CA2123128A1 - Method for making a prolineboronate ester - Google Patents
Method for making a prolineboronate esterInfo
- Publication number
- CA2123128A1 CA2123128A1 CA002123128A CA2123128A CA2123128A1 CA 2123128 A1 CA2123128 A1 CA 2123128A1 CA 002123128 A CA002123128 A CA 002123128A CA 2123128 A CA2123128 A CA 2123128A CA 2123128 A1 CA2123128 A1 CA 2123128A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- pinanediol
- yield
- ester
- boronate
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 81
- 150000002148 esters Chemical class 0.000 title claims abstract description 22
- -1 N-protected pyrrole Chemical class 0.000 claims abstract description 46
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 claims abstract description 43
- 125000006239 protecting group Chemical group 0.000 claims abstract description 32
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 27
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000002009 diols Chemical class 0.000 claims abstract description 16
- 150000001413 amino acids Chemical class 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 125000004185 ester group Chemical group 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 20
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 16
- 125000005647 linker group Chemical group 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical group [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003729 cation exchange resin Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 7
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- IHPDTPWNFBQHEB-UHFFFAOYSA-N hydrobenzoin Chemical compound C=1C=CC=CC=1C(O)C(O)C1=CC=CC=C1 IHPDTPWNFBQHEB-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- ZWGMJLNXIVRFRJ-UHFFFAOYSA-N [1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]boronic acid Chemical compound CC(C)(C)OC(=O)N1C=CC=C1B(O)O ZWGMJLNXIVRFRJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000004927 fusion Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910052720 vanadium Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 12
- MOILFCKRQFQVFS-VUMZSGCYSA-N (3r,4s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1C2C(C)(C)C1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-VUMZSGCYSA-N 0.000 claims 5
- 230000001681 protective effect Effects 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 3
- 150000004653 carbonic acids Chemical class 0.000 claims 3
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- MOILFCKRQFQVFS-AZQAYCESSA-N (1s,3s,4r,5s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@H]2C(C)(C)[C@@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-AZQAYCESSA-N 0.000 claims 2
- 150000000180 1,2-diols Chemical class 0.000 claims 2
- OVVMNBVQOPZMPY-NTEAFONJSA-N 149716-73-4 Chemical compound Cl.O([C@]1(C)[C@@H]2C[C@H](C[C@@H]1O1)C2(C)C)B1[C@H]1CCCN1 OVVMNBVQOPZMPY-NTEAFONJSA-N 0.000 claims 2
- 239000011260 aqueous acid Substances 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 14
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 8
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 229910052796 boron Inorganic materials 0.000 abstract description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 4
- 125000005620 boronic acid group Chemical group 0.000 abstract description 4
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 102000035195 Peptidases Human genes 0.000 abstract description 3
- 108091005804 Peptidases Proteins 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- WADSQZHEAXPENM-UHFFFAOYSA-N 1h-pyrrol-2-ylboronic acid Chemical compound OB(O)C1=CC=CN1 WADSQZHEAXPENM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000004365 Protease Substances 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- HISWWEXBLOFKSH-UHFFFAOYSA-N [Li]C1CCCN1 Chemical compound [Li]C1CCCN1 HISWWEXBLOFKSH-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
- 239000000243 solution Substances 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 31
- 239000007787 solid Substances 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 239000000203 mixture Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 101150041968 CDC13 gene Proteins 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000006138 lithiation reaction Methods 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 3
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- CQMHKCYAPOVFMJ-UHFFFAOYSA-N phenylboronic acid 2,6,6-trimethylbicyclo[3.1.1]heptane-1,2-diol Chemical compound OB(O)C1=CC=CC=C1.C1C2(O)C(C)(C)C1CCC2(O)C CQMHKCYAPOVFMJ-UHFFFAOYSA-N 0.000 description 2
- 229940117953 phenylisothiocyanate Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 229960004295 valine Drugs 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 238000006219 Matteson homologation reaction Methods 0.000 description 1
- KTHDTJVBEPMMGL-VKHMYHEASA-N N-acetyl-L-alanine Chemical class OC(=O)[C@H](C)NC(C)=O KTHDTJVBEPMMGL-VKHMYHEASA-N 0.000 description 1
- WXNXCEHXYPACJF-ZETCQYMHSA-N N-acetyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-N 0.000 description 1
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 1
- IHYJTAOFMMMOPX-LURJTMIESA-N N-acetyl-L-valine Chemical compound CC(C)[C@@H](C(O)=O)NC(C)=O IHYJTAOFMMMOPX-LURJTMIESA-N 0.000 description 1
- FULZLIGZKMKICU-UHFFFAOYSA-N N-phenylthiourea Chemical class NC(=S)NC1=CC=CC=C1 FULZLIGZKMKICU-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- IBFLWIOFZGYDFZ-WCCKRBBISA-N OBO.OC(=O)[C@@H]1CCCN1 Chemical compound OBO.OC(=O)[C@@H]1CCCN1 IBFLWIOFZGYDFZ-WCCKRBBISA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 229960000669 acetylleucine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 125000005621 boronate group Chemical group 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- PMPYSSMGWFNAAQ-UHFFFAOYSA-N dichloromethane;n,n-diethylethanamine Chemical compound ClCCl.CCN(CC)CC PMPYSSMGWFNAAQ-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000011905 homologation Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004073 interleukin-2 production Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- VQEVKEKJZVEGPH-UHFFFAOYSA-N lithium;chloromethane Chemical compound [Li+].Cl[CH2-] VQEVKEKJZVEGPH-UHFFFAOYSA-N 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- AGVMWTWBONEXNA-UHFFFAOYSA-N pyrrolidin-2-ylboronic acid;hydrochloride Chemical compound Cl.OB(O)C1CCCN1 AGVMWTWBONEXNA-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IZPYBIJFRFWRPR-UHFFFAOYSA-N tert-butyl pyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=C1 IZPYBIJFRFWRPR-UHFFFAOYSA-N 0.000 description 1
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US79614891A | 1991-11-22 | 1991-11-22 | |
| US07/796,148 | 1991-11-22 | ||
| US93619892A | 1992-08-26 | 1992-08-26 | |
| US07/936,198 | 1992-08-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2123128A1 true CA2123128A1 (en) | 1993-05-27 |
Family
ID=27121696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002123128A Abandoned CA2123128A1 (en) | 1991-11-22 | 1992-11-19 | Method for making a prolineboronate ester |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0641347A1 (fi) |
| JP (1) | JPH07501078A (fi) |
| CN (1) | CN1073946A (fi) |
| AU (1) | AU661362B2 (fi) |
| CA (1) | CA2123128A1 (fi) |
| CZ (1) | CZ124494A3 (fi) |
| FI (1) | FI942345A (fi) |
| HU (1) | HUT67937A (fi) |
| IL (1) | IL103817A0 (fi) |
| MX (1) | MX9206628A (fi) |
| NO (1) | NO941905L (fi) |
| NZ (1) | NZ245207A (fi) |
| PT (1) | PT101079A (fi) |
| SI (1) | SI9200332A (fi) |
| SK (1) | SK59294A3 (fi) |
| TW (1) | TW232697B (fi) |
| WO (1) | WO1993010127A1 (fi) |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| US7816364B2 (en) | 2006-04-11 | 2010-10-19 | Arena Pharmaceuticals, Inc. | GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto |
| US7833730B2 (en) | 2006-04-11 | 2010-11-16 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual |
| US7838254B2 (en) | 2008-04-07 | 2010-11-23 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
| WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
| WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | 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 |
| WO2012145361A1 (en) | 2011-04-19 | 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 |
| WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
| US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
| US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
| US5965532A (en) * | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
| US6040145A (en) | 1997-05-07 | 2000-03-21 | Tufts University | Potentiation of the immune response |
| US6100234A (en) | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
| DE69837393T2 (de) | 1997-09-29 | 2007-12-06 | Point Therapeutics, Inc., Boston | Stimulierung von hämatopoietischen zellen im vitro |
| KR20010052302A (ko) | 1998-05-04 | 2001-06-25 | 바바라 피. 월너 | 조혈 자극 |
| PT1084129E (pt) | 1998-06-05 | 2003-06-30 | Point Therapeutics Inc | Compostos de boroprolina ciclica |
| US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
| US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
| EP1259246A2 (en) * | 2000-02-25 | 2002-11-27 | Novo Nordisk A/S | Use of dpp-iv inhibitors for the treatment of diabetes |
| WO2003063903A2 (en) * | 2002-02-01 | 2003-08-07 | Probiodrug Ag | Modulation of t lymphocytes using dp iv inhibitors |
| KR20070054762A (ko) * | 2003-11-12 | 2007-05-29 | 페노믹스 코포레이션 | 헤테로시클릭 보론산 화합물 |
| US7317109B2 (en) | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| US7767828B2 (en) | 2003-11-12 | 2010-08-03 | Phenomix Corporation | Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| US7576121B2 (en) | 2003-11-12 | 2009-08-18 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| MXPA06005518A (es) | 2003-11-17 | 2006-08-17 | Novartis Ag | Uso de inhibidores de la dipeptidil peptidasa iv. |
| WO2005067976A2 (en) | 2004-01-20 | 2005-07-28 | Novartis Ag | Direct compression formulation and process |
| US7446211B2 (en) | 2004-04-27 | 2008-11-04 | Wyeth | Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls |
| US7399869B2 (en) | 2005-05-19 | 2008-07-15 | Genentech, Inc. | Fibroblast activation protein inhibitor compounds and methods |
| US7825139B2 (en) | 2005-05-25 | 2010-11-02 | Forest Laboratories Holdings Limited (BM) | Compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
| CN1331835C (zh) * | 2005-10-18 | 2007-08-15 | 武汉大学 | 光活性β－羟基酮的制备方法 |
| KR20080077024A (ko) | 2005-12-19 | 2008-08-20 | 트러스티즈 오브 터프츠 칼리지 | 소프트 단백질분해효소 억제자 및 이의 프로-소프트 폼 |
| GEP20135847B (en) | 2008-06-17 | 2013-06-10 | Millennium Pharm Inc | Boronate ester compounds and pharmaceutical compositions containing them |
| US9523687B2 (en) | 2014-02-28 | 2016-12-20 | Institut Pasteur | Levels of CXCL 10/IP-10 forms and soluble CD26/DPPIV activity as early predictive biomarkers for HIV/SIV associated mucosal inflammation and progression towards AIDS |
| SG10202003693RA (en) | 2014-05-20 | 2020-05-28 | Millennium Pharm Inc | Boron-containing proteasome inhibitors for use after primary cancer therapy |
| WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
| CN108047257B (zh) * | 2017-12-17 | 2020-03-13 | 沧州普瑞东方科技有限公司 | 一种手性n-boc-吡咯烷-2-硼酸的制备工艺 |
| CN110452258B (zh) * | 2019-09-03 | 2021-01-01 | 上海馨远医药科技有限公司 | 一种二肽缬氨酸硼脯氨酸盐的制备方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4935493A (en) * | 1987-10-06 | 1990-06-19 | E. I. Du Pont De Nemours And Company | Protease inhibitors |
| ATE148130T1 (de) * | 1990-04-14 | 1997-02-15 | New England Medical Center Inc | Typ-iv-dipeptidyl-aminopeptidase-inhibitoren |
| GB9017694D0 (en) * | 1990-08-13 | 1990-09-26 | Sandoz Ltd | Improvements in or relating to organic chemistry |
-
1992
- 1992-11-18 MX MX9206628A patent/MX9206628A/es unknown
- 1992-11-19 JP JP5509442A patent/JPH07501078A/ja active Pending
- 1992-11-19 HU HU9401350A patent/HUT67937A/hu unknown
- 1992-11-19 WO PCT/US1992/009845 patent/WO1993010127A1/en not_active Application Discontinuation
- 1992-11-19 EP EP92925238A patent/EP0641347A1/en not_active Withdrawn
- 1992-11-19 CA CA002123128A patent/CA2123128A1/en not_active Abandoned
- 1992-11-19 AU AU31368/93A patent/AU661362B2/en not_active Expired - Fee Related
- 1992-11-19 PT PT101079A patent/PT101079A/pt not_active Application Discontinuation
- 1992-11-19 SK SK592-94A patent/SK59294A3/sk unknown
- 1992-11-19 SI SI19929200332A patent/SI9200332A/sl unknown
- 1992-11-19 CZ CZ941244A patent/CZ124494A3/cs unknown
- 1992-11-20 IL IL103817A patent/IL103817A0/xx unknown
- 1992-11-20 TW TW081109304A patent/TW232697B/zh active
- 1992-11-20 NZ NZ24520792A patent/NZ245207A/en unknown
- 1992-11-23 CN CN92113215A patent/CN1073946A/zh active Pending
-
1994
- 1994-05-20 FI FI942345A patent/FI942345A/fi not_active Application Discontinuation
- 1994-05-20 NO NO941905A patent/NO941905L/no unknown
Cited By (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| US7803753B2 (en) | 2005-01-10 | 2010-09-28 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| US7803754B2 (en) | 2005-01-10 | 2010-09-28 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| US8198232B2 (en) | 2005-01-10 | 2012-06-12 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| US8030270B2 (en) | 2005-01-10 | 2011-10-04 | Arena Pharmaceuticals, Inc. | Methods for identifying GLP-1 secretagogues |
| US8022034B2 (en) | 2005-01-10 | 2011-09-20 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| US8003597B2 (en) | 2005-01-10 | 2011-08-23 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| EP2253311A2 (en) | 2006-04-11 | 2010-11-24 | Arena Pharmaceuticals, Inc. | Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto |
| US8101626B2 (en) | 2006-04-11 | 2012-01-24 | Arena Pharmaceuticals, Inc. | GPR119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto |
| US8017574B2 (en) | 2006-04-11 | 2011-09-13 | Arena Pharmaceuticals, Inc. | Methods of preparing pharmaceutical compositions comprising GPR119 agonists having the effect of glucose-dependent insulinotropic peptide secretagogues |
| US8580526B2 (en) | 2006-04-11 | 2013-11-12 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 receptor to identify compounds which stimulate glucose-dependent insulinotropic peptide secretion |
| US8026074B2 (en) | 2006-04-11 | 2011-09-27 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual |
| US8026212B2 (en) | 2006-04-11 | 2011-09-27 | Arena Pharmaceuticals, Inc. | Methods of preparing pharmaceutical compositions comprising GPR119 agonists having the effect of glucose-dependent insulinotropic peptide secretatgogues |
| US7833730B2 (en) | 2006-04-11 | 2010-11-16 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual |
| US7816364B2 (en) | 2006-04-11 | 2010-10-19 | Arena Pharmaceuticals, Inc. | GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto |
| US8486646B2 (en) | 2008-04-07 | 2013-07-16 | Arena Pharmaceuticals, Inc. | Methods of using a G protein-coupled receptor to identify peptide YY (PYY) secretagogues |
| US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
| US7838254B2 (en) | 2008-04-07 | 2010-11-23 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
| WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
| WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| EP3323818A1 (en) | 2010-09-22 | 2018-05-23 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2012145361A1 (en) | 2011-04-19 | 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 |
| WO2012145603A1 (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 |
| WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
| US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
| US10772865B2 (en) | 2015-03-09 | 2020-09-15 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
| US11400072B2 (en) | 2015-03-09 | 2022-08-02 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
| US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Also Published As
| Publication number | Publication date |
|---|---|
| AU661362B2 (en) | 1995-07-20 |
| NO941905L (no) | 1994-07-14 |
| IL103817A0 (en) | 1993-04-04 |
| FI942345A0 (fi) | 1994-05-20 |
| CZ124494A3 (en) | 1995-07-12 |
| SI9200332A (en) | 1993-06-30 |
| PT101079A (pt) | 1994-02-28 |
| NO941905D0 (no) | 1994-05-20 |
| CN1073946A (zh) | 1993-07-07 |
| AU3136893A (en) | 1993-06-15 |
| WO1993010127A1 (en) | 1993-05-27 |
| HU9401350D0 (en) | 1994-08-29 |
| HUT67937A (en) | 1995-05-29 |
| NZ245207A (en) | 1994-07-26 |
| FI942345A (fi) | 1994-05-20 |
| JPH07501078A (ja) | 1995-02-02 |
| MX9206628A (es) | 1993-05-01 |
| EP0641347A1 (en) | 1995-03-08 |
| TW232697B (fi) | 1994-10-21 |
| SK59294A3 (en) | 1995-02-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2123128A1 (en) | Method for making a prolineboronate ester | |
| CA2121369C (en) | Inhibitors of dipeptidyl-aminopeptidase type iv | |
| Snow et al. | Studies on proline boronic acid dipeptide inhibitors of dipeptidyl peptidase IV: identification of a cyclic species containing a BN bond | |
| US5462928A (en) | Inhibitors of dipeptidyl-aminopeptidase type IV | |
| EP1846424B1 (en) | Proteasome inhibitors and methods of using the same | |
| Katz et al. | Episelection: novel Ki. apprx. nanomolar inhibitors of serine proteases selected by binding or chemistry on an enzyme surface | |
| US5384410A (en) | Removal of boronic acid protecting groups by transesterification | |
| EP0528858B1 (en) | Inhibitors of dipeptidyl-aminopeptidase type iv | |
| KR102094928B1 (ko) | 리신-글루탐산 다이펩티드 유도체 | |
| US20040229820A1 (en) | Inhibitors of dipeptidyl-aminopeptidase type IV | |
| ZA200608689B (en) | Synthesis of boronic ester and acid compounds | |
| EP0724446A1 (en) | Electrophilic peptide analogs as inhibitors of trypsin-like enzymes | |
| Kelly et al. | The efficient synthesis and simple resolution of a prolineboronate ester suitable for enzyme-inhibition studies | |
| AU674067B2 (en) | Enantioselective oxazaborolidine catalysts | |
| JP2022068192A (ja) | 銅およびニッケル触媒による脱炭酸ホウ素化反応 | |
| CA2174311A1 (en) | Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring | |
| EP0599633B1 (en) | Boronic ester synthesis | |
| Frost et al. | Rhodium catalysed conjugate addition of a chiral alkenyltrifluoroborate salt: the enantioselective synthesis of hermitamides A and B | |
| JPH11255773A (ja) | Ｌ−パラボロノフェニルアラニンの製造方法 | |
| Bennacer et al. | The Synthesis of Two Furan‐Based Analogues of the α′, β′‐Epoxy Ketone Proteasome Inhibitor Eponemycin | |
| Ku et al. | An efficient synthesis of enantiomerically pure unnatural aryl glycinols and aryl glycines | |
| US7960589B2 (en) | Synthesis of sphingosines and their derivatives | |
| Zucca et al. | Synthesis of stereo-defined α-trifluoromethyl (Tfm)-malic units | |
| US5646287A (en) | Reagents for enantioselective acylation and related reactions | |
| CN1048485C (zh) | 新颖的光学活性化合物及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |