CA2680133A1 - Procedes et intermediaires pour la synthese d'inhibiteurs selectifs de dpp-iv - Google Patents

Procedes et intermediaires pour la synthese d'inhibiteurs selectifs de dpp-iv Download PDF

Info

Publication number: CA2680133A1
Authority: CA; Canada
Prior art keywords: compound; formula; cbz; salt; crystalline form
Prior art date: 2007-03-08
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

Application number

CA002680133A

Other languages

English (en)

Inventor

David Alan Campbell

Emilia P. T. Leitao

Zhen-Ping Wu

Peng Wang

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Phenomix Corp

Original Assignee

Individual

Priority date (The priority date 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 date listed.)

2007-03-08

Filing date

2008-03-05

Publication date

2008-09-12

2008-03-05 Application filed by Individual filed Critical Individual

2008-09-12 Publication of CA2680133A1 publication Critical patent/CA2680133A1/fr

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 105
230000015572 biosynthetic process Effects 0.000 title claims abstract description 33
239000003112 inhibitor Substances 0.000 title abstract description 16
238000003786 synthesis reaction Methods 0.000 title abstract description 13
239000000543 intermediate Substances 0.000 title abstract description 9
150000001875 compounds Chemical class 0.000 claims abstract description 180
-1 carboxylate salt Chemical class 0.000 claims abstract description 100
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims abstract description 18
206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
238000011282 treatment Methods 0.000 claims abstract description 10
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 66
150000003839 salts Chemical class 0.000 claims description 52
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
239000011734 sodium Substances 0.000 claims description 37
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 32
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 29
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 29
102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 22
238000002360 preparation method Methods 0.000 claims description 22
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 21
239000003153 chemical reaction reagent Substances 0.000 claims description 20
238000000634 powder X-ray diffraction Methods 0.000 claims description 19
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
239000003960 organic solvent Substances 0.000 claims description 18
229910052796 boron Inorganic materials 0.000 claims description 17
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 15
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 14
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 14
238000000113 differential scanning calorimetry Methods 0.000 claims description 14
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
239000012453 solvate Substances 0.000 claims description 13
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
238000002425 crystallisation Methods 0.000 claims description 12
230000008025 crystallization Effects 0.000 claims description 12
238000000605 extraction Methods 0.000 claims description 12
238000007127 saponification reaction Methods 0.000 claims description 12
150000002148 esters Chemical class 0.000 claims description 11
150000004677 hydrates Chemical class 0.000 claims description 10
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 9
238000005481 NMR spectroscopy Methods 0.000 claims description 9
125000000217 alkyl group Chemical group 0.000 claims description 9
150000001768 cations Chemical class 0.000 claims description 9
125000004122 cyclic group Chemical group 0.000 claims description 9
ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 9
GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 9
239000002904 solvent Substances 0.000 claims description 9
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 8
125000003118 aryl group Chemical group 0.000 claims description 8
238000001953 recrystallisation Methods 0.000 claims description 8
150000003892 tartrate salts Chemical class 0.000 claims description 8
FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 7
230000003213 activating effect Effects 0.000 claims description 7
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
229940011051 isopropyl acetate Drugs 0.000 claims description 7
239000002244 precipitate Substances 0.000 claims description 7
229910001415 sodium ion Inorganic materials 0.000 claims description 7
150000001718 carbodiimides Chemical class 0.000 claims description 6
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 6
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
230000002401 inhibitory effect Effects 0.000 claims description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
238000001228 spectrum Methods 0.000 claims description 5
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
230000009286 beneficial effect Effects 0.000 claims description 4
238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
229910021645 metal ion Inorganic materials 0.000 claims description 4
229930003658 monoterpene Natural products 0.000 claims description 4
235000002577 monoterpenes Nutrition 0.000 claims description 4
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 claims description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
150000007530 organic bases Chemical class 0.000 claims description 3
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 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
238000010521 absorption reaction Methods 0.000 claims description 2
150000001860 citric acid derivatives Chemical class 0.000 claims description 2
208000018914 glucose metabolism disease Diseases 0.000 claims description 2
238000011084 recovery Methods 0.000 claims description 2
108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims 1
239000012736 aqueous medium Substances 0.000 claims 1
239000003814 drug Substances 0.000 claims 1
101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 abstract description 33
238000005859 coupling reaction Methods 0.000 abstract description 31
159000000000 sodium salts Chemical class 0.000 abstract description 21
230000008878 coupling Effects 0.000 abstract description 10
238000010168 coupling process Methods 0.000 abstract description 10
229940124639 Selective inhibitor Drugs 0.000 abstract description 3
102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 abstract 3
239000000203 mixture Substances 0.000 description 55
239000000243 solution Substances 0.000 description 50
239000012071 phase Substances 0.000 description 49
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
229910001868 water Inorganic materials 0.000 description 26
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
239000000047 product Substances 0.000 description 24
239000010410 layer Substances 0.000 description 22
238000006243 chemical reaction Methods 0.000 description 21
239000012074 organic phase Substances 0.000 description 21
239000011541 reaction mixture Substances 0.000 description 18
229910052799 carbon Inorganic materials 0.000 description 17
238000003756 stirring Methods 0.000 description 17
239000008346 aqueous phase Substances 0.000 description 16
229910052701 rubidium Inorganic materials 0.000 description 16
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
229910052705 radium Inorganic materials 0.000 description 15
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
239000000463 material Substances 0.000 description 10
150000001412 amines Chemical class 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
238000000746 purification Methods 0.000 description 9
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
239000008235 industrial water Substances 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
208000024891 symptom Diseases 0.000 description 8
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
239000002253 acid Substances 0.000 description 7
239000008367 deionised water Substances 0.000 description 7
229910021641 deionized water Inorganic materials 0.000 description 7
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 7
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
125000003545 alkoxy group Chemical group 0.000 description 6
ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
229910052794 bromium Inorganic materials 0.000 description 6
150000001721 carbon Chemical group 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
150000004702 methyl esters Chemical class 0.000 description 6
239000007787 solid Substances 0.000 description 6
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
125000003277 amino group Chemical group 0.000 description 5
125000005621 boronate group Chemical group 0.000 description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
XBPCUCUWBYBCDP-UHFFFAOYSA-O dicyclohexylazanium Chemical compound C1CCCCC1[NH2+]C1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-O 0.000 description 5
201000010099 disease Diseases 0.000 description 5
125000004430 oxygen atom Chemical group O* 0.000 description 5
238000010992 reflux Methods 0.000 description 5
239000007858 starting material Substances 0.000 description 5
238000012546 transfer Methods 0.000 description 5
DQZLGMVLRQSEPC-UHFFFAOYSA-N 2-[phenylmethoxycarbonyl-(1-phenylmethoxycarbonylpyrrolidin-3-yl)amino]acetic acid Chemical compound C=1C=CC=CC=1COC(=O)N(CC(=O)O)C(C1)CCN1C(=O)OCC1=CC=CC=C1 DQZLGMVLRQSEPC-UHFFFAOYSA-N 0.000 description 4
102000004190 Enzymes Human genes 0.000 description 4
108090000790 Enzymes Proteins 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
239000002585 base Substances 0.000 description 4
FPXJNSKAXZNWMQ-LLVKDONJSA-N benzyl (3r)-3-aminopyrrolidine-1-carboxylate Chemical compound C1[C@H](N)CCN1C(=O)OCC1=CC=CC=C1 FPXJNSKAXZNWMQ-LLVKDONJSA-N 0.000 description 4
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
239000000460 chlorine Substances 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
239000002178 crystalline material Substances 0.000 description 4
LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
230000002349 favourable effect Effects 0.000 description 4
230000004153 glucose metabolism Effects 0.000 description 4
125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
230000001404 mediated effect Effects 0.000 description 4
YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
229910052760 oxygen Inorganic materials 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
239000013557 residual solvent Substances 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
239000000725 suspension Substances 0.000 description 4
101150041968 CDC13 gene Proteins 0.000 description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
241000124008 Mammalia Species 0.000 description 3
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000001408 amides Chemical class 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
239000007795 chemical reaction product Substances 0.000 description 3
238000010790 dilution Methods 0.000 description 3
239000012895 dilution Substances 0.000 description 3
238000001914 filtration Methods 0.000 description 3
239000008103 glucose Substances 0.000 description 3
125000005842 heteroatom Chemical group 0.000 description 3
229910052739 hydrogen Inorganic materials 0.000 description 3
150000002500 ions Chemical class 0.000 description 3
239000003921 oil Substances 0.000 description 3
235000018102 proteins Nutrition 0.000 description 3
102000004169 proteins and genes Human genes 0.000 description 3
108090000623 proteins and genes Proteins 0.000 description 3
230000000717 retained effect Effects 0.000 description 3
229910052708 sodium Inorganic materials 0.000 description 3
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
AHLIRGQTIRVUNQ-UHFFFAOYSA-N 2-(pyrrolidin-3-ylamino)acetic acid Chemical compound OC(=O)CNC1CCNC1 AHLIRGQTIRVUNQ-UHFFFAOYSA-N 0.000 description 2
108010016626 Dipeptides Proteins 0.000 description 2
102100036968 Dipeptidyl peptidase 8 Human genes 0.000 description 2
101710087011 Dipeptidyl peptidase 8 Proteins 0.000 description 2
101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
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 2
102400000322 Glucagon-like peptide 1 Human genes 0.000 description 2
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
230000004913 activation Effects 0.000 description 2
125000003368 amide group Chemical group 0.000 description 2
235000001014 amino acid Nutrition 0.000 description 2
150000001413 amino acids Chemical class 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
125000003710 aryl alkyl group Chemical group 0.000 description 2
125000002102 aryl alkyloxo group Chemical group 0.000 description 2
125000004104 aryloxy group Chemical group 0.000 description 2
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
230000000903 blocking effect Effects 0.000 description 2
239000006227 byproduct Substances 0.000 description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
150000007942 carboxylates Chemical group 0.000 description 2
125000002091 cationic group Chemical group 0.000 description 2
239000001913 cellulose Substances 0.000 description 2
229920002678 cellulose Polymers 0.000 description 2
239000013078 crystal Substances 0.000 description 2
125000000753 cycloalkyl group Chemical group 0.000 description 2
YLELLFWQFUPLCO-UHFFFAOYSA-N dicyclohexylazanium;2-[phenylmethoxycarbonyl-(1-phenylmethoxycarbonylpyrrolidin-2-yl)amino]acetate Chemical compound C1CCCCC1[NH2+]C1CCCCC1.C=1C=CC=CC=1COC(=O)N(CC(=O)[O-])C1CCCN1C(=O)OCC1=CC=CC=C1 YLELLFWQFUPLCO-UHFFFAOYSA-N 0.000 description 2
150000005690 diesters Chemical class 0.000 description 2
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
208000035475 disorder Diseases 0.000 description 2
238000004090 dissolution Methods 0.000 description 2
238000001035 drying Methods 0.000 description 2
239000012065 filter cake Substances 0.000 description 2
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
239000012458 free base Substances 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
238000006460 hydrolysis reaction Methods 0.000 description 2
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
238000002955 isolation Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
238000002844 melting Methods 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
125000001624 naphthyl group Chemical group 0.000 description 2
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
230000003287 optical effect Effects 0.000 description 2
239000012044 organic layer Substances 0.000 description 2
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
229910052700 potassium Inorganic materials 0.000 description 2
239000011591 potassium Substances 0.000 description 2
235000015320 potassium carbonate Nutrition 0.000 description 2
235000011181 potassium carbonates Nutrition 0.000 description 2
239000000843 powder Substances 0.000 description 2
230000002265 prevention Effects 0.000 description 2
238000011321 prophylaxis Methods 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
230000003595 spectral effect Effects 0.000 description 2
239000007921 spray Substances 0.000 description 2
125000000547 substituted alkyl group Chemical group 0.000 description 2
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
239000012622 synthetic inhibitor Substances 0.000 description 2
231100000331 toxic Toxicity 0.000 description 2
230000002588 toxic effect Effects 0.000 description 2
XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
238000005406 washing Methods 0.000 description 2
MOILFCKRQFQVFS-OORONAJNSA-N (1s,3r,4s,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-OORONAJNSA-N 0.000 description 1
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 description 1
KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical class CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
238000005160 1H NMR spectroscopy Methods 0.000 description 1
UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
RKHAWKWXFLWSTL-UHFFFAOYSA-N 3-oxo-3-phenylmethoxy-2-phenylmethoxycarbonyl-2-(pyrrolidin-3-ylamino)propanoic acid Chemical compound C(=O)(OCC1=CC=CC=C1)C(NC1CNCC1)(C(=O)O)C(=O)OCC1=CC=CC=C1 RKHAWKWXFLWSTL-UHFFFAOYSA-N 0.000 description 1
ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
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 description 1
101100515517 Arabidopsis thaliana XI-I gene Proteins 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
208000024172 Cardiovascular disease Diseases 0.000 description 1
102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 1
101710087005 Dipeptidyl peptidase 9 Proteins 0.000 description 1
102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
102000020897 Formins Human genes 0.000 description 1
108091022623 Formins Proteins 0.000 description 1
208000013016 Hypoglycemia Diseases 0.000 description 1
238000004566 IR spectroscopy Methods 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
101500016415 Lophius americanus Glucagon-like peptide 1 Proteins 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
150000001204 N-oxides Chemical group 0.000 description 1
208000028389 Nerve injury Diseases 0.000 description 1
FFJQEBWLOFIREW-UHFFFAOYSA-N OBO.OBO Chemical group OBO.OBO FFJQEBWLOFIREW-UHFFFAOYSA-N 0.000 description 1
208000001647 Renal Insufficiency Diseases 0.000 description 1
206010057430 Retinal injury Diseases 0.000 description 1
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
JFRKIFOHHPKORS-UHFFFAOYSA-N [C].N1CCCC1 Chemical group [C].N1CCCC1 JFRKIFOHHPKORS-UHFFFAOYSA-N 0.000 description 1
238000000862 absorption spectrum Methods 0.000 description 1
238000005903 acid hydrolysis reaction Methods 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
229910001413 alkali metal ion Inorganic materials 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
125000003342 alkenyl group Chemical group 0.000 description 1
125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
150000003973 alkyl amines Chemical class 0.000 description 1
125000000304 alkynyl group Chemical group 0.000 description 1
150000001409 amidines Chemical class 0.000 description 1
125000006242 amine protecting group Chemical group 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
150000001450 anions Chemical class 0.000 description 1
125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
150000003974 aralkylamines Chemical class 0.000 description 1
150000004982 aromatic amines Chemical class 0.000 description 1
125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
150000001540 azides Chemical class 0.000 description 1
125000003828 azulenyl group Chemical group 0.000 description 1
230000008901 benefit Effects 0.000 description 1
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
235000010290 biphenyl Nutrition 0.000 description 1
239000004305 biphenyl Substances 0.000 description 1
125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
239000008280 blood Substances 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
125000005620 boronic acid group Chemical group 0.000 description 1
229910052792 caesium Inorganic materials 0.000 description 1
TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
239000011575 calcium Substances 0.000 description 1
239000004202 carbamide Substances 0.000 description 1
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
125000002843 carboxylic acid group Chemical group 0.000 description 1
210000004027 cell Anatomy 0.000 description 1
125000002676 chrysenyl group Chemical group C1(=CC=CC=2C3=CC=C4C=CC=CC4=C3C=CC12)* 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
239000013058 crude material Substances 0.000 description 1
125000000392 cycloalkenyl group Chemical group 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
230000001627 detrimental effect Effects 0.000 description 1
125000005265 dialkylamine group Chemical group 0.000 description 1
125000005266 diarylamine group Chemical group 0.000 description 1
238000004821 distillation Methods 0.000 description 1
230000000694 effects Effects 0.000 description 1
238000000921 elemental analysis Methods 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
150000002081 enamines Chemical class 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
229910001447 ferric ion Inorganic materials 0.000 description 1
229910001448 ferrous ion Inorganic materials 0.000 description 1
210000002950 fibroblast Anatomy 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000012467 final product Substances 0.000 description 1
230000009969 flowable effect Effects 0.000 description 1
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
238000004817 gas chromatography Methods 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
150000002357 guanidines Chemical class 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
125000002192 heptalenyl group Chemical group 0.000 description 1
125000000623 heterocyclic group Chemical group 0.000 description 1
229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
150000007857 hydrazones Chemical class 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
150000002443 hydroxylamines Chemical group 0.000 description 1
230000002218 hypoglycaemic effect Effects 0.000 description 1
150000003949 imides Chemical class 0.000 description 1
150000002466 imines Chemical class 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
125000003427 indacenyl group Chemical group 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
150000008040 ionic compounds Chemical class 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
201000006370 kidney failure Diseases 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
239000000693 micelle Substances 0.000 description 1
238000012986 modification Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
150000004682 monohydrates Chemical class 0.000 description 1
150000002773 monoterpene derivatives Chemical class 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000008764 nerve damage Effects 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
125000004433 nitrogen atom Chemical group N* 0.000 description 1
PSACHCMMPFMFAJ-UHFFFAOYSA-N nmm n-methylmorpholine Chemical compound CN1CCOCC1.CN1CCOCC1 PSACHCMMPFMFAJ-UHFFFAOYSA-N 0.000 description 1
125000000962 organic group Chemical group 0.000 description 1
150000002923 oximes Chemical class 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
238000010979 pH adjustment Methods 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
238000005192 partition Methods 0.000 description 1
230000003132 peptidolytic effect Effects 0.000 description 1
238000005191 phase separation Methods 0.000 description 1
125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
239000002243 precursor Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000010926 purge Methods 0.000 description 1
239000008213 purified water Substances 0.000 description 1
125000001725 pyrenyl group Chemical group 0.000 description 1
WGBPCMYISDZTQA-UHFFFAOYSA-N pyrrolidin-1-ylboronic acid Chemical compound OB(O)N1CCCC1 WGBPCMYISDZTQA-UHFFFAOYSA-N 0.000 description 1
VEBQYHFHXCAREJ-UHFFFAOYSA-N pyrrolidin-2-ylboronic acid Chemical compound OB(O)C1CCCN1 VEBQYHFHXCAREJ-UHFFFAOYSA-N 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
230000029964 regulation of glucose metabolic process Effects 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
238000000926 separation method Methods 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
YJMLRPJMPXRDTD-UHFFFAOYSA-M sodium 3-oxo-3-phenylmethoxy-2-phenylmethoxycarbonyl-2-(pyrrolidin-3-ylamino)propanoate Chemical compound [Na+].C(=O)(OCC1=CC=CC=C1)C(NC1CNCC1)(C(=O)[O-])C(=O)OCC1=CC=CC=C1 YJMLRPJMPXRDTD-UHFFFAOYSA-M 0.000 description 1
239000001488 sodium phosphate Substances 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
238000001694 spray drying Methods 0.000 description 1
CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
229910001427 strontium ion Inorganic materials 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
125000003107 substituted aryl group Chemical group 0.000 description 1
239000000758 substrate Substances 0.000 description 1
125000000565 sulfonamide group Chemical group 0.000 description 1
125000001174 sulfone group Chemical group 0.000 description 1
125000003375 sulfoxide group Chemical group 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
238000012360 testing method Methods 0.000 description 1
125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000000101 thioether group Chemical group 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
238000005809 transesterification reaction Methods 0.000 description 1
229910001428 transition metal ion Inorganic materials 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
125000005259 triarylamine group Chemical group 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
150000003673 urethanes Chemical class 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
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Diabetes (AREA)
Emergency Medicine (AREA)
Endocrinology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Hematology (AREA)
Obesity (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Pyrrole Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

CA002680133A 2007-03-08 2008-03-05 Procedes et intermediaires pour la synthese d'inhibiteurs selectifs de dpp-iv Abandoned CA2680133A1 (fr)

Applications Claiming Priority (9)

Application Number	Priority Date	Filing Date	Title
US89384207P	2007-03-08	2007-03-08
US60/893,842		2007-03-08
US95922607P	2007-07-12	2007-07-12
US60/959,226		2007-07-12
US2348708P	2008-01-25	2008-01-25
US61/023,487		2008-01-25
US2950608P	2008-02-18	2008-02-18
US61/029,506		2008-02-18
PCT/US2008/055927 WO2008109681A2 (fr)	2007-03-08	2008-03-05	Procédés et intermédiaires pour la synthèse d'inhibiteurs sélectifs de dpp-iv

Publications (1)

Publication Number	Publication Date
CA2680133A1 true CA2680133A1 (fr)	2008-09-12

Family

ID=39711954

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002680133A Abandoned CA2680133A1 (fr)	2007-03-08	2008-03-05	Procedes et intermediaires pour la synthese d'inhibiteurs selectifs de dpp-iv

Country Status (7)

Country	Link
EP (1)	EP2173709A2 (fr)
CN (1)	CN101679238A (fr)
AR (1)	AR065666A1 (fr)
CA (1)	CA2680133A1 (fr)
MX (1)	MX2009009575A (fr)
TW (1)	TW200843784A (fr)
WO (1)	WO2008109681A2 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA2617310A1 (fr)	2005-08-01	2007-02-08	Phenomix Corporation	Procedes de preparation d'acides boroniques heterocycliques et de derives de ceux-ci
CL2007002499A1 (es)	2006-08-30	2008-03-14	Phenomix Corp	Sales citrato y tartrato de compuestos derivados de acido pirrolidinilaminoacetilpirrolidinboronico, inhibidores de dpp-iv; metodo de preparacion; forma solida; combinacion farmaceutica, util para el tratamiento de diabetes.
UY32030A (es)	2008-08-06	2010-03-26	Boehringer Ingelheim Int	"tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
NZ604091A (en)	2008-08-15	2014-08-29	Boehringer Ingelheim Int	Purin derivatives for use in the treatment of fab-related diseases
AR074990A1 (es)	2009-01-07	2011-03-02	Boehringer Ingelheim Int	Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina
AR075204A1 (es)	2009-01-29	2011-03-16	Boehringer Ingelheim Int	Inhibidores de dpp-4 y composiciones farmaceuticas que los comprenden, utiles para tratar enfermedades metabolicas en pacientes pediatricos, particularmente diabetes mellitus tipo 2
AU2010212823B2 (en)	2009-02-13	2016-01-28	Boehringer Ingelheim International Gmbh	Antidiabetic medications comprising a DPP-4 inhibitor (linagliptin) optionally in combination with other antidiabetics
KR20240090632A (ko)	2009-11-27	2024-06-21	베링거 인겔하임 인터내셔날 게엠베하	리나글립틴과 같은 ｄｐｐ－ｉｖ 억제제를 사용한 유전자형 검사된 당뇨병 환자의 치료
EP2547339A1 (fr)	2010-03-18	2013-01-23	Boehringer Ingelheim International GmbH	Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
CN102946875A (zh)	2010-05-05	2013-02-27	贝林格尔.英格海姆国际有限公司	组合疗法
WO2011161161A1 (fr)	2010-06-24	2011-12-29	Boehringer Ingelheim International Gmbh	Thérapie du diabète
WO2013174767A1 (fr)	2012-05-24	2013-11-28	Boehringer Ingelheim International Gmbh	Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans la modification de l'apport alimentaire et dans la régulation des préférences alimentaires
CN111533675B (zh) *	2019-11-29	2021-09-28	杭州华东医药集团新药研究院有限公司	杂环硼酸化合物的杂质及其控制方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US7317109B2 (en) *	2003-11-12	2008-01-08	Phenomix Corporation	Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
CA2617310A1 (fr) *	2005-08-01	2007-02-08	Phenomix Corporation	Procedes de preparation d'acides boroniques heterocycliques et de derives de ceux-ci

2008
- 2008-03-05 CN CN200880015066A patent/CN101679238A/zh active Pending
- 2008-03-05 EP EP08743692A patent/EP2173709A2/fr not_active Withdrawn
- 2008-03-05 MX MX2009009575A patent/MX2009009575A/es not_active Application Discontinuation
- 2008-03-05 CA CA002680133A patent/CA2680133A1/fr not_active Abandoned
- 2008-03-05 WO PCT/US2008/055927 patent/WO2008109681A2/fr not_active Ceased
- 2008-03-07 TW TW097108175A patent/TW200843784A/zh unknown
- 2008-03-07 AR ARP080100973A patent/AR065666A1/es not_active Application Discontinuation

Also Published As

Publication number	Publication date
WO2008109681A2 (fr)	2008-09-12
WO2008109681A3 (fr)	2008-11-13
MX2009009575A (es)	2009-11-12
TW200843784A (en)	2008-11-16
AR065666A1 (es)	2009-06-24
EP2173709A2 (fr)	2010-04-14
CN101679238A (zh)	2010-03-24

Legal Events

Date	Code	Title	Description
2014-04-30	FZDE	Dead	Effective date: 20140305

Publication	Publication Date	Title
CA2680133A1 (fr)	2008-09-12	Procedes et intermediaires pour la synthese d'inhibiteurs selectifs de dpp-iv
KR101292707B1 (ko)	2013-08-02	디펩티딜펩티다아제 ⅳ의 억제제
AU2004296553B2 (en)	2008-09-04	DPP-IV inhibitors
AU2005229330A1 (en)	2005-10-13	DPP-IV inhibitors
CZ20033413A3 (cs)	2004-05-12	@@Fluorpyrrolidiny jako antidiabetická činidla
CZ298089B6 (cs)	2007-06-20	Inhibitory bunecné adheze, zpusob jejich prípravya farmaceutické prostredky s jejich obsahem
EP0877737A1 (fr)	1998-11-18	Nouveaux derives de n-(arylsulfonyl)aminoacides ayant une affinite pour les recepteurs de la bradykinine
IL163286A (en)	2007-06-03	1-(substituted glycyl)pyrrolidine-2-carbonitriles, their preparation and pharmaceutical compositions containing them
EP1981873A1 (fr)	2008-10-22	Derives de sulfonamides, leur preparation et leur application en tant qu'antagonistes des recepteurs de l'orexine 2
CA2542727A1 (fr)	2005-04-28	Derives de n-[phenyl(pyrrolidin-2-yl)methyl]benzamide, et n-[[azepan-2-yl)phenylmethyl]benzamide, leur preparation et leur application en therapeutique
CN115461335A (zh)	2022-12-09	Bcl-2蛋白抑制剂
AU2005251461A1 (en)	2005-12-22	1-`(3r)-amino-4-(2-fluoro-phenyl)-butyl !-pyrrolidine-(2r)-carboxilic acid-benzyl amine derivatives and related compounds as dipeptidyl-peptidase IV (DPP-IV) inhibitors for the treatment of Type 2 diabetes mellitus
CA2970546A1 (fr)	2016-06-23	Polymyxines antimicrobiennes pour le traitement d'infections bacteriennes
CA3116198A1 (fr)	2020-04-23	Composes contenant du deuterium
JPH10509727A (ja)	1998-09-22	Ｎ−末端スルホニル−又はアミノスルホニル基を有する新規のジペプチドのｐ−アミノベンジルアミド
JPH04234857A (ja)	1992-08-24	３，５−ジ置換２−イソキサゾリンおよびイソキサゾール、それらの製法およびそれらを含有する薬学的組成物
JPWO2019088270A1 (ja)	2020-12-03	蛋白分解酵素の双頭型阻害剤
AU2018228555B2 (en)	2022-04-07	Azetidine derivative
US20100087658A1 (en)	2010-04-08	Methods and intermediates for synthesis of selective dpp-iv inhibitors
WO2022234867A1 (fr)	2022-11-10	Sulfonamide ayant une action inhibitrice vis-à-vis de la mmp 7
TW530049B (en)	2003-05-01	Isoquinolines
JPH0776211B2 (ja)	1995-08-16	ピログルタミン酸誘導体
WO2020120606A1 (fr)	2020-06-18	Nouveaux dérivés d'acide pyrrolidine-2-carboxylique pour le traitement de la douleur et d'états pathologiques associés à la douleur
EP0001266B1 (fr)	1981-04-01	Sulfamates substitués de 2-aminométhyl-phényle, leur procédé de préparation et compositions pharmaceutiques les contenant
MX2008015759A (es)	2009-03-16	Derivados de pirrolidina utiles contra enfermedades que dependen de la actividad de la renina.