HRP20040344A2 - N-substituted pyrrolidin derivatives as dipeptidyl peptidase iv inhibitors - Google Patents
N-substituted pyrrolidin derivatives as dipeptidyl peptidase iv inhibitorsInfo
- Publication number
- HRP20040344A2 HRP20040344A2 HR20040344A HRP20040344A HRP20040344A2 HR P20040344 A2 HRP20040344 A2 HR P20040344A2 HR 20040344 A HR20040344 A HR 20040344A HR P20040344 A HRP20040344 A HR P20040344A HR P20040344 A2 HRP20040344 A2 HR P20040344A2
- Authority
- HR
- Croatia
- Prior art keywords
- phenyl
- methyl
- pyridin
- acetyl
- pyrrolidine
- Prior art date
Links
- -1 N-substituted pyrrolidin Chemical class 0.000 title claims description 432
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 title 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 396
- 150000003839 salts Chemical class 0.000 claims description 91
- 125000001424 substituent group Chemical group 0.000 claims description 90
- 229910052736 halogen Inorganic materials 0.000 claims description 81
- 150000002367 halogens Chemical class 0.000 claims description 80
- 238000011282 treatment Methods 0.000 claims description 77
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 68
- 125000001072 heteroaryl group Chemical group 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims description 23
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 23
- 125000004076 pyridyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 238000011321 prophylaxis Methods 0.000 claims description 20
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 18
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 14
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 10
- 208000011231 Crohn disease Diseases 0.000 claims description 10
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 10
- 208000008589 Obesity Diseases 0.000 claims description 10
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 10
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 6
- RHMINIBXILOOLC-KRWDZBQOSA-N (2s)-1-[2-[[2-methyl-1-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CC(C)(C)NCC(=O)N1CCC[C@H]1C#N RHMINIBXILOOLC-KRWDZBQOSA-N 0.000 claims description 5
- FNBGYGSBQXNGMV-AWEZNQCLSA-N (2s)-1-[2-[[2-methyl-1-[(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)amino]propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNC(C)(C)CNC(ON=1)=NC=1C1=CC=CN=C1 FNBGYGSBQXNGMV-AWEZNQCLSA-N 0.000 claims description 5
- HPCVFMYWLKNCHA-SFHVURJKSA-N (2s)-1-[2-[[2-methyl-4-(5-methyl-3-pyridin-3-ylpyrazol-1-yl)butan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CC1=CC(C=2C=NC=CC=2)=NN1CCC(C)(C)NCC(=O)N1CCC[C@H]1C#N HPCVFMYWLKNCHA-SFHVURJKSA-N 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
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- MMXPNIQJMULULS-INIZCTEOSA-N (2s)-1-[2-[2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethylamino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CC=1OC(C=2C=CC(F)=CC=2)=NC=1CCNCC(=O)N1CCC[C@H]1C#N MMXPNIQJMULULS-INIZCTEOSA-N 0.000 claims description 4
- UGRDWVKNSOHGRX-INIZCTEOSA-N (2s)-1-[2-[2-[[4-(3-phenyl-1,2-oxazol-5-yl)-1,3-thiazol-2-yl]amino]ethylamino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNCCNC(SC=1)=NC=1C(ON=1)=CC=1C1=CC=CC=C1 UGRDWVKNSOHGRX-INIZCTEOSA-N 0.000 claims description 4
- BTQXXKSKFXDOPD-INIZCTEOSA-N (2s)-1-[2-[2-[[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino]ethylamino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNCCNC(SC=1)=NC=1C1=CC=C(C#N)C=C1 BTQXXKSKFXDOPD-INIZCTEOSA-N 0.000 claims description 4
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- FEYLJXXHJSPVCN-YOEHRIQHSA-N (2s)-1-[2-[[(2s)-1-(2,3-dimethylindol-1-yl)propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N([C@H](CN1C2=CC=CC=C2C(C)=C1C)C)CC(=O)N1CCC[C@H]1C#N FEYLJXXHJSPVCN-YOEHRIQHSA-N 0.000 claims description 4
- VUVQYJFNDZMWBF-IBGZPJMESA-N (2s)-1-[2-[[1-[[5-(4-methoxyphenyl)pyridin-2-yl]amino]-2-methylpropan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound C1=CC(OC)=CC=C1C(C=N1)=CC=C1NCC(C)(C)NCC(=O)N1[C@H](C#N)CCC1 VUVQYJFNDZMWBF-IBGZPJMESA-N 0.000 claims description 4
- OFPWYRCWIXVCKM-AWEZNQCLSA-N (2s)-1-[2-[[2-methyl-1-[(3-pyridin-4-yl-1,2,4-oxadiazol-5-yl)amino]propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNC(C)(C)CNC(ON=1)=NC=1C1=CC=NC=C1 OFPWYRCWIXVCKM-AWEZNQCLSA-N 0.000 claims description 4
- DOYXLXJWTNTMQD-KRWDZBQOSA-N (2s)-1-[2-[[2-methyl-4-(3-pyridin-3-ylpyrazol-1-yl)butan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNC(C)(C)CCN(N=1)C=CC=1C1=CC=CN=C1 DOYXLXJWTNTMQD-KRWDZBQOSA-N 0.000 claims description 4
- BLGNGWMPCLADMR-INIZCTEOSA-N (2s)-1-[2-[[2-methyl-4-(5-methyl-3-pyrazin-2-ylpyrazol-1-yl)butan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CC1=CC(C=2N=CC=NC=2)=NN1CCC(C)(C)NCC(=O)N1CCC[C@H]1C#N BLGNGWMPCLADMR-INIZCTEOSA-N 0.000 claims description 4
- VDBVGWZVLBCBIE-YOEHRIQHSA-N 1-[(2s)-2-[[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]propyl]indole-5-carbonitrile Chemical compound N([C@H](CN1C2=CC=C(C=C2C=C1)C#N)C)CC(=O)N1CCC[C@H]1C#N VDBVGWZVLBCBIE-YOEHRIQHSA-N 0.000 claims description 4
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 4
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- KBVUIBGUSADKSG-SFHVURJKSA-N (2s)-1-[2-[2-[[5-(3-methoxyphenyl)pyridin-2-yl]amino]ethylamino]acetyl]pyrrolidine-2-carbonitrile Chemical compound COC1=CC=CC(C=2C=NC(NCCNCC(=O)N3[C@@H](CCC3)C#N)=CC=2)=C1 KBVUIBGUSADKSG-SFHVURJKSA-N 0.000 claims description 3
- OOFUHXAKVVLBKA-AWEZNQCLSA-N (2s)-1-[2-[2-[[5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]amino]ethylamino]acetyl]pyrrolidine-2-carbonitrile Chemical compound O1C(C)=NN=C1C(C=N1)=CC=C1NCCNCC(=O)N1[C@H](C#N)CCC1 OOFUHXAKVVLBKA-AWEZNQCLSA-N 0.000 claims description 3
- PJDGWAXAFQNDBX-YOEHRIQHSA-N (2s)-1-[2-[[(2s)-1-(2-methylindol-1-yl)propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N([C@H](CN1C2=CC=CC=C2C=C1C)C)CC(=O)N1CCC[C@H]1C#N PJDGWAXAFQNDBX-YOEHRIQHSA-N 0.000 claims description 3
- PACXNTNOHFGJKC-YOEHRIQHSA-N (2s)-1-[2-[[(2s)-1-(5-methoxy-2-methylindol-1-yl)propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N([C@@H](C)CN1C2=CC=C(C=C2C=C1C)OC)CC(=O)N1CCC[C@H]1C#N PACXNTNOHFGJKC-YOEHRIQHSA-N 0.000 claims description 3
- RHDZIQUKUSTPHL-LSLKUGRBSA-N (2s)-1-[2-[[1-[(6-acetyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)amino]-2-methylpropan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound S1C=2CNC(C(=O)C)CC=2N=C1NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N RHDZIQUKUSTPHL-LSLKUGRBSA-N 0.000 claims description 3
- NFKNTRKCAYVDHL-ZDUSSCGKSA-N (2s)-1-[2-[[2-methyl-1-[(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)amino]propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNC(C)(C)CNC(ON=1)=NC=1C1=CC=CC=N1 NFKNTRKCAYVDHL-ZDUSSCGKSA-N 0.000 claims description 3
- KJRBPXVLFQZCBZ-HNNXBMFYSA-N (2s)-1-[2-[[2-methyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)amino]propan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNC(C)(C)CNC(O1)=NN=C1C1=CC=CC=C1 KJRBPXVLFQZCBZ-HNNXBMFYSA-N 0.000 claims description 3
- ZOLJOQLDVLKSLA-SFHVURJKSA-N (2s)-1-[2-[[2-methyl-4-(2-methyl-4-pyridin-3-ylimidazol-1-yl)butan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CC1=NC(C=2C=NC=CC=2)=CN1CCC(C)(C)NCC(=O)N1CCC[C@H]1C#N ZOLJOQLDVLKSLA-SFHVURJKSA-N 0.000 claims description 3
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- KCPFBPIGKAWMLH-KRWDZBQOSA-N (2s)-1-[2-[[2-methyl-4-(5-methyl-3-pyridin-3-yl-1,2,4-triazol-1-yl)butan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CC1=NC(C=2C=NC=CC=2)=NN1CCC(C)(C)NCC(=O)N1CCC[C@H]1C#N KCPFBPIGKAWMLH-KRWDZBQOSA-N 0.000 claims description 3
- ZMCVWJADOONXIK-KSSFIOAISA-N 1-[(2s)-2-[[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]propyl]-2-methylindole-5-carbonitrile Chemical compound N([C@H](CN1C2=CC=C(C=C2C=C1C)C#N)C)CC(=O)N1CCC[C@H]1C#N ZMCVWJADOONXIK-KSSFIOAISA-N 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- SZHNGFHGTJBFMS-ZDUSSCGKSA-N (2s)-1-[2-[[1-(1,3-benzothiazol-2-ylamino)-2-methylpropan-2-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound N=1C2=CC=CC=C2SC=1NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N SZHNGFHGTJBFMS-ZDUSSCGKSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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EP01125338 | 2001-10-26 | ||
EP02018227 | 2002-08-21 | ||
PCT/EP2002/011711 WO2003037327A1 (en) | 2001-10-26 | 2002-10-18 | N-substituted pyrrolidin derivatives as dipeptidyl peptidase iv inhibitors |
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HRP20040344A2 true HRP20040344A2 (en) | 2005-02-28 |
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HR20040344A HRP20040344A2 (en) | 2001-10-26 | 2004-04-15 | N-substituted pyrrolidin derivatives as dipeptidyl peptidase iv inhibitors |
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US (3) | US6861440B2 (pt) |
EP (1) | EP1441719B1 (pt) |
JP (1) | JP4171417B2 (pt) |
KR (1) | KR100645671B1 (pt) |
CN (1) | CN1713907B (pt) |
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AT (1) | ATE503477T1 (pt) |
AU (1) | AU2002338902B2 (pt) |
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HU (1) | HUP0402107A3 (pt) |
IL (2) | IL161158A0 (pt) |
MA (1) | MA26342A1 (pt) |
MX (1) | MXPA04003759A (pt) |
NO (1) | NO20041709L (pt) |
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UY (1) | UY27518A1 (pt) |
WO (1) | WO2003037327A1 (pt) |
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