用无机或有机碱,优选三乙胺作为催化剂,将其中Y是叔-丁氧基羰基的通式(IV)的化合物与其中Z是离去基团,优选地是氯原子的通式R1a-COZ-的酸性衍生物有利地在约0℃的温度下进行反应。在酸性条件下将离去基团Y从通式(V)的化合物上裂解下来,优选地通过在二氯甲烷溶液中使用三氟醋酸在0-30℃下来进行,得到其中R1的含义是式R1a-CO的基团的通式(II)的胺。
其中R2和R3的含义与上面所定义的含义相同的通式(III)的1-(2-氯乙酰基)-2-吡咯烷腈是用一种四步合成来进行制备的(流程图3)。
起始化合物是具有用叔-丁氧基羰基保护的氮的氟脯氨酸衍生物,优选地是L-氟脯氨酸衍生物——其中R2和R3的含义与上面所定义的含义相同的。这些化合物可以用文献中所记载的方法来进行制备(Tetrahedron Lett.1998,39,1169)。在第一步中,用新戊酰氯或氯甲酸乙酯制备混合酸酐,然后形成其中R2和R3具有上述含义的通式(VII)的氨基甲酰基衍生物。
该反应是在卤化溶剂(CHCl3、CH2Cl2)中,在0-25℃下进行的。
在第二步中,在乙醇性氯化氢溶液中对叔-丁氧基羰基进行裂解。该水解是在0-25℃下发生的,得到其中R2和R3的含义如上所述的通式(VIII)的甲酰胺的盐酸盐。
在第三步中将由此而获得的通式(VIII)的氟吡咯烷甲酰胺用氯乙酰氯在卤化溶剂(CHCl3、CH2Cl2)中进行酰化,优选地在0℃下进行。从而形成其中R2和R3具有上述含义的通式(IX)的氯乙酰基氨基甲酰基衍生物。
在第四步中,将通式(IX)的氯乙酰基氨基甲酰基衍生物脱水,得到其中R2和R3具有上述含义的通式(III)的氯乙酰基氰基衍生物。脱水优选地是用氯氧化磷在二氯甲烷中在反应混合物的沸点下进行的。
反应过程1
反应过程2
反应过程3
生物学研究
用下面的方法来测定通式(I)的化合物的DPP-IV酶抑制活性:
测定的应用条件:
DPP-IV.来源: 得自CaCo/Tc-7的溶解的粗浸膏
细胞含量:0.8-1μg/测定
底物: H-Gly-Pro-AMC(Bachem)
反应: 用样品下37℃下预培养1小时,
在37℃下反应30分钟
终止溶液: 1M醋酸Na缓冲剂(pH=4.2)
反应混合物: 10μl酶溶液
10μl试验化合物或测定缓冲剂
55μl测定缓冲剂
25μl底物
300μl终止溶液
测量: 用Tecan plate读数器进行的分光荧光法测定
(Ex:360nm Em:465nm)
通过在37℃下在100mM Tris-HCl,pH=7.5(测定缓冲剂)中AMC(7-氨基-4-甲基香豆素)的释放来记录DPP-IV酶和H-Gly-Pro-AMC底物的反应。AMC的标准曲线的线性高至31.25μM的浓度,这是我们为什么使用所形成的AMC的相对荧光单位(RFU)的原因。通过使用360nm激发滤器和465发射滤器(30μs的级分时间,Gain 25,No.of Flashes 50),通过Tecan Spectrofluor加板式读数器来进行探测。在这些条件下,在至少30分钟的时间内酶反应是线性的,并且酶依赖性在高至2.5μg蛋白(高至700RFU)都是线性的。使用1-0.8μg所提取蛋白,H-Gly-Pro-AMC的Km是50μM。底物浓度高于500μM会造成荧光探测问题(内部滤器影响),可以通过对样品进行稀释来解决这一问题。
该测定被设计成用来尽可能有效地对活性抑制剂进行探测,其在37℃下使用60分钟的预培养。通过向包含10μl体积和55μl测定缓冲剂(在对照的情况中为65μl测定缓冲剂)的各孔中加入0.8-1μg位于10μl酶溶液(使用测定缓冲剂:100mM Tris-HCl,pH=7.5)中的蛋白提取物来进行测定。在预培养后,通过加入25μl 1mMH-Gly-Pro-AMC底物溶液(250μM的终浓度)来开始反应。最终的试验体积为100μl,并且试验溶液包含1%得自试验化合物溶液的DMSO。反应时间为在37℃下进行30分钟,并通过加入300μl 1M醋酸Na缓冲剂,pH=4.2来终止该反应。在Tecan spectrofluor加板式读数器中用360nm激发和465发射滤器来对所形成的AMC的荧光(RFU)进行探测(30μs级分时间,Gain 25 No.of Flashes 50)。用对照的RFU和空白的RFU来计算抑制%。
用于对本发明通式(I)的化合物的酶抑制作用进行定性描述的IC50值小于100nM。
可以用本身公知的方法通过将其与一种或多种可药用的赋形剂进行混合来将通式(I)的化合物及其盐溶剂化物和异构体制备成可口服或胃肠外使用的药物组合物并且可以以单位剂型的形式将其进行给药。
适宜的单位剂型包括口服形式,如片剂、硬或软明胶胶囊、粉末、颗粒、和口服溶液或混悬液、舌下、颊、气管内、眼内、通过吸入的鼻内形式、局部、经皮、皮下、肌内或静脉内形式、直肠形式和植入物。对于局部应用而言,本发明的化合物可以以乳膏、凝胶、软膏、或洗剂的形式被应用。
作为实例,片剂形式的本发明化合物的单位剂型可以包含下面的成分:
通式(I)的化合物 50.0mg
甘露醇 223.75mg
交联羧甲基纤维素钠 6.0mg
玉米淀粉 15.0mg
羟丙基甲基纤维素 2.25mg
硬脂酸镁 3.0mg
通式(I)的化合物的日剂量将取决于一些因素,如患者疾病的性质和严重程度、应用方式以及化合物本身。
用下面的实施例对本发明进行进一步详细说明,但是并不是要将本发明限制到这些实施例上。
图1表示通式(I)的化合物,
图2表示通式(II)的化合物,
图3表示通式(III)的化合物,
图4表示通式(IV)的化合物,
图5表示通式(V)的化合物,
图6表示通式(VI)的化合物,
图7表示通式(VII)的化合物,
图8表示通式(VIII)的化合物,
图9表示通式(IX)的化合物,
图10表示通式(X)的化合物,
图11表示式(1),
图12表示式(2),
图13表示式(3),
图14表示式(4),
图15表示式(5),
图16表示式(6),
图17表示式(7)。
实施例
实施例1
(2S)-4,4-二氟-1-(2-{[8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基]外-氨基}乙酰基)-2-吡咯烷腈
在通式(I)中,R1的含义是2-嘧啶基,B指的是式(4)的基团,R2和R3指的是氟原子。
a.)具有通式(V)的8-(2-嘧啶-8-氮杂二环[3.2.1]辛-3-基-外-氨基甲酸叔-丁酯-其中R1是2-嘧啶基、Y是COOC(CH3)3、B是基团(4)
将14,7g 8-苯甲基-8-氮杂二环[3.2.1]辛-3-基-外-氨基甲酸叔-丁酯(65mmol)(J.Med.Chem.1991,34,656)和8,93g 2-氯嘧啶(78mmol)和12,7ml 1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)(85mmol)溶解于230ml 1-戊醇中并将其在回流下加热4小时。蒸发掉溶剂并将残余物溶解于250ml氯仿中并用2×300ml水进行洗涤,用Na2SO4进行干燥,用柱色谱法进行纯化,用正-己烷-乙酸乙酯-氯仿(1∶1∶1)作为洗脱剂,产生白色结晶,用正-己烷对其进行研磨。收率:13,25g(67%)。熔点:113-115℃。1H-NMR(400MHz,CDCl3):δ1.34(s,9H),1.49(t,2H),1.66-1.97(m,6H),3.89(br,1H),4.61(d,2H),6.60(t+br,1+1H),8.34(d,2H)。
b.)具有通式(II)的8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基-外-胺——其中R1和B是在步骤1a.)中所给出的。
将13g 8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基-外-氨基甲酸叔-丁酯(43mmol)溶解于120ml三氟醋酸和120ml二氯甲烷的混合物中。将该溶液搅拌30分钟并对其进行蒸发。将残余物溶解于50ml二氯甲烷中并进行蒸发。将这种方法重复进行三次,将最后的有机溶液用100ml饱和碳酸钠水溶液进行萃取。进行层分离并将水相用4×50ml二氯甲烷进行洗涤。将所合并的有机层用Na2SO4进行干燥并进行蒸发,得到白色粉末,用正-己烷对其进行研磨。收率:6,7g(77%)。熔点:56-59℃。1H-NMR(400MHz,DMSO-d6):δ1.29(t,2H),1.64-1.98(m,6H),3.19(m,1H),4.58(dd,2H),6.57(t,1H),8,33(d,2H)。
c.)其中R2和R3指的是氟原子的通式(VII)的(2S)-2-(氨基羰基)-4,4-二氟-1-吡咯烷羧酸叔-丁酯
将5.7g(22.7mmol)叔-丁基(2S)-2-(氨基羰基)-4,4-二氟-2-吡咯烷羧酸(Tetraberon Lett.1998,39,1169)溶解于57ml二氯甲烷中并向该溶液中加入3.8ml(27.2mmol)三乙胺。在-15℃下向所得的混合物中滴加3ml(25mmol)新戊酰氯并将该混合物在该温度下搅拌1小时,然后向其中滴加7ml 25%氨水溶液并将该混合物搅拌1小时。将该混合物用水、1N NaOH溶液、然后用水进行洗涤,用硫酸钠进行干燥并进行蒸发。在加入乙醚时,结晶出3.94g(69%)上面的产物。熔点:136-138℃。1H-NMR(400MHz,CDCl3):δ1.48(s,9H);2.3-2.9(m,3-CH2),3.69(br,较小)+3.86(m,主峰)(5-CH2),4.53(br,2-CH).6.0(br,主峰)+6.81(br,较小)(NH2)。
d.)其中R2和R3指的是氟原子的通式(VIII)的(2S)-4,4-二氟-2-吡咯烷甲酰胺盐酸盐
将3.93g(15.7mmol)的(2S)-2-(氨基羰基)-4,4-二氟-1-吡咯烷羧酸叔-丁酯溶解于75ml 25%氯化氢乙醇溶液中并将其在室温下搅拌4小时。向所得的混悬液中加入150ml乙醚,将所得的白色结晶材料滤出。得到2.55g(87%)上面的产物。熔点:232-233℃。1H-NMR(400MHz,DMSO-d6):δ2.43-2.51(m,较小)和2.81-3.05(m,主峰)(3-CH2),3.71(t,2H,5-CH2),4.46(t,1H,2-CH),7.81(s,1H,)+8.12(s,1H)(NH2),10.12(br,2H,NH2 +)。
e.)其中R2和R3指的是氟原子的通式(IX)的(2S)-1-(2-氯乙酰基)-4,4-二氟-2-吡咯烷-甲酰胺
将2.54g(13.6mmol)(2S)-4,4-二氟-2-吡咯烷甲酰胺盐酸盐混悬于25ml二氯甲烷中并向该混悬液中加入4.1ml(29.3mmol)三乙胺。在-10℃下向所得的混合物中滴加1.2ml在20ml二氯甲烷中的(15mmol)氯乙酰氯。在搅拌1小时后,将混悬液倒入到450ml乙酸乙酯中,将沉淀的三乙胺盐酸盐滤出,将滤液蒸发并用使用氯仿-甲醇4∶1混合物作为洗脱剂的色谱法进行纯化。得到3.0g(97%)无色油状物形式的上述产物。
1H-NMR(400MHz,DMSO-d6):δ2.34-2.52(m,1H)+2.66-2.83(m,1H)(3-CH2),4.07-4.29(m,2H,5-CH2),4.40(qv,2H,CH2Cl),4.71(m,1H,2-CH),7.17(br,1H,)+7.42(d,1H)(NH2)。
f.)其中R2和R3是氟原子的通式(III)的(2S)-1-(2-氯乙酰基)-4,4-二氟-2-吡咯烷腈
将10.4g(46mmol)(2S)-1-(2-氯乙酰基)-4,4-二氟-2-吡咯烷-甲酰胺溶解于230ml二氯甲醇中并向其中加入13ml(140mmol)氯氧化磷。将该混合加热24小时(如果仍然有起始材料则将其进一步进行回流)。在回流期间,溶液将变成浅黄色并沉淀出有粘性的固体物质。将该溶液倾倒到另一个罐中并向其中加入50g碳酸钾。在搅拌1小时后,将固体盐滤出并对溶液进行蒸发。得到浅黄色的油状物,用正-己烷对其进行研制。收集所得到的黄色结晶并向其中加入70ml乙醚。由此而将杂质溶解,并得到纯净的白色固体结晶产物。收率:6.0g(56%).熔点:86-87℃。1H-NMR(400MHz,CDCl3):δ2.76-2.98(m,2H,3-CH2),3.92-4.26(m,2H,5-CH2),4.46(qv,2H,CH2Cl),5.11(m,1H,2-CH)。
g.)(2S)-4,4-二氟-1-(2-{[8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基]外-氨基}乙酰基)-2-吡咯烷腈
将6,13g 8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基-外-胺(30mmol)和5,74g(2S)-1-(2-氯乙酰基)-4,4-二氟-2-吡咯烷腈(27,5mmol)和12,5ml三乙胺(90mmol)溶解于250ml无水乙腈中并将其在70℃下搅拌3小时,然后在室温下搅拌一整夜。然后将该混合物蒸发,得到一种褐色的浓稠的油状物,用柱色谱法对其进行纯化,用氯仿-甲醇(6∶1)作为洗脱剂,得到固态产物,用无水乙醇对其进行结晶。收率:5,7g(77%)。熔点:162-163℃。1H-NMR(400MHz,DMSO-d6):δ1.32(td,2H),1.6-2.0(m,7H),2.6-2.9(m,2H),2.85(tt,1H),3.0-3.5(m,2H),3.97(ddd,1H),4.13(ddd,1H),4.61(m,2H),5.05(dd,1H),6.60(t,1H),8.35(m,2H)。
实施例2
(2S,4S)-4-氟-1-(2-{[8-(2-吡嗪基)-8-氮杂二环-[3,2.1]-辛-3-基]外-氨基}乙酰基)-2-吡咯烷腈二盐酸盐
在通式(I)中R1指的是2-吡嗪基,B指的是式(4)的基团,R2指的是氢原子和R3指的是氟原子。
a)其中R1是2-吡嗪基、Y是COOC(CH3)3、B是基团(4)的具有通式(V)的8-(2-吡嗪基)-8-氮杂二环[3.2.1]辛-3-基-外-氨基甲酸叔-丁酯
将0,54ml氯吡嗪(6mmol)和1,13g 8-苯甲基-8-氮杂二环[3.2.1]辛-3-基-外-氨基甲酸叔-丁酯(6mmol)、0,97ml 1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)(6,5mmol)溶解于40ml 1-戊醇中并将其在回流下加热50小时。蒸发掉溶剂,将残余物溶解于50ml氯仿中,用4×30ml水进行洗涤,用Na2SO4进行干燥,用柱色谱法进行纯化,用正-己烷-乙酸乙酯-氯仿(3∶1∶1)作为洗脱剂,产生白色结晶,用正-己烷对其进行研制。收率:0,55g(36%)。熔点:122-123℃。
1H-NMR(200MHz,DMSO-d6):δ1.34(s,9H);1.44-1.66(m;2H),1.67-1.99(m,6H),3.88(m,1H),4.56(bs,2H),6.59(d,1H),7.77(d,1H),8.07(dd,1H),8.17(d,1H)。
b.)其中R1和B具有在步骤2a.)中所给出的含义的8-(2-吡嗪基)-8-氮杂二环[3.2.1]辛-3-基-外-胺
将3,85mg 8-(2-嘧啶基)-8-氮杂二环[3.2.1]辛-3-基-外-氨基甲酸叔-丁酯(1,26mmol)溶解于20ml 12%乙醇性盐酸中并将该溶液搅拌7小时。向所形成的混悬液中加入20ml水并用含水氢氧化钾将其pH调节至11。进行层分离,将有机相干燥,蒸发,用柱色谱法进行纯化,用乙酸乙酯-甲醇-25%NH3水溶液(17∶3∶1)作为洗脱剂,得到一种浅黄色油状物。收率为167mg(65%)。1H-NMR(200MHz,DMSO-d6):δ1.29(t,2H),1.62-1.83(m,4H),1.84-2.00(m,2H),3.12(sp,1H),4.57(dd,2H),7.74(d,1H),8.05(dd,1H),8.15(d,1H)。
c.)其中R2是氢原子和R3是氟原子的通式(VII)的(2S,4S)-2-(氨基羰基)-4-氟-1-吡咯烷羧酸叔-丁酯
将1.63g(7mmol)(2S,4S)-1-(叔-丁氧基羰基)-4-氟-2-吡咯烷羧酸(Tetraheron Lett.1998,39,1169)溶解于25ml二氯甲烷中并向其中加入1.2ml(8.4mmol)三乙胺。在-15℃下向该混合物中滴加0.86ml(7mmol)新戊酰氯并将其搅拌1小时并向其中加入2ml 25%氢氧化铵水溶液。在搅拌1小时后,将该反应混合物用水、1N氢氧化钠溶液进行洗涤,然后再用水进行洗涤,用硫酸钠干燥并蒸发。用乙醚进行结晶,得到0.88g(54%)标题化合物。熔点是173-175℃。1H-NMR(400MHz,DMSO-d6):δ1.38(s,9H);2.07-2.25(m,2H,3-CH2),3.49-3.67(m,2H,5-CH2),4.13(d,1H,2-CH),5.07和5.35(br,1H,4-H),6.91+7.17(br,2H,NH2)。
d.)(2S,4S)-4-氟-2-吡咯烷甲酰胺盐酸盐
在通式(VIII)中,R2指的是氢原子和R3指的是氟原子。
将4g(17.2mmol)(2S,4S)-2-(氨基羰基)-4-氟-1-吡咯烷羧酸叔-丁酯溶解于75ml 25%氯化氢乙醇溶液并将其在室温下搅拌4小时。将所得的白色结晶物质滤出,用乙醚进行洗涤,干燥。得到2.56g(88%)上面的产物。熔点:250-251℃。
1H-NMR(400MHz,DMSO-d6):δ2.31(t,1H),2.49-2.65(m,1H),3.46(m,1H),4.30(dd,1H),5.37(d,1H),7.71(s,1H,)和8.09(s,1H)(NH2),9.7(br,2H,NH2 +)。
e.)(2S,4S)-1-(2-氯乙酰基)-4-氟-2-吡咯烷甲酰胺
在通式(IX)中,R2指的是氢原子和R3指的是氟原子。
将2.54g(15mmol)(2S,4S)-4-氟-2-吡咯烷甲酰胺盐酸盐混悬于60ml二氯甲烷中并向其中加入4.6ml(33mmol)三乙胺。在低于-10℃下向所得的混合物中滴加1.27ml(16mmol)溶解于15ml二氯甲烷中的氯乙酰氯。将该反应混合物搅拌1小时并将该混悬液倒入到500ml乙酸乙酯中,将沉淀下来的三乙胺盐酸盐滤出,将滤液浓缩并用使用氯仿-甲醇4∶1混合物的色谱法进行纯化。
由此得到3.0g(97%)无色油状物形式的标题化合物,其在静置过程中发生结晶。其熔点为95-96℃。
1H-NMR(400MHz,DMSO-d6):δ2.22-2.50(m,2H,3-CH2),3.57-4.04(m,2H,5-CH2),4.36(qv,2H,CH2Cl),5.22(d,0,5H)和5.39(d,0,5H)(4-CH),7.03(s,0,74H)和7,22(s,1H)和7.56(s,0,26H)(NH2)。
f.)(2S,4S)-1-(2-氯乙酰基)-4-氟-2-吡咯烷腈
在通式(III)中,R2指的是氢原子和R3指的是氟原子。
将1.73g(46mmol)(2S,4S)-1-(2-氯乙酰基)-4-氟-2-吡咯烷甲酰胺溶解于20ml无水乙腈和30ml无水二氯甲烷的混合物中并向其中加入32ml(25mmol)氯氧化磷。将该混合物回流24小时。将该溶液倾倒到另一个烧瓶中,并向其中加入50g碳酸钾并将该混合物搅拌1小时。将固体盐滤出,在对滤液进行蒸发后得到一种浅黄色油状物,用使用氯仿和甲醇的9∶1混合物的色谱法对其进行纯化。纯的上面的产物是0.6g(43%)白色结晶态固体。熔点:134-136℃。
1H-NMR(400MHz,CDCl3):δ2.23-2.62(m,2H,3-CH2),3.59-4.06(m,2H,5-CH2),4.46(qv,2H,CH2Cl),4.99(m,1H,2-CH),5.36(m,0,5H)和5.64(m,0,5H)(4-H)。
g)其中R1指的是2-吡嗪基、B指的是式(4)的基团、R2代表氢原子和R3代表氟原子的通式(I)的(2S,4S)-4-氟-1-(2-{[8-(2-吡嗪基)-8-氮杂二环[3.2.1]辛-3-基]外氨基}乙酰基-2-吡咯烷腈二盐酸盐
如实施例1/g.)中所述的那样将243mg(1.2mmol)8-(2-吡嗪基)-8-氮杂二环[3.2.1]辛-3-基-外-胺与191mg(1mmol)of(2S,4S)-1-(2-氯乙酰基)-4-氟-2-吡咯烷腈进行反应。将产物用使用氯仿和甲醇的4∶1混合物的色谱法进行纯化,并制备其二盐酸盐。由此得到125mg(29%)白色结晶形式的标题化合物。熔点:201-202℃。1H-NMR(400MHz,DMSO-d6):δ1.76-1.80(m,4H),1.94-2.01(m,4H),2.47-2.51(m,2H),3.64-3.80(m,1H),3.79-4.03(m,2H),4.15(m,1H),4.67(m,2H),5.03(m,1H),5.52(d,1H),7.86(s,1H),8.15(dd,1H),8.28(d,2H),8.90 and 9.00(s,2H)。
实施例3
(2S)-4,4-二氟-1-(2-{[1-(2-吡嗪基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈二盐酸盐
在通式(I)中,R1的含义是2-吡嗪基,B指的是式(1)的基团,R2和R3指的是氟原子。
a)具有通式(V)的1-(2-吡嗪基)-4-乙酰氨基-哌啶——其中R1是2-吡嗪基,Y是COCH3,B是基团(1)
将0,45ml氯吡嗪(5mmol)和1,6g 4-乙酰氨基pyperidine(10mmol)溶解于15ml 1-戊醇中并将其在回流下加热14小时。将溶剂蒸发掉,并将残余物用柱色谱法进行纯化,用乙酸乙酯-甲醇-25%NH3水溶液(17∶3∶1)作为洗脱剂,得到0,81g(76%)上面的结晶产物。熔点:158-160℃。1H-NMR(200MHz,DMSO-d6):δ1.34(dq,2H),1.78(m,5H),3.03(dt,2H),3.74-3.89(m,1H),4.21(td,2H),7.77(d,1H,3`-H),7.80(s,1H,NH),8.05(dd,1H,5`-H),8.31(d,1H,6`-H)。
b.)具有通式(II)的1-(2-吡嗪基)-4-氨基-哌啶——其中R1和B具有步骤3a.)中所给出的含义。
将697mg 1-(2-吡嗪基)-4-乙酰氨基-哌啶(3,2mmol)溶解于15ml2N盐酸中,并将该溶液在回流下加热8小时。在冷却后,将该混合物用20%氢氧化钠进行处理,将水溶液用4×20ml二氯甲烷进行洗涤。将所合并的有机层用Na2SO4干燥并进行蒸发,得到292mg(52%)黄色结晶形式的上面的产物。
熔点:113-115℃。
1H-NMR(200MHz,DMSO-d6-CDCl3):δ1.09-1.36(m,2H),1.78(d,2H),2.78-3.31(m,4H),3.54(m,1H),7.76(d,1H,3`-H),8.03(dd,1H,5`-H),8.29(d,1H,6`-H)。
c.)其中R1是2-吡嗪基、B是式(1)的基团、R2和R3指的是氟原子的通式(I)的(2S)-4,4-二氟-1-(2-{[1-(2-吡嗪基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈二盐酸盐
将63mg 1-(2-吡嗪基)-4-氨基-哌啶(0,32mmol)和62mg(2S)-1-(2-氯乙酰基)-4,4-二氟-2-吡咯烷腈(0,32mmol)和285mg聚合键合的2-叔-丁基亚氨基-2-二乙基氨基-1,3-二甲基-全氢化-1,3,2-二氮杂磷(phosphorine)(PBEMP)(0,73mmol)溶解于20ml无水乙腈中并将其在55℃下搅拌8小时。通过过滤除去树脂,将滤液真空浓缩并将残余物用柱色谱法进行纯化,用氯仿-甲醇(9∶1)作为洗脱剂,得到一种油状物,将其用位于乙醚中的盐酸进行处理,得到83mg(60%)白色结晶形式的标题化合物。熔点:158-160℃。1H-NMR(400MHz,DMSO-d6):δ1.54(m,2H),2.15(m,2H),2.80-2.95(m,4H),4.20-4.25(m,4H),4.55(d,2H,),5.20(t,1H),7.00(d,1H),7.87(dd,1H),8.50(d,1H);9.38(br,2H)。
实施例4
(2S)-4,4-二氟-1-(2-{[1-(5-氰基吡啶-2-基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈二盐酸盐
在通式(I)中,R1的含义是5-氰基-吡啶-2-基,B的含义是式(1)的基团,R2和R3指的是氟原子。
a.)具有通式(V)的1-(5-氰基吡啶-2-基)-4-乙酰氨基-哌啶——其中R1是5-氰基吡啶-2-基,Y是COCH3,B是基团(1)
按照实施例3a)所概括的方法,分离出上面的结晶产物。熔点为246-251℃。1H-NMR(200MHz,DMSO-d6):δ1.19-1.39(m,2H),1.82(m,5H),3.04-3.18(m,2H),3.85(m,1H),4.29(dd,2H),6.94(d,1H),7.82(dd,1H),8.46(d,1H)。
b.)具有通式(II)的1-(5-氰基吡啶-2-基)-4-氨基-哌啶——其中R1和B具有步骤4a.)中给出的含义。
按照实施例3b)所概括的方法,分离出上面的结晶产物。熔点:65-68℃。1H-NMR(200MHz,CDCl3-DMSO-d6):δ1.16-1.38(m,2H),1.83-1.92(m,2H),2.89-3.06(m,2H),4.26(dd,2H),6.54(d,1H),7.50(dd,1H),8.29(d,1H)。
c.)(2S)-4,4-二氟-1-(2-{[1-(5-氰基吡啶-2-基)哌啶-4-基]氨基}乙酰基)-2-吡咯烷腈二盐酸盐
按照实施例3c)所概括的方法,分离出上面的结晶产物。熔点:146-147℃。1H-NMR(DMSO-d6):δ1.56(m,2H),2.15(d,2H),2.92(m,4H),4.20(m,4H),4.55(d,2H),5.20(t,2H),7.01(d,1H),7.88(d,1H),8.49(dd,1H),9.38(d,2H)。
按照实施例1-2所概括的方法,制备游离碱或盐形式的表1中所列的化合物。
表1.
按照实施例3-4所概括的方法,制备游离碱或盐形式的表2所列的化合物。
表2.
按照实施例1-4所概括的方法,制备游离碱或盐形式的表3所列的通式(I)的化合物。
表3.
按照实施例1a)和2a)所概括的方法,制备表4所列的通式(V)的中间体化合物。
表4
按照实施例1a)和2a)所概括的方法,制备表5所列的通式(V)的中间体化合物。
表5.
按照实施例3a)和-4a)所概括的方法,制备表6所列的通式(V)的中间体化合物(Y=Ac(乙酰基)或Boc=叔丁氧基-羰基)。
按照实施例1b)和2b)所概括的方法,制备表7中所列的通式(II)的中间体化合物。
表7.
按照实施例1b)和2b)概括的方法,制备下面表8所列的通式(II)的中间体化合物。
表8.
R1——B——NH2
(II)
按照实施例3b)和4b)所概括的方法,制备下面表9所列的通式(II)的中间体化合物。
表9.
Claims (5)
1.Y代表乙酰基或叔-丁氧基羰基的通式(V)的化合物及其异构体和盐,
R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基、四唑基、三嗪基环;在给定的情况中,其被一个或两个彼此独立地选自下面基团的基团所单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基、氨基或苯基;或
-噻吩基、呋喃基或苯甲基;或
-对-甲苯磺酰基;或
-式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基或硝基-或卤素原子所取代的苯基、吡啶基或苯乙烯基;被含1-3个碳原子的亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表-
式(1)或(2)或(3)或(4)或(5)或(6)或(7)的基团;
条件是如果B代表式(1)的基团,则R1不同于苄基或乙酰基并且Y不同于乙酰基;或者条件是如果B代表式(2)的基团,则R1不同于苄基并且Y不同于乙酰基;或者条件是如果B代表式(3)的基团,则R1不同于苯甲酰基并且Y不同于乙酰基;或者如果B代表式(1)的基团,则R1不同于5-氰基-2-吡啶-2-基-并且Y不同于叔丁氧基-羰基;或如果B代表式(4)、(6)或(7)的基团,则R1不同于苄基并且Y不同于叔丁氧基羰基。
4.通式(IX)的化合物及其异构体,
其中R2代表氢原子或氟原子;
R3代表氟原子。
5.如权利要求1至4任一项所述的通式(V)、(VII)、(VIII)和(IX)的化合物用于制备通式(I)的化合物的用途,
R1指的是包含氮的由一个或两个芳族环所组成的芳族部分,吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、二唑基、喹啉基、异喹啉基、肉啉基、2,3-二氮杂萘基、喹唑啉基、喹喔啉基、苯并咪唑基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基或苯并异唑基、四唑基、三嗪基环;在给定的情况中,其被一个或两个彼此独立地选自下面基团的基团所单-或二取代:C1-4烷基、C1-4烷氧基、卤素原子、三卤代甲基、甲硫基、硝基、氰基、氨基或苯基;或
-噻吩基、呋喃基或苯甲基;或
-对-甲苯磺酰基;或
-式R1a-CO的酰基,其中R1a指的是C1-4烷基、苯基;被一个或多个烷基-和/或烷氧基或硝基-或卤素原子所取代的苯基、吡啶基或苯乙烯基;被含1-3个碳原子的亚烷基-二氧基所取代的苯乙烯基或苯基乙基;哌啶-1-基、4-甲基哌嗪-1-基、吡咯烷-1-基,
B代表-
式(1)或(2)或(3)或(4)或(5)或(6)或(7)的基团;
R2代表氢原子或氟原子;
R3代表氟原子。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUP0200849 | 2002-03-06 | ||
HU0200849A HUP0200849A2 (hu) | 2002-03-06 | 2002-03-06 | N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA038052636A Division CN1639159A (zh) | 2002-03-06 | 2003-03-04 | N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1990486A true CN1990486A (zh) | 2007-07-04 |
Family
ID=90001540
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006101640208A Pending CN1990486A (zh) | 2002-03-06 | 2003-03-04 | N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 |
CNA038052636A Pending CN1639159A (zh) | 2002-03-06 | 2003-03-04 | N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA038052636A Pending CN1639159A (zh) | 2002-03-06 | 2003-03-04 | N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 |
Country Status (28)
Country | Link |
---|---|
US (3) | US7348327B2 (zh) |
EP (1) | EP1487807B1 (zh) |
JP (1) | JP4559737B2 (zh) |
KR (1) | KR100977898B1 (zh) |
CN (2) | CN1990486A (zh) |
AR (1) | AR038868A1 (zh) |
AT (1) | ATE443054T1 (zh) |
AU (1) | AU2003209514B2 (zh) |
BR (1) | BR0307960A (zh) |
CA (1) | CA2475312C (zh) |
DE (1) | DE60329282D1 (zh) |
EA (1) | EA007410B1 (zh) |
EC (1) | ECSP045274A (zh) |
HR (1) | HRP20040910A2 (zh) |
HU (1) | HUP0200849A2 (zh) |
IL (2) | IL163286A (zh) |
IS (1) | IS7434A (zh) |
MA (1) | MA27105A1 (zh) |
MX (1) | MXPA04008613A (zh) |
NO (1) | NO20044221L (zh) |
NZ (1) | NZ535662A (zh) |
PL (1) | PL371099A1 (zh) |
RS (1) | RS79004A (zh) |
TN (1) | TNSN04141A1 (zh) |
TW (1) | TWI250978B (zh) |
UA (1) | UA78291C2 (zh) |
WO (1) | WO2003074500A2 (zh) |
ZA (1) | ZA200406467B (zh) |
Families Citing this family (122)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE370943T1 (de) * | 2001-06-27 | 2007-09-15 | Smithkline Beecham Corp | Fluoropyrrolidine als dipeptidyl-peptidase inhibitoren |
HUP0202001A2 (hu) * | 2002-06-14 | 2005-08-29 | Sanofi-Aventis | DDP-IV gátló hatású azabiciklooktán- és nonánszármazékok |
TW200401635A (en) * | 2002-07-23 | 2004-02-01 | Yamanouchi Pharma Co Ltd | 2-Cyano-4-fluoropyrrolidine derivative or salt thereof |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
WO2004098591A2 (en) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases |
HU227684B1 (en) * | 2003-08-29 | 2011-11-28 | Sanofi Aventis | Adamantane and azabicyclo-octane and nonane derivatives and their use as dpp-iv inhibitors |
EP1680120A2 (en) | 2003-11-03 | 2006-07-19 | Probiodrug AG | Combinations useful for the treatment of neuronal disorders |
KR20140089408A (ko) * | 2003-11-17 | 2014-07-14 | 노파르티스 아게 | 디펩티딜 펩티다제 ⅳ 억제제의 용도 |
PT1715893E (pt) | 2004-01-20 | 2009-10-20 | Novartis Pharma Ag | Formulação para compressão directa e processos |
KR101130433B1 (ko) | 2004-02-05 | 2012-03-27 | 교린 세이야꾸 가부시키 가이샤 | 비시클로에스테르 유도체 |
CN1918131B (zh) | 2004-02-05 | 2011-05-04 | 前体生物药物股份公司 | 谷氨酰胺酰基环化酶抑制剂 |
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 |
EA013463B1 (ru) | 2004-10-12 | 2010-04-30 | ГЛЕНМАРК ФАРМАСЬЮТИКАЛС Эс.Эй. | Новые ингибиторы дипептидилпептидазы iv, содержащие их фармацевтические композиции, способ их получения и способ лечения с их применением |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
DOP2006000008A (es) * | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
JP2008024592A (ja) * | 2005-01-28 | 2008-02-07 | Taisho Pharmaceut Co Ltd | シアノピロリジン誘導体含有固形製剤用組成物、それを含有する固形製剤及びその製造方法 |
AU2006239929B2 (en) | 2005-04-22 | 2011-11-03 | Alantos Pharmaceuticals Holding, Inc. | Dipeptidyl peptidase-IV inhibitors |
MX2008001799A (es) * | 2005-08-11 | 2008-04-16 | Hoffmann La Roche | Composicion farmaceutica que comprende un inhibidor de dipeptidil peptidasa iv. |
WO2007033350A1 (en) | 2005-09-14 | 2007-03-22 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors for treating diabetes |
EP1924567B1 (en) | 2005-09-16 | 2012-08-22 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
GB0526291D0 (en) | 2005-12-23 | 2006-02-01 | Prosidion Ltd | Therapeutic method |
US20090156465A1 (en) | 2005-12-30 | 2009-06-18 | Sattigeri Jitendra A | Derivatives of beta-amino acid as dipeptidyl peptidase-iv inhibitors |
CN101395131B (zh) | 2006-03-08 | 2012-11-14 | 杏林制药株式会社 | 氨基乙酰基吡咯烷甲腈衍生物的制备方法及其制备中间体 |
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 |
AR060406A1 (es) * | 2006-04-11 | 2008-06-11 | Arena Pharm Inc | Metodos para usar el receptor gpr119 en la identificacion de compuestos utiles para aumentar la masa osea en un individuo |
PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
MX2008014024A (es) | 2006-05-04 | 2008-11-14 | Boehringer Ingelheim Int | Formas poliformas. |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
RU2009108280A (ru) | 2006-08-08 | 2010-09-20 | Санофи-Авентис (Fr) | Ариламиноарилалкилзамещенные имидазолидин-2,4-дионы, способы их получения, содержащие эти соединения лекарственные средства и их применение |
US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
SI2091948T1 (sl) | 2006-11-30 | 2012-07-31 | Probiodrug Ag | Novi inhibitorji glutaminil ciklaze |
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 |
DE102007005045B4 (de) | 2007-01-26 | 2008-12-18 | Sanofi-Aventis | Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
JPWO2008114857A1 (ja) | 2007-03-22 | 2010-07-08 | 杏林製薬株式会社 | アミノアセチルピロリジンカルボニトリル誘導体の製造方法 |
DK2142514T3 (da) | 2007-04-18 | 2015-03-23 | Probiodrug Ag | Thioureaderivater som glutaminylcyclase-inhibitorer |
EP2155689B1 (en) | 2007-05-31 | 2015-07-08 | Boehringer Ingelheim International GmbH | Ccr2 receptor antagonists and uses thereof |
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 |
WO2009037719A1 (en) * | 2007-09-21 | 2009-03-26 | Lupin Limited | Novel compounds as dipeptidyl peptidase iv (dpp iv) inhibitors |
JP5438028B2 (ja) * | 2008-01-23 | 2014-03-12 | ジエンス ハンセン ファーマセウティカル カンパニー リミテッド | アザビシクロオクタンの誘導体、その製造方法及びそのジペプチジルペプチダーゼivの阻害剤としての用途 |
PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
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 |
BRPI0916997A2 (pt) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | Inibidor de dpp-4 e seu uso |
CA2732984A1 (en) | 2008-08-07 | 2010-02-11 | Kyorin Pharmaceutical Co., Ltd. | Process for production of bicyclo[2.2.2]octylamine derivative |
CN102186474A (zh) * | 2008-08-14 | 2011-09-14 | 杏林制药株式会社 | 稳定的医药组合物 |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
WO2010054183A2 (en) * | 2008-11-07 | 2010-05-14 | President And Fellows Of Harvard College | Dyes, compositions and related methods of use |
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 |
MA33085B1 (fr) | 2008-12-19 | 2012-03-01 | Boehringer Ingelheim Int | Pyrimidine-4 carboxamides cycliques en tant qu'antagonistes du recepteur ccr2 pour le traitement d'inflammations, de l'asthme et des broncho-pneumopathies chroniques obstructives |
GB2483614B (en) | 2009-06-18 | 2014-12-03 | Lupin Ltd | 2-Amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent dpp-iv inhibitors |
AR077642A1 (es) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo |
WO2011023754A1 (en) | 2009-08-26 | 2011-03-03 | Sanofi-Aventis | Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
AU2010294214B2 (en) | 2009-09-11 | 2015-05-07 | Vivoryon Therapeutics N.V. | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
EP3646859A1 (en) | 2009-11-27 | 2020-05-06 | Boehringer Ingelheim International GmbH | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
JP5632014B2 (ja) | 2009-12-17 | 2014-11-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ccr2受容体アンタゴニスト及びこれらの使用 |
JP6026284B2 (ja) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤 |
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
AU2011226074B2 (en) | 2010-03-10 | 2015-01-22 | Vivoryon Therapeutics N.V. | Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) |
CN102918027A (zh) | 2010-04-06 | 2013-02-06 | 艾尼纳制药公司 | Gpr119受体调节剂和对与所述受体有关的障碍的治疗 |
EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
AU2011249722B2 (en) | 2010-05-05 | 2015-09-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
WO2011141474A1 (en) | 2010-05-12 | 2011-11-17 | Boehringer Ingelheim International Gmbh | Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
WO2011141477A1 (en) | 2010-05-12 | 2011-11-17 | Boehringer Ingelheim International Gmbh | New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
WO2011144501A1 (en) | 2010-05-17 | 2011-11-24 | Boehringer Ingelheim International Gmbh | Ccr2 antagonists and uses thereof |
US9018212B2 (en) | 2010-05-25 | 2015-04-28 | Boehringer Ingelheim International Gmbh | Pyridazine carboxamides as CCR2 receptor antagonists |
WO2011151251A1 (en) | 2010-06-01 | 2011-12-08 | Boehringer Ingelheim International Gmbh | New ccr2 antagonists |
EP2582709B1 (de) | 2010-06-18 | 2018-01-24 | Sanofi | Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
AU2011305525B2 (en) | 2010-09-22 | 2016-08-18 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
EP2683701B1 (de) | 2011-03-08 | 2014-12-24 | Sanofi | Mit benzyl- oder heteromethylengruppen substituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
WO2012120054A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US8895547B2 (en) | 2011-03-08 | 2014-11-25 | Sanofi | Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof |
WO2012120051A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Mit adamantan- oder noradamantan substituierte benzyl-oxathiazinderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
EP2683702B1 (de) | 2011-03-08 | 2014-12-24 | Sanofi | Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
EP2683704B1 (de) | 2011-03-08 | 2014-12-17 | Sanofi | Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
EP2683699B1 (de) | 2011-03-08 | 2015-06-24 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
JP6050264B2 (ja) | 2011-03-16 | 2016-12-21 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤としてのベンゾイミダゾール誘導体 |
US20140018371A1 (en) | 2011-04-01 | 2014-01-16 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
US20140066369A1 (en) | 2011-04-19 | 2014-03-06 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013010839A1 (en) | 2011-07-15 | 2013-01-24 | Boehringer Ingelheim International Gmbh | Novel and selective ccr2 antagonists |
EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
CA2873097A1 (en) * | 2012-05-11 | 2013-11-14 | Todd M. Hansen | Pyridazine and pyridine derivatives as nampt inhibitors |
EP3685839A1 (en) | 2012-05-14 | 2020-07-29 | Boehringer Ingelheim International GmbH | Linagliptin for use in the treatment of albuminuria and kidney related diseases |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
EP2865666B1 (en) | 2012-06-25 | 2017-05-31 | Sunshine Lake Pharma Co., Ltd. | Hexahydropentaleno derivatives, preparation method and use in medicine thereof |
TWI500613B (zh) | 2012-10-17 | 2015-09-21 | Cadila Healthcare Ltd | 新穎之雜環化合物 |
EP2911655A1 (en) | 2012-10-24 | 2015-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Tpl2 kinase inhibitors for preventing or treating diabetes and for promoting -cell survival |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
EP3085700B1 (en) * | 2013-12-20 | 2018-10-31 | Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. China | Novel piperidine carboxamide compound, preparation method, and usage thereof |
ES2950384T3 (es) | 2014-02-28 | 2023-10-09 | Boehringer Ingelheim Int | Uso médico de un inhibidor de DPP-4 |
CN104529858A (zh) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | 含卤代金刚烷和酰胺类衍生物、其制备方法和用途 |
CN104529856A (zh) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | 一种硝基金刚烷酰胺衍生物、其制备方法和用途 |
EP3053577A1 (en) * | 2015-02-09 | 2016-08-10 | F. Hoffmann-La Roche AG | Compounds for the treatment of cancer |
EP3256126B1 (en) | 2015-02-09 | 2024-03-27 | F. Hoffmann-La Roche AG | Compounds for the treatment of cancer |
DK3265126T3 (da) | 2015-03-03 | 2021-09-13 | Saniona As | Kombinationsformulering af tesofensin og metoprolol |
CA2979033A1 (en) | 2015-03-09 | 2016-09-15 | Intekrin Therapeutics, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
ES2805743T3 (es) | 2015-03-24 | 2021-02-15 | Inst Nat Sante Rech Med | Método y composición farmacéutica para uso en el tratamiento de la diabetes |
WO2017004537A1 (en) | 2015-07-02 | 2017-01-05 | Centrexion Therapeutics Corporation | (4-((3r,4r)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2r,6s)-6-(p-tolyl)tetrahydro-2h-pyran-2-yl)methylamino)pyrimidin-4yl)methanone citrate |
BR112018072401A2 (pt) | 2016-06-10 | 2019-02-19 | Boehringer Ingelheim International Gmbh | combinações de linagliptina e metformina |
WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
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 |
PL3461819T3 (pl) | 2017-09-29 | 2020-11-30 | Probiodrug Ag | Inhibitory cyklazy glutaminylowej |
RU2020122712A (ru) | 2017-12-15 | 2022-01-18 | ПРАКСИС БАЙОТЕК ЭлЭлСи | Ингибиторы белка активации фибробластов |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2005A (en) * | 1841-03-16 | Improvement in the manner of constructing molds for casting butt-hinges | ||
US2004A (en) * | 1841-03-12 | Improvement in the manner of constructing and propelling steam-vessels | ||
US3225037A (en) | 1959-03-30 | 1965-12-21 | Sterling Drug Inc | 10-[(amino- and acylamino-1-piperidyl) lower-alkyl]-phenothiazines |
GB1460389A (en) * | 1974-07-25 | 1977-01-06 | Pfizer Ltd | 4-substituted quinazoline cardiac stimulants |
US4302455A (en) * | 1980-04-14 | 1981-11-24 | Merck & Co., Inc. | 2-(4-Aminopiperidino)pyrazines |
US5001125A (en) * | 1984-03-26 | 1991-03-19 | Janssen Pharmaceutica N.V. | Anti-virally active pyridazinamines |
JP2869561B2 (ja) * | 1989-05-22 | 1999-03-10 | 大塚製薬株式会社 | 血小板粘着抑制剤 |
CA2106840A1 (en) * | 1992-09-25 | 1994-03-26 | Marco Baroni | Heteroarylazetidines and -pyrrolidines, process for their preparation and pharmaceutical compositions containing them |
ES2079323B1 (es) * | 1994-06-21 | 1996-10-16 | Vita Invest Sa | Derivados de indol utiles para el tratamiento de la migraña, composicion y uso correspondientes. |
UA51716C2 (uk) * | 1996-07-08 | 2002-12-16 | Авентіс Фармасьютікалз Продактс Інк. | Сполуки, що мають гіпотензивну, кардіопротекторну, анти-ішемічну та антиліполітичну властивості, фармацевтична композиція та способи лікування |
TW492957B (en) * | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
FR2780057B1 (fr) | 1998-06-18 | 2002-09-13 | Sanofi Sa | Phenoxypropanolamines, procede pour leur preparation et compositions pharmaceutiques les contenant |
EP1178982B1 (en) * | 1999-05-21 | 2004-06-30 | Abbott Laboratories | Heterocyclic substituted aminoazacycles useful as central nervous system agents |
TW583185B (en) * | 2000-06-13 | 2004-04-11 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines and pharmaceutical composition for inhibiting dipeptidyl peptidase-IV (DPP-IV) or for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV comprising the same |
EP1950199B1 (en) | 2000-08-10 | 2009-12-02 | Mitsubishi Tanabe Pharma Corporation | Proline derivatives and use thereof as drugs |
KR100526091B1 (ko) * | 2000-10-06 | 2005-11-08 | 다나베 세이야꾸 가부시키가이샤 | 지방족 질소 함유 오원환 화합물 |
TWI243162B (en) * | 2000-11-10 | 2005-11-11 | Taisho Pharmaceutical Co Ltd | Cyanopyrrolidine derivatives |
JP2002264450A (ja) * | 2000-12-21 | 2002-09-18 | Ricoh Co Ltd | 画像処理ユニット、画像形成装置、画像形成方法及び画像処理システム |
JPWO2002051836A1 (ja) * | 2000-12-27 | 2004-04-22 | 協和醗酵工業株式会社 | ジペプチジルペプチダーゼ−iv阻害剤 |
GB0115517D0 (en) * | 2001-06-25 | 2001-08-15 | Ferring Bv | Novel antidiabetic agents |
IL158923A0 (en) * | 2001-06-27 | 2004-05-12 | Smithkline Beecham Corp | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
ATE370943T1 (de) | 2001-06-27 | 2007-09-15 | Smithkline Beecham Corp | Fluoropyrrolidine als dipeptidyl-peptidase inhibitoren |
WO2004000799A1 (en) | 2002-06-20 | 2003-12-31 | Akzo Nobel N.V. | (stabilised) peroxide compositions phlegmatised with a specific unsaturated phlegmatising agent |
TW200401635A (en) | 2002-07-23 | 2004-02-01 | Yamanouchi Pharma Co Ltd | 2-Cyano-4-fluoropyrrolidine derivative or salt thereof |
CN1706726A (zh) * | 2004-02-17 | 2005-12-14 | 梅加特雷德国际公司 | 带发光部件的容器 |
-
2002
- 2002-03-06 HU HU0200849A patent/HUP0200849A2/hu unknown
-
2003
- 2003-03-04 CN CNA2006101640208A patent/CN1990486A/zh active Pending
- 2003-03-04 EA EA200401157A patent/EA007410B1/ru not_active IP Right Cessation
- 2003-03-04 JP JP2003572969A patent/JP4559737B2/ja not_active Expired - Fee Related
- 2003-03-04 DE DE60329282T patent/DE60329282D1/de not_active Expired - Lifetime
- 2003-03-04 KR KR1020047013870A patent/KR100977898B1/ko not_active IP Right Cessation
- 2003-03-04 WO PCT/HU2003/000017 patent/WO2003074500A2/en active Application Filing
- 2003-03-04 AT AT03743452T patent/ATE443054T1/de not_active IP Right Cessation
- 2003-03-04 AU AU2003209514A patent/AU2003209514B2/en not_active Ceased
- 2003-03-04 CN CNA038052636A patent/CN1639159A/zh active Pending
- 2003-03-04 MX MXPA04008613A patent/MXPA04008613A/es active IP Right Grant
- 2003-03-04 RS YU79004A patent/RS79004A/sr unknown
- 2003-03-04 US US10/507,005 patent/US7348327B2/en not_active Expired - Fee Related
- 2003-03-04 CA CA2475312A patent/CA2475312C/en not_active Expired - Fee Related
- 2003-03-04 EP EP03743452A patent/EP1487807B1/en not_active Expired - Lifetime
- 2003-03-04 PL PL03371099A patent/PL371099A1/xx not_active Application Discontinuation
- 2003-03-04 NZ NZ535662A patent/NZ535662A/en unknown
- 2003-03-04 BR BR0307960-0A patent/BR0307960A/pt not_active IP Right Cessation
- 2003-03-05 AR ARP030100723A patent/AR038868A1/es unknown
- 2003-03-06 TW TW092104743A patent/TWI250978B/zh not_active IP Right Cessation
- 2003-04-03 UA UA20041008080A patent/UA78291C2/uk unknown
-
2004
- 2004-07-29 IL IL163286A patent/IL163286A/en not_active IP Right Cessation
- 2004-07-29 MA MA27806A patent/MA27105A1/fr unknown
- 2004-07-29 TN TNP2004000141A patent/TNSN04141A1/en unknown
- 2004-08-13 ZA ZA200406467A patent/ZA200406467B/en unknown
- 2004-09-02 IS IS7434A patent/IS7434A/is unknown
- 2004-09-03 EC EC2004005274A patent/ECSP045274A/es unknown
- 2004-10-04 HR HR20040910A patent/HRP20040910A2/hr not_active Application Discontinuation
- 2004-10-05 NO NO20044221A patent/NO20044221L/no not_active Application Discontinuation
-
2006
- 2006-09-07 IL IL177933A patent/IL177933A0/en unknown
-
2008
- 2008-03-05 US US12/042,595 patent/US7655663B2/en not_active Expired - Fee Related
-
2010
- 2010-02-01 US US12/697,762 patent/US8063045B2/en not_active Expired - Fee Related
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1990486A (zh) | N-氨基乙酰基-吡咯烷-2-腈和它们作为ddp-iv抑制剂的用途 | |
CN100347170C (zh) | 具有dpp-iv抑制活性的氮杂二环辛烷与壬烷衍生物 | |
CN1028758C (zh) | 吡唑并嘧啶酮类抗心绞痛剂的制备方法 | |
CN1164573C (zh) | 新的α-氨基酸化合物、其制备方法和包含它们的药物组合物 | |
CN1304390C (zh) | 新颖的γ—分泌酶抑制剂 | |
CN1036920C (zh) | 含杂环碳酸衍生物 | |
CN1231478C (zh) | 光学活性的哌啶中间体的制备方法和该中间体 | |
CN1134442C (zh) | 吡唑并嘧啶酮cGMP PDE5抑制剂、其制备方法及用途及中间体 | |
CN1088456C (zh) | 取代的噁唑烷需钙蛋白酶和/或组织蛋白酶b抑制剂 | |
CN1083431C (zh) | 新的杂环化合物 | |
CN1845921A (zh) | 金刚烷和氮杂双环-辛烷及壬烷衍生物、其制备方法及其作为dpp-iv抑制剂的用途 | |
CN1344160A (zh) | 用作生长激素促分泌剂的杂环芳族化合物 | |
CN1051359A (zh) | 提高了水溶度的咪唑并[4,5-b]喹啉氧烷酰胺 | |
CN1524080A (zh) | 作为pde4抑制剂的2,3-二氮杂萘酮哌啶子基衍生物 | |
CN1930146A (zh) | 哌啶基羰基-吡咯烷和它们作为黑皮质素激动剂的用途 | |
CN1468224A (zh) | 用作α-2拮抗剂的喹啉衍生物 | |
CN1681784A (zh) | 作为霉蝇碱受体拮抗剂的氮杂二环衍生物 | |
CN1798744A (zh) | 作为nmda/nr2b拮抗剂的3-氟-哌啶化合物 | |
CN1111528C (zh) | 用作神经激肽拮抗药的哌嗪衍生物 | |
CN1031619C (zh) | 噁唑烷酮衍生物用于制备药物 | |
CN1056844C (zh) | 二氧代吡咯并吡咯衍生物 | |
CN1350536A (zh) | 氨基甲酰基四氢吡啶衍生物 | |
CN1043990C (zh) | 咪唑啉酮衍生物、其酸的加成盐及老年痴呆症的治疗药物 | |
CN86104681A (zh) | 治疗老年精神病的环酰胺和酰亚胺的二氮杂苯基哌啶衍生物 | |
CN1301991C (zh) | 哌啶衍生物、其制备方法、以及含有该衍生物的用于治疗阿耳茨海默氏病的药物组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20070704 |