NZ534990A - Heterocyclic amide derivatives as inhibitors of glycogen phosphorylase - Google Patents

Info

Publication number

NZ534990A

NZ534990A NZ534990A NZ53499003A NZ534990A NZ 534990 A NZ534990 A NZ 534990A NZ 534990 A NZ534990 A NZ 534990A NZ 53499003 A NZ53499003 A NZ 53499003A NZ 534990 A NZ534990 A NZ 534990A

Authority

NZ

New Zealand

Prior art keywords

oxo

thieno

chloro

pyrrole

carboxamide

Prior art date

2002-03-06

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• -1 Heterocyclic amide Chemical class 0.000 title claims abstract description 438
• 108010046163 Glycogen Phosphorylase Proteins 0.000 title abstract description 18
• 102000007390 Glycogen Phosphorylase Human genes 0.000 title abstract description 18
• 239000003112 inhibitor Substances 0.000 title description 13
• 150000001875 compounds Chemical class 0.000 claims abstract description 257
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 131
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 127
• 239000001257 hydrogen Substances 0.000 claims abstract description 122
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 122
• 125000001424 substituent group Chemical group 0.000 claims abstract description 70
• 125000005843 halogen group Chemical group 0.000 claims abstract description 68
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 68
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 59
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 46
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 45
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 39
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 32
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 31
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 30
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 28
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 27
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims abstract description 20
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 19
• 125000003118 aryl group Chemical group 0.000 claims abstract description 16
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 14
• 125000005549 heteroarylene group Chemical group 0.000 claims abstract description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 13
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 12
• 239000001301 oxygen Substances 0.000 claims abstract description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• 229910052796 boron Inorganic materials 0.000 claims abstract description 8
• 206010051161 Hyperglucagonaemia Diseases 0.000 claims abstract description 7
• 206010060378 Hyperinsulinaemia Diseases 0.000 claims abstract description 7
• 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 7
• 208000008589 Obesity Diseases 0.000 claims abstract description 7
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
• 230000035879 hyperinsulinaemia Effects 0.000 claims abstract description 7
• 235000020824 obesity Nutrition 0.000 claims abstract description 7
• 208000011580 syndromic disease Diseases 0.000 claims abstract description 7
• 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 4
• 238000000034 method Methods 0.000 claims description 143
• 150000002148 esters Chemical class 0.000 claims description 79
• 150000003839 salts Chemical class 0.000 claims description 75
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 71
• 239000007787 solid Substances 0.000 claims description 63
• 238000001727 in vivo Methods 0.000 claims description 62
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 52
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
• 239000000243 solution Substances 0.000 claims description 46
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 43
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
• 239000000203 mixture Substances 0.000 claims description 36
• 229910001868 water Inorganic materials 0.000 claims description 30
• 239000002253 acid Substances 0.000 claims description 29
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
• 238000011282 treatment Methods 0.000 claims description 28
• 125000000217 alkyl group Chemical group 0.000 claims description 27
• 239000012044 organic layer Substances 0.000 claims description 25
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 22
• 241001465754 Metazoa Species 0.000 claims description 21
• 125000002883 imidazolyl group Chemical group 0.000 claims description 21
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 21
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 20
• 230000002829 reductive effect Effects 0.000 claims description 20
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 19
• 238000004440 column chromatography Methods 0.000 claims description 19
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
• 125000006239 protecting group Chemical group 0.000 claims description 18
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 18
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 17
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 17
• SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 16
• 230000008569 process Effects 0.000 claims description 16
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 14
• 125000001425 triazolyl group Chemical group 0.000 claims description 14
• 150000001412 amines Chemical class 0.000 claims description 13
• 125000005936 piperidyl group Chemical group 0.000 claims description 13
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 13
• 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 13
• 239000003814 drug Substances 0.000 claims description 12
• JCZPOYAMKJFOLA-UHFFFAOYSA-N pyrrolidine-3,4-diol Chemical compound OC1CNCC1O JCZPOYAMKJFOLA-UHFFFAOYSA-N 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• 239000000651 prodrug Substances 0.000 claims description 11
• 229940002612 prodrug Drugs 0.000 claims description 11
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
• 229920006395 saturated elastomer Polymers 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 239000012267 brine Substances 0.000 claims description 9
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 9
• 238000003756 stirring Methods 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 8
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
• 239000011541 reaction mixture Substances 0.000 claims description 8
• 125000002541 furyl group Chemical group 0.000 claims description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 125000002971 oxazolyl group Chemical group 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 7
• HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 7
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
• 125000002755 pyrazolinyl group Chemical group 0.000 claims description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 7
• 239000000706 filtrate Substances 0.000 claims description 6
• 125000004043 oxo group Chemical group O=* 0.000 claims description 6
• 238000002360 preparation method Methods 0.000 claims description 6
• 239000011734 sodium Substances 0.000 claims description 6
• 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 5
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 5
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 125000005505 thiomorpholino group Chemical group 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000001422 pyrrolinyl group Chemical group 0.000 claims description 4
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 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 claims description 3
• 150000003857 carboxamides Chemical class 0.000 claims description 3
• 229910052708 sodium Inorganic materials 0.000 claims description 3
• 238000005406 washing Methods 0.000 claims description 3
• 125000004953 trihalomethyl group Chemical group 0.000 claims description 2
• VGENLLAEDBMNSC-UHFFFAOYSA-N 4-methyl-2-nitropyridine Chemical compound CC1=CC=NC([N+]([O-])=O)=C1 VGENLLAEDBMNSC-UHFFFAOYSA-N 0.000 claims 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
• ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims 1
• UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 claims 1
• 230000002401 inhibitory effect Effects 0.000 abstract description 8
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 abstract 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 3
• JPQPVYASXUNYSU-UHFFFAOYSA-N 2-chloro-n-(1-methyl-2-oxo-3,4-dihydroquinolin-3-yl)-6h-thieno[2,3-b]pyrrole-5-carboxamide Chemical compound C1=CC=C2N(C)C(=O)C(NC(=O)C=3NC=4SC(Cl)=CC=4C=3)CC2=C1 JPQPVYASXUNYSU-UHFFFAOYSA-N 0.000 abstract 1
• LJAHIGGEXIWVJG-UHFFFAOYSA-N 2-chloro-n-(2-oxo-3,4-dihydro-1h-quinolin-3-yl)-6h-thieno[2,3-b]pyrrole-5-carboxamide Chemical compound C1C2=CC=CC=C2NC(=O)C1NC(=O)C1=CC(C=C(S2)Cl)=C2N1 LJAHIGGEXIWVJG-UHFFFAOYSA-N 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 100
• 238000006243 chemical reaction Methods 0.000 description 79
• 238000001819 mass spectrum Methods 0.000 description 66
• 235000019439 ethyl acetate Nutrition 0.000 description 31
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 20
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
• 125000001309 chloro group Chemical group Cl* 0.000 description 19
• 230000000694 effects Effects 0.000 description 19
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 235000019198 oils Nutrition 0.000 description 18
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
• 238000010992 reflux Methods 0.000 description 17
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 15
• 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 14
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
• 239000002585 base Substances 0.000 description 14
• 239000008103 glucose Substances 0.000 description 14
• 229960001031 glucose Drugs 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 13
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• 241000282414 Homo sapiens Species 0.000 description 12
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 238000001816 cooling Methods 0.000 description 12
• 230000005764 inhibitory process Effects 0.000 description 12
• 239000004480 active ingredient Substances 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• 238000005859 coupling reaction Methods 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• 239000003054 catalyst Substances 0.000 description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• 125000002252 acyl group Chemical group 0.000 description 9
• 238000003556 assay Methods 0.000 description 9
• 238000000451 chemical ionisation Methods 0.000 description 9
• 230000008878 coupling Effects 0.000 description 9
• 238000010168 coupling process Methods 0.000 description 9
• 230000007062 hydrolysis Effects 0.000 description 9
• 238000006460 hydrolysis reaction Methods 0.000 description 9
• 239000007858 starting material Substances 0.000 description 9
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
• 229920002527 Glycogen Polymers 0.000 description 8
• 239000012131 assay buffer Substances 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 229940096919 glycogen Drugs 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 229910000104 sodium hydride Inorganic materials 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• 239000012298 atmosphere Substances 0.000 description 7
• 239000007859 condensation product Substances 0.000 description 7
• 206010012601 diabetes mellitus Diseases 0.000 description 7
• 238000001704 evaporation Methods 0.000 description 7
• 230000008020 evaporation Effects 0.000 description 7
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 7
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 7
• 125000001715 oxadiazolyl group Chemical group 0.000 description 7
• 239000000843 powder Substances 0.000 description 7
• 238000003786 synthesis reaction Methods 0.000 description 7
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
• 150000001299 aldehydes Chemical class 0.000 description 6
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
• 125000001153 fluoro group Chemical group F* 0.000 description 6
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 6
• 239000003755 preservative agent Substances 0.000 description 6
• 239000012312 sodium hydride Substances 0.000 description 6
• 238000012360 testing method Methods 0.000 description 6
• KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 5
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
• 102000051325 Glucagon Human genes 0.000 description 5
• 108060003199 Glucagon Proteins 0.000 description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
• HXXFSFRBOHSIMQ-UHFFFAOYSA-N [3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] dihydrogen phosphate Chemical compound OCC1OC(OP(O)(O)=O)C(O)C(O)C1O HXXFSFRBOHSIMQ-UHFFFAOYSA-N 0.000 description 5
• 150000007513 acids Chemical class 0.000 description 5
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