CA2673164C - Derivatives of azabicyclo octane, the method of making them and the uses thereof as inhibitors of dipeptidyl peptidase iv - Google Patents
Derivatives of azabicyclo octane, the method of making them and the uses thereof as inhibitors of dipeptidyl peptidase iv Download PDFInfo
- Publication number
- CA2673164C CA2673164C CA2673164A CA2673164A CA2673164C CA 2673164 C CA2673164 C CA 2673164C CA 2673164 A CA2673164 A CA 2673164A CA 2673164 A CA2673164 A CA 2673164A CA 2673164 C CA2673164 C CA 2673164C
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- Prior art keywords
- alkyl
- heteroaryl
- aryl
- heterocyclo
- cycloalkyl
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- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 title abstract description 30
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- QUIJMHDIAFOPRK-UHFFFAOYSA-N 1-cyclooctylazocane Chemical class C1CCCCCCC1N1CCCCCCC1 QUIJMHDIAFOPRK-UHFFFAOYSA-N 0.000 title abstract description 4
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 title abstract 3
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 239000000203 mixture Substances 0.000 claims abstract description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 148
- 125000003118 aryl group Chemical group 0.000 claims description 130
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 127
- 125000001072 heteroaryl group Chemical group 0.000 claims description 121
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 97
- 125000003545 alkoxy group Chemical group 0.000 claims description 91
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 67
- 125000004104 aryloxy group Chemical group 0.000 claims description 59
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 57
- -1 cycloalkoxyl Chemical group 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 49
- 125000005842 heteroatom Chemical group 0.000 claims description 46
- 238000002360 preparation method Methods 0.000 claims description 46
- 150000001733 carboxylic acid esters Chemical group 0.000 claims description 45
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 125000001188 haloalkyl group Chemical group 0.000 claims description 26
- 239000005457 ice water Substances 0.000 claims description 26
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- 125000004438 haloalkoxy group Chemical group 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- XRSFPEFHACEZSM-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-5-one Chemical compound C1NCC2CC(=O)CC21 XRSFPEFHACEZSM-UHFFFAOYSA-N 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 claims description 8
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
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- 230000002401 inhibitory effect Effects 0.000 claims description 6
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
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- 239000000543 intermediate Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- GGNDIMLSSMWKDR-UHFFFAOYSA-N tert-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate Chemical compound C1C(=O)CC2CN(C(=O)OC(C)(C)C)CC21 GGNDIMLSSMWKDR-UHFFFAOYSA-N 0.000 claims description 3
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004310 lactic acid Substances 0.000 claims description 2
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- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 9
- 239000000243 solution Substances 0.000 description 58
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- 239000008103 glucose Substances 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 238000003304 gavage Methods 0.000 description 45
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 34
- 230000002829 reductive effect Effects 0.000 description 32
- 210000004369 blood Anatomy 0.000 description 31
- 239000008280 blood Substances 0.000 description 31
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 28
- 235000001727 glucose Nutrition 0.000 description 23
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 23
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- 239000000284 extract Substances 0.000 description 19
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
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- 238000006243 chemical reaction Methods 0.000 description 13
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 9
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
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- WFPLXVOHETVYQM-UHFFFAOYSA-N 2-(pyrrolidine-1-carbonyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one Chemical compound C1C2CC(=O)CC2CN1C(=O)N1CCCC1 WFPLXVOHETVYQM-UHFFFAOYSA-N 0.000 description 3
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
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Classifications
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- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Applications Claiming Priority (3)
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| CN200710004330.8 | 2007-01-23 | ||
| CNA2007100043308A CN101230058A (zh) | 2007-01-23 | 2007-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
| PCT/CN2007/070990 WO2008089636A1 (en) | 2007-01-23 | 2007-10-30 | Derivatives of azabicyclo octane, the method of making them and the uses thereof as inhibitors of dipeptidyl peptidase iv |
Publications (2)
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| CA2673164A1 CA2673164A1 (en) | 2008-07-31 |
| CA2673164C true CA2673164C (en) | 2016-05-10 |
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| EP (1) | EP2133077B1 (OSRAM) |
| JP (1) | JP5424256B2 (OSRAM) |
| KR (1) | KR101482159B1 (OSRAM) |
| CN (2) | CN101230058A (OSRAM) |
| AU (1) | AU2007345133B8 (OSRAM) |
| BR (1) | BRPI0719650A2 (OSRAM) |
| CA (1) | CA2673164C (OSRAM) |
| MX (1) | MX2009007765A (OSRAM) |
| RU (1) | RU2447063C2 (OSRAM) |
| WO (1) | WO2008089636A1 (OSRAM) |
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| CA2712352C (en) * | 2008-01-23 | 2016-05-10 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
| CN101919851B (zh) * | 2009-06-09 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | 治疗哺乳动物包括人2型糖尿病的药物组合物 |
| WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
| 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 |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| 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 |
| EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| SMT201800497T1 (it) * | 2011-12-21 | 2018-11-09 | Shanghai hengrui pharmaceutical co ltd | Derivato di pirrolo ad anello eteroarilico a sei elementi, relativo metodo di preparazione, e relativi usi medicinali |
| CN102827064B (zh) * | 2012-08-14 | 2014-01-29 | 华东师范大学 | 一种氮杂双环[3.3.0]辛烷衍生物的合成方法 |
| CN102827063B (zh) * | 2012-08-14 | 2014-06-25 | 华东师范大学 | 一种氮杂双环[3.3.0]辛烷衍生物的合成方法 |
| CN103709150B (zh) * | 2012-10-09 | 2017-06-30 | 江苏豪森药业集团有限公司 | 托西酸贝格列汀晶型及其制备方法和用途 |
| IN2015DN03795A (OSRAM) | 2012-10-24 | 2015-10-02 | Inserm Inst Nat De La Santé Et De La Rech Médicale | |
| AR097794A1 (es) * | 2013-09-26 | 2016-04-13 | Mnemosyne Pharmaceuticals Inc | Moduladores octahidro-ciclopenta[c]pirrol negativos de nr2b |
| WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
| CN108884100B (zh) | 2016-11-23 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂芳环类衍生物的制备方法及中间体 |
| CA3079617A1 (en) | 2017-10-20 | 2019-04-25 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| WO2019089676A1 (en) | 2017-10-31 | 2019-05-09 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| EP3723753A4 (en) | 2017-12-15 | 2022-01-26 | Praxis Biotech LLC | FIBROBLAST ACTIVATION PROTEIN INHIBITORS |
| IL276411B2 (en) | 2018-02-02 | 2024-04-01 | Univ Vanderbilt | M4 muscarinic acetylcholine receptor antagonists |
| CN113811529A (zh) | 2018-12-21 | 2021-12-17 | 普拉西斯生物技术有限责任公司 | 成纤维细胞激活蛋白抑制剂 |
| CN111620816B (zh) * | 2020-05-27 | 2023-06-02 | 上海赛默罗生物科技有限公司 | 螺桨烷类衍生物、其制备方法、药物组合物和用途 |
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| US5280028A (en) * | 1992-06-24 | 1994-01-18 | G. D. Searle & Co. | Benzimidazole compounds |
| DE69511086T2 (de) * | 1994-05-18 | 2000-01-05 | Nisshin Flour Milling Co., Ltd. | Pyrimidinderivate |
| TW492957B (en) | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
| US6110949A (en) | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US6395767B2 (en) * | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
| HUP0200849A2 (hu) | 2002-03-06 | 2004-08-30 | Sanofi-Synthelabo | N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra |
| TW200401635A (en) * | 2002-07-23 | 2004-02-01 | Yamanouchi Pharma Co Ltd | 2-Cyano-4-fluoropyrrolidine derivative or salt thereof |
| EP2385040A1 (en) * | 2003-03-14 | 2011-11-09 | ONO Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient |
| GB0307856D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
| CA2521271C (en) * | 2003-04-04 | 2011-01-04 | Novartis Ag | Quinoline-2-one-derivatives for the treatment of airways diseases |
| US7381738B2 (en) * | 2004-02-19 | 2008-06-03 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
| US7288563B2 (en) * | 2004-02-19 | 2007-10-30 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
| JP2008507543A (ja) * | 2004-07-22 | 2008-03-13 | グラクソ グループ リミテッド | 抗細菌剤 |
| US7423056B2 (en) | 2004-09-03 | 2008-09-09 | Athersys, Inc. | Tricyclic heteroaryl piperazines, pyrrolidines and azetidines as serotonin receptor modulators |
| 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 |
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- 2007-01-23 CN CNA2007100043308A patent/CN101230058A/zh active Pending
- 2007-10-30 RU RU2009124304/04A patent/RU2447063C2/ru not_active IP Right Cessation
- 2007-10-30 AU AU2007345133A patent/AU2007345133B8/en not_active Ceased
- 2007-10-30 EP EP07817181.6A patent/EP2133077B1/en active Active
- 2007-10-30 WO PCT/CN2007/070990 patent/WO2008089636A1/zh not_active Ceased
- 2007-10-30 KR KR1020097017567A patent/KR101482159B1/ko not_active Expired - Fee Related
- 2007-10-30 BR BRPI0719650-4A patent/BRPI0719650A2/pt not_active IP Right Cessation
- 2007-10-30 CA CA2673164A patent/CA2673164C/en not_active Expired - Fee Related
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- 2007-10-30 US US12/518,259 patent/US8178575B2/en not_active Expired - Fee Related
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2008
- 2008-01-23 CN CN2010102292364A patent/CN101914092B/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20100016314A1 (en) | 2010-01-21 |
| JP2010516635A (ja) | 2010-05-20 |
| HK1117164A1 (en) | 2009-01-09 |
| AU2007345133A1 (en) | 2008-07-31 |
| AU2007345133B2 (en) | 2013-02-21 |
| KR20090108093A (ko) | 2009-10-14 |
| EP2133077A4 (en) | 2010-12-22 |
| EP2133077B1 (en) | 2014-08-13 |
| RU2009124304A (ru) | 2011-02-27 |
| KR101482159B1 (ko) | 2015-01-13 |
| MX2009007765A (es) | 2009-07-30 |
| EP2133077A1 (en) | 2009-12-16 |
| JP5424256B2 (ja) | 2014-02-26 |
| CN101914092B (zh) | 2012-12-26 |
| CN101914092A (zh) | 2010-12-15 |
| US8178575B2 (en) | 2012-05-15 |
| CA2673164A1 (en) | 2008-07-31 |
| BRPI0719650A2 (pt) | 2013-12-10 |
| WO2008089636A1 (en) | 2008-07-31 |
| AU2007345133B8 (en) | 2013-05-02 |
| RU2447063C2 (ru) | 2012-04-10 |
| CN101230058A (zh) | 2008-07-30 |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20181030 |