WO2004052869A1 - 5-substituted-pyrazine or pyridine glucokinase activators - Google Patents
5-substituted-pyrazine or pyridine glucokinase activators Download PDFInfo
- Publication number
- WO2004052869A1 WO2004052869A1 PCT/EP2003/014055 EP0314055W WO2004052869A1 WO 2004052869 A1 WO2004052869 A1 WO 2004052869A1 EP 0314055 W EP0314055 W EP 0314055W WO 2004052869 A1 WO2004052869 A1 WO 2004052869A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- methanesulfonyl
- cyclopentyl
- propionamide
- chloro
- Prior art date
Links
- -1 5-substituted-pyrazine Chemical class 0.000 title claims description 232
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 82
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 41
- 102000030595 Glucokinase Human genes 0.000 title abstract description 25
- 108010021582 Glucokinase Proteins 0.000 title abstract description 25
- 239000012190 activator Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 477
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 229940080818 propionamide Drugs 0.000 claims description 169
- 229920006395 saturated elastomer Polymers 0.000 claims description 118
- 239000000203 mixture Substances 0.000 claims description 80
- 229910052799 carbon Inorganic materials 0.000 claims description 73
- 125000001424 substituent group Chemical group 0.000 claims description 53
- 150000001721 carbon Chemical group 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 39
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical group CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 229910052760 oxygen Chemical group 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000001301 oxygen Chemical group 0.000 claims description 16
- 239000011593 sulfur Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- DVSOMGQPQXDSTH-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-formylpyrazin-2-yl)propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(C=O)=NC=1)CC1CCCC1 DVSOMGQPQXDSTH-UHFFFAOYSA-N 0.000 claims description 11
- UILCYGKPSXGBPC-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2-hydroxyethylsulfanyl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(SCCO)=NC=1)CC1CCCC1 UILCYGKPSXGBPC-MRXNPFEDSA-N 0.000 claims description 9
- RSWSKYSBRPWBFL-NNJIEVJOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-n-[5-[cyano(hydroxy)methyl]pyrazin-2-yl]-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(O)C#N)CC1CCCC1 RSWSKYSBRPWBFL-NNJIEVJOSA-N 0.000 claims description 9
- KFAOCUVRWMNQHM-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methanesulfonamido)pyridin-2-yl]propanamide Chemical compound N1=CC(NS(=O)(=O)C)=CC=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 KFAOCUVRWMNQHM-QGZVFWFLSA-N 0.000 claims description 8
- BMOGJRFSZYYMPK-HXUWFJFHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[3-(dimethylamino)propyl]pyrazin-2-yl]propanamide Chemical compound C1=NC(CCCN(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BMOGJRFSZYYMPK-HXUWFJFHSA-N 0.000 claims description 8
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 8
- BPUNDRVIOJADLI-UHFFFAOYSA-N n-(5-acetylpyrazin-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=NC(C(=O)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BPUNDRVIOJADLI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- XHGUXJHPFQFDCQ-OAHLLOKOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-methylsulfanylpyrazin-2-yl)propanamide Chemical compound C1=NC(SC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 XHGUXJHPFQFDCQ-OAHLLOKOSA-N 0.000 claims description 7
- ZRXYEXRHPSYMDY-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(dimethoxymethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(OC)OC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 ZRXYEXRHPSYMDY-MRXNPFEDSA-N 0.000 claims description 7
- MLHOQMZPSCAVOH-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(CC2C(NC(=O)S2)=O)=NC=1)CC1CCCC1 MLHOQMZPSCAVOH-UHFFFAOYSA-N 0.000 claims description 7
- NESMGVQBWDEZAO-CQSZACIVSA-N chembl2337925 Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(\N)=N/O)CC1CCCC1 NESMGVQBWDEZAO-CQSZACIVSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- OJWKFRQGNQMXJY-HXUWFJFHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[3-(dimethylamino)prop-1-ynyl]pyrazin-2-yl]propanamide Chemical compound C1=NC(C#CCN(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 OJWKFRQGNQMXJY-HXUWFJFHSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- SXHFVJNXGCUJRL-YHVXIASJSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-methylsulfinylpyrazin-2-yl)propanamide Chemical compound C1=NC(S(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 SXHFVJNXGCUJRL-YHVXIASJSA-N 0.000 claims description 5
- BFPODEUMNZELOT-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3-hydroxyprop-1-ynyl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C#CCO)CC1CCCC1 BFPODEUMNZELOT-GOSISDBHSA-N 0.000 claims description 5
- VFRFXGJYDITECZ-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(dimethylamino)methyl]pyrazin-2-yl]propanamide Chemical compound C1=NC(CN(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 VFRFXGJYDITECZ-GOSISDBHSA-N 0.000 claims description 5
- DHTQDLARMJZTRI-MJTSIZKDSA-N (2r)-n-[5-(2-amino-1-hydroxy-2-oxoethyl)pyrazin-2-yl]-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(O)C(N)=O)CC1CCCC1 DHTQDLARMJZTRI-MJTSIZKDSA-N 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- PIBVOMAOFIPNJU-OAHLLOKOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methanesulfonamido)pyrazin-2-yl]propanamide Chemical compound C1=NC(NS(=O)(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 PIBVOMAOFIPNJU-OAHLLOKOSA-N 0.000 claims description 4
- LPTXOARRBIFFCR-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(1-hydroxyethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(O)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 LPTXOARRBIFFCR-UHFFFAOYSA-N 0.000 claims description 4
- RGCOLBLUBXBSDY-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2-methylpropanoyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(=O)C(C)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 RGCOLBLUBXBSDY-UHFFFAOYSA-N 0.000 claims description 4
- LKHZSMIUTBLQBD-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(2,5-dioxoimidazolidin-4-yl)methyl]pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(CC2C(NC(=O)N2)=O)=NC=1)CC1CCCC1 LKHZSMIUTBLQBD-UHFFFAOYSA-N 0.000 claims description 4
- CWABTKLTGPCPGM-UHFFFAOYSA-N C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(=NC=1)C(=NO)C#N)CC1CCCC1 Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(=NC=1)C(=NO)C#N)CC1CCCC1 CWABTKLTGPCPGM-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- BNAMDSLGAAEBSX-GOSISDBHSA-N (2R)-3-cyclopentyl-N-[5-(N-hydroxy-C-methylcarbonimidoyl)pyrazin-2-yl]-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=NC(C(=NO)C)=CN=C1NC(=O)[C@@H](C=1C=CC(=CC=1)S(C)(=O)=O)CC1CCCC1 BNAMDSLGAAEBSX-GOSISDBHSA-N 0.000 claims description 3
- MHHLRNDLIDHPMN-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfanylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CSC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 MHHLRNDLIDHPMN-QGZVFWFLSA-N 0.000 claims description 3
- WUBYGXHOAJQAQK-OYGDXLDBSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfinylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CS(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 WUBYGXHOAJQAQK-OYGDXLDBSA-N 0.000 claims description 3
- ZYABJVQMTAQRIB-QGZVFWFLSA-N (2r)-3-cyclopentyl-n-(5-methylsulfanylpyrazin-2-yl)-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=NC(SC)=CN=C1NC(=O)[C@@H](C=1C=CC(=CC=1)S(C)(=O)=O)CC1CCCC1 ZYABJVQMTAQRIB-QGZVFWFLSA-N 0.000 claims description 3
- BPUNDRVIOJADLI-MRXNPFEDSA-N (2r)-n-(5-acetylpyrazin-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=NC(C(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BPUNDRVIOJADLI-MRXNPFEDSA-N 0.000 claims description 3
- ALRUAKYXLTVWEZ-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(1-hydroxy-2-methylpropyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(O)C(C)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 ALRUAKYXLTVWEZ-UHFFFAOYSA-N 0.000 claims description 3
- MHHLRNDLIDHPMN-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfanylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CSC)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 MHHLRNDLIDHPMN-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- TZQZTAAKWYSXKV-OAQYLSRUSA-N (2r)-2-(3-chloro-2-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3-methoxyphenyl)pyrazin-2-yl]propanamide Chemical compound COC1=CC=CC(C=2N=CC(NC(=O)[C@H](CC3CCCC3)C=3C(=C(Cl)C=CC=3)S(C)(=O)=O)=NC=2)=C1 TZQZTAAKWYSXKV-OAQYLSRUSA-N 0.000 claims description 2
- LKRYWWFJGDPNAI-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-thiophen-2-ylpyrazin-2-yl)propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C=1SC=CC=1)CC1CCCC1 LKRYWWFJGDPNAI-QGZVFWFLSA-N 0.000 claims description 2
- VAHRJRSQYMEOGT-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-thiophen-3-ylpyrazin-2-yl)propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C1=CSC=C1)CC1CCCC1 VAHRJRSQYMEOGT-GOSISDBHSA-N 0.000 claims description 2
- NSCFSRADOKMZBF-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2,2-dimethoxyethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CC(OC)OC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 NSCFSRADOKMZBF-GOSISDBHSA-N 0.000 claims description 2
- QBHPRPNEIQLVPP-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2-hydroxyethylamino)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(NCCO)=NC=1)CC1CCCC1 QBHPRPNEIQLVPP-MRXNPFEDSA-N 0.000 claims description 2
- CNVAJAVRHFZQPJ-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2-methoxyethylamino)pyrazin-2-yl]propanamide Chemical compound C1=NC(NCCOC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 CNVAJAVRHFZQPJ-QGZVFWFLSA-N 0.000 claims description 2
- KHJVZSPWNIRVSV-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3,4-dihydro-2h-pyran-6-yl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C=1OCCCC=1)CC1CCCC1 KHJVZSPWNIRVSV-GOSISDBHSA-N 0.000 claims description 2
- UPRQDMBDVXJVEB-LJQANCHMSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3-hydroxy-3-methylbut-1-ynyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C#CC(C)(O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 UPRQDMBDVXJVEB-LJQANCHMSA-N 0.000 claims description 2
- AJIOFORGXXYNQT-NKTHEXPSSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(4-methyl-2,5-dioxoimidazolidin-4-yl)pyrazin-2-yl]propanamide Chemical compound C=1N=C(NC(=O)[C@H](CC2CCCC2)C=2C=C(Cl)C(=CC=2)S(C)(=O)=O)C=NC=1C1(C)NC(=O)NC1=O AJIOFORGXXYNQT-NKTHEXPSSA-N 0.000 claims description 2
- GJKVAFLVPCJHNN-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(furan-3-yl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C1=COC=C1)CC1CCCC1 GJKVAFLVPCJHNN-GOSISDBHSA-N 0.000 claims description 2
- QOJCHOUNEOJSGO-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfonylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CS(=O)(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 QOJCHOUNEOJSGO-QGZVFWFLSA-N 0.000 claims description 2
- BNPHFJXHGASNCQ-YMBRHYMPSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(oxolan-2-yl)pyridin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=CC=1)C1OCCC1)CC1CCCC1 BNPHFJXHGASNCQ-YMBRHYMPSA-N 0.000 claims description 2
- AREATSLFYVZJHZ-QZTJIDSGSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(2r)-2,3-dihydroxypropyl]pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(C[C@@H](O)CO)=NC=1)CC1CCCC1 AREATSLFYVZJHZ-QZTJIDSGSA-N 0.000 claims description 2
- NEWXAIVVAQRVLU-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-n-[5-(5-cyanothiophen-2-yl)pyrazin-2-yl]-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C=1SC(=CC=1)C#N)CC1CCCC1 NEWXAIVVAQRVLU-GOSISDBHSA-N 0.000 claims description 2
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- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- PDOHFLCDPWIDHH-UHFFFAOYSA-N n,n-dimethyl-6-nitropyridin-3-amine Chemical compound CN(C)C1=CC=C([N+]([O-])=O)N=C1 PDOHFLCDPWIDHH-UHFFFAOYSA-N 0.000 description 1
- SJKUQADNNQSBNR-UHFFFAOYSA-N n-(5-aminopyrazin-2-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CN=C(N)C=N1 SJKUQADNNQSBNR-UHFFFAOYSA-N 0.000 description 1
- DRHCJJDGMITEQM-UHFFFAOYSA-N n-(5-bromopyrazin-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(Br)=NC=1)CC1CCCC1 DRHCJJDGMITEQM-UHFFFAOYSA-N 0.000 description 1
- XMLHIGAJEMTILR-UHFFFAOYSA-N n-(5-nitropyrazin-2-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CN=C([N+]([O-])=O)C=N1 XMLHIGAJEMTILR-UHFFFAOYSA-N 0.000 description 1
- JPFAHPJSRHMENV-UHFFFAOYSA-N n-(6-aminopyridin-3-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=C(N)N=C1 JPFAHPJSRHMENV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- REDMJGWYHYGRMF-UHFFFAOYSA-N o-[(2-methylpropan-2-yl)oxy]hydroxylamine;hydrochloride Chemical compound Cl.CC(C)(C)OON REDMJGWYHYGRMF-UHFFFAOYSA-N 0.000 description 1
- ZBDXGNXNXXPKJI-UHFFFAOYSA-N o-tert-butylhydroxylamine;hydrochloride Chemical compound Cl.CC(C)(C)ON ZBDXGNXNXXPKJI-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- 150000002923 oximes Chemical group 0.000 description 1
- OEOFQABUOAWYMP-UHFFFAOYSA-N oxiren-2-ol Chemical compound OC1=CO1 OEOFQABUOAWYMP-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- JAMNHZBIQDNHMM-UHFFFAOYSA-N pivalonitrile Chemical compound CC(C)(C)C#N JAMNHZBIQDNHMM-UHFFFAOYSA-N 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical class NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 230000029964 regulation of glucose metabolic process Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CQXDYHPBXDZWBA-UHFFFAOYSA-N tert-butyl 2,2,2-trichloroethanimidate Chemical compound CC(C)(C)OC(=N)C(Cl)(Cl)Cl CQXDYHPBXDZWBA-UHFFFAOYSA-N 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- LCVKHZVBMDXYAH-UHFFFAOYSA-N tert-butyl n-(5-cyanopyrazin-2-yl)-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=CN=C(C#N)C=N1 LCVKHZVBMDXYAH-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QTYBKWIPVOTUQI-UHFFFAOYSA-N tributyl(2,3-dihydrofuran-5-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CCCO1 QTYBKWIPVOTUQI-UHFFFAOYSA-N 0.000 description 1
- LWNCDBSQZPDFOG-UHFFFAOYSA-N tributyl(2-methylprop-1-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C(C)C LWNCDBSQZPDFOG-UHFFFAOYSA-N 0.000 description 1
- ZQMLPLBDZBCQCV-UHFFFAOYSA-N tributyl(3,4-dihydro-2h-pyran-6-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CCCCO1 ZQMLPLBDZBCQCV-UHFFFAOYSA-N 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- ISPSHPOFLYFIRR-UHFFFAOYSA-N trihexylsilicon Chemical compound CCCCCC[Si](CCCCCC)CCCCCC ISPSHPOFLYFIRR-UHFFFAOYSA-N 0.000 description 1
- 239000012178 vegetable wax Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/20—Nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- Glucokinase is one of four hexokinases that are found in mammals [Colowick, S.P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, NY, pages 1-48, 1973].
- the hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate.
- Glucokinase has a limited cellular distribution, being found principally in pancreatic ⁇ -cells and liver parenchymal cells.
- GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S.R., Kelly, K.L., and Ruderman, N.B. in Joslin 's Diabetes (C.R. Khan and G.C. Wier, eds.), Lea and Febiger, Philadelphia, PA, pages 97-115, 1994].
- concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM.
- the other three hexokinases are saturated with glucose at much lower concentrations ( ⁇ 1 mM).
- GK does indeed play a critical role in whole-body glucose homeostasis.
- Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grape, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J, 10, 1213-1218, 1996).
- An increase in glucose exposure is coupled through GK in ⁇ -cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
- GK gene is not found in the majority of patients with type II diabetes, compounds that activate GK, and thereby increase the sensitivity of the GK sensor system, will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes.
- Glucokinase activators will increase the flux of glucose metabolism in ⁇ - cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
- This invention provides a compound, comprising an amide of the formula:
- R 1 is a lower alkyl having from 1 to 5 carbon atoms
- R 2 is hydrogen, halo, nitro, cyano, methyl, trifluoromethyl, hydroxy, or methoxy;
- R 3 is cycloalkyl having from 4 to 6 carbons
- Y is independently selected from the group of CH and N to form a pyridine or pyrazine ring, respectively;
- R is a substituent in position 5 of the pyridine or pyrazine ring selected from
- Q is a 5-membered saturated, substituted, heterocyclic ring connected by a ring carbon atom, said heterocyclic ring containing two heteroatoms selected from nitrogen, sulfur and oxygen, and substituted at each of two ring carbons with an oxo group, and optionally substituted at the connecting ring carbon with a substituent which is methyl or amino;
- V is an unsubstituted or mono-substituted five-or six- membered saturated or unsaturated heterocyclic ring connected by a ring carbon, which said heterocyclic ring containing from one to three hetero atoms selected from sulfur, oxygen or nitrogen; said mono-substituted heterocyclic ring being a heterocyclic ring which is mono-substituted with a substituent selected from the group consisting of cyano, halo, nitro, amino, methyl, methoxy and hydroxy; [0007] or a nine-or ten- membered bicyclic heterocyclic ring connected by a ring carbon atom, said bicyclic heterocyclic ring containing one hetero atom seleced from the group consisting of oxygen, nitrogen or sulfur;
- R 5 is hydrogen or lower alkyl
- R 6 is lower alkyl
- R 8 is hydroxy, methoxy, or dimethylamine
- R 9 is hydrogen or methyl
- R 10 is lower alkyl, cyano, or -NH 2 ;
- R 1 ' is hydrogen, lower alkyl, or NHOH; m is 0, 1, 2, or 3; n is 0 or 1 ; p is 1 or 2;
- U is S, SO, or SO 2 ;
- Z is O, S, or NH
- the present invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or adjuvants. Furthermore, the present invention relates to the use of such compounds as therapeutic active substances as well as their use for the preparation of medicaments for the treatment of type II diabetes. The present invention further relates to processes for the preparation of the compounds of formula I. In addition, the present invention relates to a method for the prophylactic or therapeutic treatment of type II diabetes, which method comprises administering a compound of formula I to a human being or animal.
- this invention provides a compound, comprising an amide of the formula:
- R 1 is a lower alkyl having from 1 to 5 carbon atoms
- R 2 is hydrogen, halo, nitro, cyano, methyl, trifluoromethyl, hydroxy, or methoxy;
- R 3 is cycloalkyl having from 4 to 6 carbons
- Y is independently selected from the group of CH and N to form a pyridine or pyrazine ring, respectively;
- R 4 is a substituent in position 5 of the pyridine or pyrazine ring (N being ring position 1 and Y being ring position 4) selected from the group consisting of O R 6 O ⁇ CH 3 CH,
- Q is a 5-membered saturated, substituted, heterocyclic ring connected by a ring carbon atom, said heterocyclic ring containing two heteroatoms selected from nitrogen, sulfur and oxygen, and substituted at each of two ring carbons with an oxo group, and optionally substituted at the connecting ring carbon with a substituent which is methyl or amino;
- V is an unsubstituted or mono-substituted five-or six-membered saturated or unsaturated heterocyclic ring connected by a ring carbon, which said heterocyclic ring containing from one to three hetero atoms selected from sulfur, oxygen or nitrogen; said mono-substituted heterocyclic ring being a heterocyclic ring which is mono-substituted with a substituent selected from the group consisting of cyano, halo, nitro, amino, methyl, methoxy and hydroxy;
- bicyclic heterocyclic ring connected by a ring carbon atom, said bicyclic heterocyclic ring containing one hetero atom seleced from the group consisting of oxygen, nitrogen or sulfur;
- R 5 is hydrogen or lower alkyl
- R 6 is lower alkyl
- R 8 is hydroxy, methoxy, or dimethylamine
- R 9 is hydrogen or methyl;
- R 10 is lower alkyl, cyano, or -NH 2 ;
- R 1 ' is hydrogen, lower alkyl, or NHOH; m is 0, 1, 2, or 3; n is 0 or 1 ; p is 1 or 2; U is S, SO, or SO 2 ;
- Z is O. S, orNH
- the compound of formula I may be present either as a racemate or in the isolated “R" configuration at the asymmetric carbon shown. In a prefened embodiment, the "R" enantiomers are prefened. In another preferred embodiment, a compound of formula I is present as a racemic mixture at the chiral carbon upon which -CH 2 R 3 is a substituent.
- lower alkyl includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl.
- perfluoro- lower alkyl means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro.
- prefened perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
- cycloalkyl means a saturated hydrocarbon ring having from 3 to 10 carbon atoms, preferably from 4 to 6 carbon atoms.
- a prefened cycloalkyl is cyclopentyl.
- halogen and the term “halo” unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine, and iodine.
- a prefened halogen is chlorine.
- the "heterocyclic" ring defined under R 4 can be a saturated or unsaturated five- or six-membered ring having from one to three heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur and connected by a ring carbon atom, optionally through a linking methyl group, to position 5 of the pyridine or pyrazine ring shown in formula I.
- Unsaturated heterocyclic rings may be partially saturated or aromatic.
- the heterocyclic rings include, for example, pyridinyl and furanyl.
- Substituted heterocyclic rings are heterocyclic rings that may be substituted on a ring carbon by oxo, lower alkyl, amino, cyano, halo, nitro, amino, methoxy and hydroxy, for example.
- the prefened lower alkyl substituent is methyl.
- Prefened halo substituents are chloro and bromo.
- the ring carbon that is connected, optionally through a linking methyl group to the remainder of a formula I compound cannot contain any substituent.
- Bicyclic heterocyclic rings defined by R 4 may be a nine-or ten-membered bicyclic ring having one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and connected by a ring carbon atom, optionally through a linking methyl group, to position 5 of the pyridine or pyrazine ring.
- Such bicyclic heterocyclic rings include indole rings.
- aryl signifies aryl mononuclear aromatic hydrocarbon groups which are unsubstituted. Substituted aryl has ring substitution, unless otherwise indicated, on one or more positions with cyano halogen, nitro, amino lower alkyl, lower alkoxy or hydroxy substituents.
- aryl also signifies polynuclear aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aformentioned groups. Examples of aryl and substituted aryl include phenyl and tolyl. Prefened are phenyl groups.
- arylalkyl denotes an alkyl group, preferably lower alkyl, in which one of the hydrogen atoms can be replaced by an aryl group.
- arylalkyl groups are benzyl, 2- phenylethyl, 3 -phenylpropyl, 4-chlorobenzyl, 4-methoxybenzyl and the like.
- lower alkoxy includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy.
- lower alkanoic acid denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like.
- lower alkanoyl denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms such as propionoyl, acetyl and the like.
- aromatic acids denotes aryl alkanoic acids where aryl is as defined above and alkanoic contains from 1 to 6 carbon atoms.
- aroyl denotes aroic acids wherein aryl is as defined hereinbefore, with the hydroxy group of the COOH moiety removed. Among the prefened aroyl groups is benzoyl.
- lower alkyl thio means a lower alkyl group as defined above bound to a thio group which is bound to the rest of the molecule, for example, -SCH 3 .
- lower alkyl sulfmyl means a lower alkyl group as defined above bound to a sulfinyl group (sulfoxide) which is bound to the rest of the molecule.
- lower alkyl sulfonyl means a lower alkyl group as defined above bound to a sulfonyl group which is bound to the rest of the molecule.
- hydrolyzable ester or ether protecting groups designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective carboxy or hydroxy group.
- ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxylic acid.
- activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids.
- anhydrides are anhydrides derived from monocarboxylic acids such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxylic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloromethyl chloroformate and ethyl chloroformate being prefened.
- a suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers.
- Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or ⁇ -lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
- amino protecting group designates any conventional amino protecting group which can be cleaved to yield the free amino group.
- pharmaceutically acceptable salts include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, . ⁇ ra-toluene sulfonic acid and the like.
- pharmaceutically acceptable salts also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
- Prefened compounds of formula I include those in which R 1 is methyl, those in which R 2 is hydrogen or halo such as chlorine, and those in which R 3 is cyclopentyl.
- Prefened compounds of formula I also include those in which R 4 is (CH 2 ) n -Q, such as
- Prefened compounds in which R 4 is -(CH 2 ) n -V include those in which n (of- (CH 2 ) n -V) is zero and V is an unsubstituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to position 5 of the pyridine or pyrazine ring shown in formula I, with said five- or six-membered heteroaromatic ring containing one heteroatom selected from sulfur, oxygen or nitrogen.
- R 4 is an unsubstituted or mono-substituted six-membered aryl ring connected by a ring carbon atom to position 5 of the pyridine or pyrazine ring shown in formula I, said mono- substituted aryl ring being mono-substituted at a position on a ring carbon atom other than the said connecting carbon atom with a substituent selected from the group consisting of chloro, bromo, nitro, amino, methyl, or methoxy or hydroxy.
- R 4 is an unsubstituted or mono-substituted 6-membered aryl ring selected from the group consisting of unsubstituted aryl, aryl substituted with methoxy and aryl substituted with hydroxy.
- R 4 is an unsubstituted or substituted heteroaromatic ring selected from the group consisting of:
- R 4 is a substituted heteroaromatic ring selected from the group consisting of:
- R is a bicyclic heteroaromatic ring which is
- R 12 is an unbranched alkyl chain of 2 or 3 carbon atoms wherein the chain, in combination with the oxygen atoms to which it is bonded, forms a five-or six membered- ring.
- R 10 is as indicated above.
- Prefened R , 10 groups of formula II are methyl or -NH .
- the prefened p value is 1.
- the prefened R 8 is hydroxy or dimethylamine.
- the configuration at the chiral carbon of R 4 is R.
- R is 0) OH
- the configuration at the chiral carbon of R is R.
- the compound of formula I are those wherein R 4 is
- R 4 is in the S configuration.
- Preferable compounds in accordance with the present invention are selected from the group consistmg of:
- compounds in accordance with the present invention are selected from:
- compounds of the present invention are selected from:
- R 20 is lower alkyl sulfonyl or a functional group that will be converted into a lower alkyl sulfone (such as the methylthio group or a halo group, preferably chloro or fluoro);
- R 1 , R 2 , R 3 , R 4 , R 6 , and Y are as above.
- the carboxylic acids of formula V wherein R 2 is hydrogen and R 20 is mercapto [4-(mercapto)phenylacetic acid], methylthio [4-(methylthio)phenylacetic acid], or methylsulfonyl [4-(methylsulfonyl)phenylacetic acid] are commercially available.
- the carboxylic acid of formula V wherein R 2 is trifluoromethyl and R 20 is fluoro [4-fluoro-3- (trifluoromethyl)phenyl acetic acid], and the carboxylic acid of formula V wherein R 2 is nitro and R 20 is chloro [4-chloro-3-nitrophenyl acetic acid] are also commercially available. If necessary for further chemical modification to produce the desired substitutions at R and R , the carboxylic acids can be converted to the conesponding esters of lower alkyl alcohols using any conventional esterification methods.
- the known 4-(mercapto)phenylacetic acid can be used as a starting material.
- the compound of formula V where R 2 is hydrogen and R 20 is mercapto can be alkylated by conventional methods (for example, with a lower alkyl halide) to the conesponding lower alkyl thio compounds of formula V.
- the lower alkyl thio compounds can then be converted to the conesponding lower alkyl sulfonyl compounds of formula V by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the conesponding sulfone group can be utilized to effect this conversion.
- R 20 is lower alkyl sulfonyl
- the known 2-halothiophenols can be used as starting materials.
- the mercapto group can be alkylated by conventional methods (for example, with a lower alkyl halide) to the corresponding 2-halo-l -lower alkyl thio benzenes. These compounds can then be converted to the conesponding 3- halo-4-(lower alkyl thio)-phenyl acetic acids.
- the 2-halo-l -lower alkyl thio benzenes can be acylated with a (lower alkyl)oxalyl chloride (such as methyloxalyl chloride or ethyloxalyl chloride) via a Friedel-Crafts acylation to produce the alpha-keto carboxylic ester in the position para to the lower alkyl thio functional group.
- the alpha- keto carboxylic ester can then be hydrolyzed by any conventional method for converting an alpha-keto carboxylic ester to an alpha-keto carboxylic acid.
- This compound can be converted to the compounds of formula V wherein R 2 is nitro and R 20 is lower alkyl thio. Any conventional method for the nucleophilic displacement of an aromatic chlorine group with a lower alkyl thiol can be utilized to effect this conversion (Synthesis 1983, 751-755).
- R 2 is nitro and R 20 is lower alkyl thio
- they can be converted to the corresponding compounds of formula N wherein R 2 is nitro and R 20 is lower alkyl sulfonyl by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the conesponding sulfone group can be utilized to effect this conversion.
- any conventional method for the nucleophilic displacement of an aromatic chlorine group with a lower alkane sulfinate can be utilized to effect this conversion (J. Org. Chem., 1989, 54, 4691-4692).
- the commercially available 2-methylthiophenol can be used as starting material.
- the mercapto group may be alkylated by conventional methods (for example, with a lower alkyl halide) to the conesponding 2- methyl-1 -lower alkyl thio benzenes. These compounds can then be converted to the conesponding 3-methyl-4-(lower alkyl thio)-phenyl acetic acids.
- the 2-methyl-l- lower alkyl thio benzenes can be acylated with a (lower alkyl)oxalyl chloride (such as methyloxalyl chloride or ethyloxalyl chloride) via a Friedel-Crafts acylation to produce the alpha-keto carboxylic ester in the position para to the lower alkyl thio functional group.
- the alpha-keto carboxylic ester can then be hydrolyzed by any conventional method for converting an alpha-keto carboxylic ester to an alpha-keto carboxylic acid.
- Any conventional method for the demethylation of an aromatic methoxy group to an aromatic hydroxy group can be utilized to effect this conversion.
- This compound of formula N wherein R 2 is hydroxy and R is lower alkyl sulfonyl would have to be protected throughout the remaining reaction scheme.
- the aromatic hydroxy group may be protected via a conventional hydrolyzable ether protecting group.
- the ether protecting group can then be removed to produce the respective hydroxy group conesponding to the desired compound of formula I wherein R 2 is hydroxy.
- this compound can be converted to the desired compound of formula I wherein R 2 is hydroxy.
- Any conventional method for the demethylation of an aromatic methoxy group to an aromatic hydroxy group can be utilized to effect this conversion
- the carboxylic acids of formula V can be directly alkylated or first converted to the conesponding esters of lower alkyl alcohols of formula VI using any conventional esterification methods and then alkylated.
- the alkyl halide of formula VII is reacted with the dianion of formula V to produce the compound of formula IX or reacted with the anion of formula VI to produce the compound of formula VIII.
- the compounds of formula V and VI represent an organic acid and an organic acid derivative having an alpha carbon atom
- the compound of formula VII is an alkyl halide so that alkylation occurs at the alpha carbon atom of the carboxylic acid and the carboxylic acid ester.
- This reaction is carried out by any conventional means of alkylation of the alpha carbon atom of a carboxylic acid or a lower alkyl ester of a carboxylic acid.
- an alkyl halide is reacted with the dianion of the acetic acid or the anion generated from an acetic acid ester.
- the anion can be generated by using a strong organic base such as lithium diisopropylamide or n-butyl lithium as well as other organic lithium bases.
- a strong organic base such as lithium diisopropylamide or n-butyl lithium as well as other organic lithium bases.
- low boiling ether solvents are utilized such as tetrahydrofuran at low temperatures, from -80°C to about -10°C being prefened. However, any temperature from -80°C to room temperature can be used.
- the alkylation reactions may proceed using a triflate alkylation subunit instead of the halo alkylation subunit of compound VII. These triflate alkylation reactions can be performed according to procedures well-known in the art of synthetic organic chemistry.
- the compound of formula VIII can be converted to the compound of formula IX by any conventional procedure for converting a carboxylic acid ester to a carboxylic acid.
- the compound of formula IX is then condensed with the compounds of formula X via conventional peptide coupling to produce the compounds of formula I.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- alkyl halides of formula VII wherein R 3 is cyclobutyl [cyclobutylmethyl bromide] or cyclohexyl [cyclohexylmethyl bromide] are commercially available.
- the alkyl halide of formula VII wherein R 3 is cyclopentyl [iodomethylcyclopentane] is known in the chemical literature, and a synthesis of this compound is described in the Examples.
- amino heteroaromatic compounds of formula X are known in the chemical literature or can be prepared from those skilled in the art by using adaptations of standard synthetic transformations reported in the chemical literature.
- the synthetic conversions described herein to produce the desired R 4 substituents can take place either before or after the compounds of formula X are converted to the compounds of formula I.
- the bromo substituent can be converted to the compounds of formula X wherein R 4 is a methylthio substituent.
- Any conventional method for the nucleophilic displacement of an aromatic bromo substituent with sodium thiomethoxide can be utilized to effect this conversion (Tetrahedron 2002, 58, 1125-1129).
- the resulting compounds of formula X wherein R 4 is methylthio can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is methylthio.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of tert-butyl alcohol can provide the compounds of formula X wherein R 4 is methyl and wherein the amino group is protected as the tert-butyl carbamate.
- the 5-(methyl)heteroaromatic-2-carbamic acid tert-butyl ester can then be brominated to afford the 5-(bromomethyl)heteroaromatic-2-carbamic acid tert-butyl ester. Any conventional method of benzylic bromination can be utilized to effect this conversion.
- the resulting 5-(bromomethyl) substituent can then be converted to the conesponding 5-[(methylthio)methyl] substituent.
- any conventional method for the nucleophilic displacement of a benzylic bromide with sodium thiomethoxide can be utilized to effect this conversion.
- Deprotection of the tert- butyl carbamate under standard conditions can provide the desired amino heteroaromatic compounds of formula X wherein R 4 is (methylthio)methyl.
- the resulting compounds of formula X wherein R 4 is (methylthio)methyl can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is (methylthio)methyl.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the compounds of formula I wherein R 4 is bromo can be used as starting materials.
- the aforementioned known compounds of formula X wherein R 4 is bromo can be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is bromo.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the bromo substituent can then be converted to the compounds of formula I wherein R 4 is cyano.
- Any conventional method for the nucleophilic displacement of an aromatic bromo substituent with a cyano group transferring agent [such as copper(I) cyanide] can be utilized to effect this conversion.
- the resulting cyano substituent can then be converted to compounds of formula I wherein R 4 is an N- (hydroxy)-carboximidamide substituent (an amidoxime substituent).
- Any conventional method for converting a cyano substituent to an N-(hydroxy)-carboximidamide substituent (an amidoxime substituent) can be utilized to effect this conversion.
- (cyano-hydroxyimino-methyl) substituent the aforementioned compounds of formula X wherein R 4 is methyl and wherein the amino group is protected as the tert-butyl carbamate can be used as starting materials.
- the 5-(methyl)heteroaromatic-2-carbamic acid acid tert-butyl ester can then be brominated to afford the 5- (bromomethyl)heteroaromatic-2-carbamic acid tert-butyl ester. Any conventional method of benzylic bromination can be utilized to effect this conversion.
- the resulting 5- (bromomethyl) substituent can then be converted to the conesponding 5-(cyanomethyl) substituent.
- any conventional method for the nucleophilic displacement of a benzylic bromide with a cyano group transferring agent can be utilized to effect this conversion.
- Deprotection of the tert-butyl carbamate under standard conditions can provide the desired amino heteroaromatic compounds of formula X wherein R 4 is cyanomethyl.
- the resulting compounds of formula X wherein R 4 is cyanomethyl can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 cyanomethyl.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the cyanomethyl substituent can then be converted to compounds of formula I wherein R 4 is a (cyano-hydroxyimino-methyl) substituent. Any conventional method for converting a cyanomethyl substituent to (cyano-hydroxyimino- methyl) substituent can be utilized to effect this conversion (US4539328).
- the bromo substituent in the compounds of formula I can be directly converted to the compounds of formula I wherein R 4 is a 3 -substituted- 1-propyne substituent or a 4-substituted-l-butyne substituent, -C ⁇ C-(CH 2 ) P -R 8 , and R 8 is hydroxy, methoxy, or dimethylamine and p is 1 or 2.
- Any conventional method for the catalytic substitution of an acetylenic hydrogen for example, propargyl alcohol and 3-butyn-l-ol
- an aryl bromide such as the Sonogashira reaction
- a two-step procedure which involves a Pummerer methyl sulfoxide reanangement using trifluoroacetic anhydride followed by hydrolysis of the Pummerer reanangement intermediate with triethylamine and methanol can be utilized to effect this conversion.
- R 4 is thiol
- these compounds can be converted to the compounds of formula I wherein R 4 is sulfonyl chloride. Any conventional method of oxidizing a thiol substituent to a sulfonyl chloride substituent can be utilized to effect this conversion.
- the carboxylic acid can be esterified and the methyl group can be converted to the NN-dimethyl-ethenamine concurrently using dimethylformamide dimethylacetal.
- the aromatic NN-dimethyl-ethenamine functionality can then be oxidatively cleaved to produce the conesponding heteroaromatic aldehyde. Any conventional method of oxidatively cleaving a vinyl dimethyl amine to an aldehyde can be utilized to effect this conversion.
- the resulting heteroaromatic aldehyde can then be converted to the conesponding heteroaromatic dimethyl acetal. Any conventional method for converting an aldehyde to a dimethyl acetal can be utilized to effect this conversion.
- the resulting 5-(dimethoxymethyl)heteroaromatic-2-carboxylic acid methyl ester can then be converted to the conesponding carboxylic acid. Any conventional means of hydrolyzing a carboxylic acid ester to the carboxylic acid under basic conditions can be utilized to effect this conversion.
- (dimethoxymethyl)heteroaromatic-2-carboxylic acid can be converted to the conesponding acyl azide. Any conventional method for converting a carboxylic acid to an acyl azide can be utilized to effect this conversion. Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of benzyl alcohol can provide the compounds of formula X wherein R 4 is dimethoxymethyl and wherein the amino group is protected as the benzyl carbamate. Deprotection of the benzyl carbamate under standard hydrogenation conditions can provide the desired compounds of formula X wherein R 4 is dimethoxymethyl.
- Any conventional method of reacting an aldehyde with ethylene glycol to produce a 1,3-dioxolane cyclic acetal or reacting an aldehyde with 1,3- propanediol to produce a 1,3-dioxane cyclic acetal can be utilized to effect this conversion.
- the desired cyclic acetals are produced, the remaining sequence of reactions as described above are utilized to produce the compounds of formula I wherein R 4 is l,3-dioxolan-2-yl or wherein R 4 is l,3-dioxan-2-yl.
- the NN-dimethyl-ethenamine functionality can then be hydrolyzed to produce the conesponding aldehyde. Any conventional method of hydrolyzing an enamine to an aldehyde can be utilized to effect this conversion.
- the resulting heteroaromatic acetaldehyde can then be converted to the conesponding dimethyl acetal. Any conventional method for converting an aldehyde to a dimethyl acetal can be utilized to effect this conversion.
- the resulting 5-[2,2-(dimethoxy)ethyl]heteroaromatic-2- carboxylic acid methyl ester can then be converted to the conesponding carboxylic acid.
- any conventional means of hydrolyzing a carboxylic acid ester to the carboxylic acid under basic conditions can be utilized to effect this conversion.
- the 5-[2,2- (dimethoxy)ethyl]heteroaromatic-2-carboxylic acid can be converted to the conesponding acyl azide.
- Any conventional method for converting a carboxylic acid to an acyl azide can be utilized to effect this conversion.
- Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of benzyl alcohol can provide the compounds of formula X wherein R 4 is 2,2-(dimethoxy)ethyl and wherein the amino group is protected as the benzyl carbamate.
- Deprotection of the benzyl carbamate under standard hydrogenation conditions can provide the desired compounds of formula X wherein R 4 is 2,2-(dimethoxy)ethyl.
- the resulting compounds of formula X wherein R 4 is 2,2-(dimethoxy)ethyl can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is 2,2-(dimethoxy)ethyl.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- Any conventional method of reacting an aldehyde with ethylene glycol to produce a 1,3-dioxolane cyclic acetal or reacting an aldehyde with 1,3- propanediol to produce a 1,3 -dioxane cyclic acetal can be utilized to effect this conversion.
- the desired cyclic acetals are produced, the remaining sequence of reactions as described above are utilized to produce the compounds of formula I wherein R 4 is (l,3-dioxolan-2-yl)methyl or wherein R 4 is (l,3-dioxan-2-yl)methyl.
- the 5-chloro substituent can be displaced to produce a 5-allyloxy substituent
- the 2-carboxylic acid methyl ester substituent can be hydrolyzed to produce to the 2-carboxylic acid concurrently using allyl alcohol and potassium hydroxide under heating conditions, preferably from 90°C to 100°C.
- the 5-[allyloxy]heteroaromatic-2-carboxylic acid can be converted to the conesponding acyl azide. Any conventional method for converting a carboxylic acid to an acyl azide can be utilized to effect this conversion.
- Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of tert-butyl alcohol can provide the compounds of formula X wherein R 4 is an allyloxy substituent and wherein the amino group is protected as the tert-butyl carbamate.
- Deprotection of the tert-butyl carbamate under standard acidic conditions can provide the desired compounds of formula X wherein R 4 is an allyloxy substituent.
- the resulting compounds of formula X wherein R 4 is an allyloxy substituent can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is an allyloxy substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- R 4 is allyloxy
- they can be converted to the desired compounds of formula I wherein R 4 is a [2(S),3- dihydroxy-propoxyl] substituent, a [2(R),3-dihydroxy-propoxyl] substituent, or a (2,3- dihydroxy-propoxyl) substituent.
- the allyloxy substituent can be subjected to Sharpless asymmetric dihydroxylation conditions to produce the desired chiral diols (Chem. Rev. 1994, 94, 2483-2547; J. Chem. Soc, Perkin Trans.
- the compounds of formula I wherein R 4 is allyloxy can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQ) 2 PHAL [hydroquinine 1,4-phthalazinediyl diether] to produce the desired compounds of formula I wherein R 4 is a [2(R),3- dihydroxy-propoxyl] substituent. If the compounds of formula I wherein R 4 is allyloxy are subjected to conventional non-asymmetric dihydroxylation conditions, the racemic diols of formula I wherein R 4 is a (2,3-dihydroxy-propoxyl) substituent can be produced.
- the prefened stereoconfiguration at the chiral center with the hydroxyl functional group is "R.”
- R 4 is a (2,3- dihydroxy-propyl) substituent
- the known amino heteroaromatic compounds of formula X wherein R 4 is bromo can be used as starting materials.
- the bromo substituent can be directly converted to the compounds of formula X wherein R 4 is an allyl substituent.
- the palladium-mediated Stille coupling reaction of the heteroaromatic bromo substituent with the commercially available allyltri--j-butyltin can be utilized to effect this conversion.
- the resulting compounds of formula X wherein R 4 is an allyl substituent can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is an allyl substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the compounds of formula I wherein R 4 is allyl are available, they can be converted to the desired compounds of formula I wherein R 4 is a [2(R),3-dihydroxy- propyl] substituent, a [2(S),3-dihydroxy-propyl] substituent, or a (2,3-dihydroxy-propyl) substituent.
- the allyl substituent can be subjected to Sharpless asymmetric dihydroxylation conditions to produce the desired chiral diols.
- the compounds of formula I wherein R 4 is allyl can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQD) 2 PHAL to produce the desired compounds of formula I wherein R 4 is a [2(R),3-dihydroxy-propyl] substituent.
- the compounds of formula I wherein R is allyl can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQ) 2 PHAL to produce the desired compounds of formula I wherein R 4 is a [2(S),3-dihydroxy-propyl] substituent.
- the racemic diols of formula I wherein R is a (2,3-dihydroxy-propyl) substituent can be produced.
- the prefened stereoconfiguration at the chiral center with the hydroxyl functional group is "R.”
- the resulting compounds of formula X wherein R 4 is a vinyl substituent can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is a vinyl substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the compounds of formula I wherein R 4 is vinyl are available, they can be converted to the desired compounds of formula I wherein R 4 is a [l(R),2-dihydroxy- ethyl] substituent, a [l(S),2-dihydroxy-ethyl] substituent, or a (1,2-dihydroxy-ethyl) substituent.
- the vinyl substituent can be subjected to Sharpless asymmetric dihydroxylation conditions to produce the desired chiral diols.
- the compounds of formula I wherein R 4 is vinyl can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQD) 2 PHAL to produce the desired compounds of formula I wherein R 4 is a [l(R),2-dihydroxy-ethyl] substituent.
- the compounds of formula I wherein R is vinyl can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQ) 2 PHAL to produce the desired compounds of formula I wherein R 4 is a [l(S),2-dihydroxy-ethyl] substituent.
- the racemic diols of formula I wherein R 4 is a (1,2-dihydroxy-ethyl) substituent can be produced.
- the prefened stereoconfiguration at the chiral center with the hydroxyl functional group is "S.”
- the known amino heteroaromatic compounds of formula X wherein R 4 is bromo can also be used as starting materials.
- the bromo substituent can be directly converted to the compounds of formula X wherein R 4 is an isobutenyl substituent.
- the palladium-mediated Stille coupling reaction of the heteroaromatic bromo substituent with the known isobutenyltri-n-butyltin can be utilized to effect this conversion.
- R 4 isobutenyl
- R 4 is a [1(R),2- dihydroxy-2-methyl-propyl] substituent, a [l(S),2-dihydroxy-2-methyl-propyl] substituent, or a (l,2-dihydroxy-2-methyl-propyl) substituent.
- the isobutenyl substituent can be subjected to Sharpless asymmetric dihydroxylation conditions to produce the desired chiral diols.
- the compounds of formula I wherein R 4 is isobutenyl can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQD) 2 PHAL to produce the desired compounds of formula I wherein R 4 is a [1(R),2- dihydroxy-2-methyl-propyl] substituent.
- the compounds of formula I wherein R 4 is isobutenyl can be subjected to conventional Sharpless asymmetric dihydroxylation conditions using (DHQ) 2 PHAL to produce the desired compounds of formula I wherein R 4 is a [l(S),2-dihydroxy-2-methyl-propyl] substituent.
- the racemic diols of formula I wherein R is a (l,2-dihydroxy-2-methyl-propyl) substituent can be produced.
- the prefened stereoconfiguration at the chiral center with the hydroxyl functional group is "S.”
- the bromo substituent can be directly converted to the compounds of formula X wherein R 4 is a (2-methoxy-ethylamino) substituent or wherein R 4 is a (2-methoxy-ethoxy) substituent.
- Any conventional method for the nucleophilic displacement of an aromatic bromo substituent with 2-methoxyethylamine or 2- methoxyethanol, respectively, can be utilized to effect this conversion.
- the nitro substituent can be converted to the amino heteroaromatic compounds of formula X wherein R 4 is the desired (2-methoxy-ethylamino) substituent or the desired (2-methoxy- ethoxy) substituent. Any conventional method for the reduction of a nitro substituent to an amino substituent can be utilized to effect this conversion.
- the nitro substituent can be converted to the amino heteroaromatic compounds of formula X wherein R 4 is the [2-(tetrahydropyran-2-yloxy)-ethylamino] substituent or the [2-(tetrahydropyran-2- yloxy)-ethoxy] substituent. Any conventional method for the reduction of a nitro substituent to an amino substituent can be utilized to effect this conversion.
- the nitro substituent can be converted to the amino heteroaromatic compounds of formula X wherein R 4 is the desired methanesulfonylamino substituent. Any conventional method for the reduction of a nitro substituent to an amino substituent can be utilized to effect this conversion.
- These compounds of formula X wherein R 4 is methanesulfonylamino can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is a methanesulfonylamino substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the nitro substituent can be converted to the heteroaromatic amines of formula X wherein R 4 is dimethylamino. Any conventional method for the reduction of a nitro substituent to an amino substituent can be utilized to effect this conversion.
- These compounds of formula X wherein R 4 is dimethylamino can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is dimethylamino.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the carboxylic acid can be converted to the conesponding methyl ester. Any conventional esterification method for converting a carboxylic acid to a carboxylic acid methyl ester can be utilized to effect this conversion.
- the 5-(methyl)heteroaromatic-2-carboxylic acid methyl ester can then be brominated to afford the 5-(bromomethyl)heteroaromatic-2-carboxylic acid methyl ester.
- any conventional method of benzylic bromination can be utilized to effect this conversion.
- the resulting bromomethyl substituent can then be converted to the conesponding (dimethylamino)methyl substituent.
- any conventional method for the nucleophilic displacement of a benzylic bromide with dimethylamine can be utilized to effect this conversion.
- the resulting 5-[(dimethylamino)methyl]heteroaromatic-2- carboxylic acid methyl ester can then be converted to the conesponding carboxylic acid. Any conventional means of hydrolyzing a carboxylic acid ester to the carboxylic acid can be utilized to effect this conversion.
- [(dimethylamino)methyl]heteroaromatic-2-carboxylic acid can be converted to the conesponding acyl azide. Any conventional method for converting a carboxylic acid to an acyl azide can be utilized to effect this conversion. Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of benzyl alcohol can provide the compounds of formula X wherein R 4 is (dimethylamino)methyl and wherein the amino group is protected as the benzyl carbamate. Deprotection of the benzyl carbamate under standard hydrogenation conditions can provide the desired amino heteroaromatic compounds of formula X wherein R 4 is (dimethylamino)methyl.
- the heteroaromatic NN-dimethyl-ethenamine substituent can then be reduced to produce the conesponding heteroaromatic 2- (dimethylamino) ethyl substituent.
- Any conventional method for the reduction of a carbon-carbon double bond to a saturated hydrocarbon can be utilized to effect this conversion.
- the resulting 5-[2-(dimethylamino)ethyl]heteroaromatic-2-carboxylic acid methyl ester can then be converted to the conesponding carboxylic acid. Any conventional means of hydrolyzing a carboxylic acid ester to the carboxylic acid can be utilized to effect this conversion.
- the 5-[2-(dimethylamino)ethyl]heteroaromatic-2- carboxylic acid can be converted to the conesponding acyl azide.
- Any conventional method for converting a carboxylic acid to an acyl azide can be utilized to effect this conversion.
- Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of benzyl alcohol can provide the compounds of formula X wherein R 4 is 2- (dimethylamino) ethyl and wherein the amino group is protected as the benzyl carbamate.
- Deprotection of the benzyl carbamate under standard hydrogenation conditions can provide the desired amino heteroaromatic compounds of formula X wherein R 4 is 2- (dimethylamino)ethyl.
- the resulting compounds of formula X wherein R 4 is 2- (dimethylamino) ethyl can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is 2-(dimethylamino) ethyl.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the compounds of formula I wherein R 4 is 3- (dimethylamino)propyl
- the compounds of formula I wherein R 4 is bromo can be used as starting materials.
- the aforementioned known compounds of formula X wherein R 4 is bromo can be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is bromo.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the bromo substituent can then be converted to compounds of formula I wherein R 4 is a 3-(dimethylamino)-l- propyne substituent.
- Any conventional method for the catalytic substitution of the acetylenic hydrogen of l-dimethylamino-2-propyne with an aryl bromide, such as the Sonogashira reaction, can be utilized to effect this conversion.
- the compounds of formula I wherein R 4 is 3-(dimethylamino)-l-propyne are available, they can be converted to the desired compounds of formula I wherein R 4 is 3-(dimethylamino)propyl.
- the heteroaromatic 3 -(dimethylamino)- 1-propyne substituent can be reduced to produce the conesponding heteroaromatic 3-(dimethylamino)propyl substituent. Any conventional method for the reduction of an alkyne to a saturated hydrocarbon can be utilized to effect this conversion.
- the aforementioned compounds of formula I wherein R 4 is bromo can be used as starting materials. Once the compounds of formula I wherein R 4 is bromo are available, the bromo substituent can then be converted to compounds of formula I wherein R 4 is a formyl substituent. Any conventional method for the carbonylation of an aryl bromide can be utilized to effect this conversion.
- the amino group can be protected using any conventional amino protecting group which can be cleaved to yield the free amino group, the prefened group being the trimethylacetyl amino protecting group.
- the bromo substituent can be directly converted to the compounds of formula X wherein R 4 is an acetyl substituent and wherein the amino group is protected as the trimethylacetyl amide.
- the palladium-mediated Stille coupling reaction of the heteroaromatic bromo substituent with the commercially available 1-ethoxyvinyl-tri-n-butyltin followed by acid hydrolysis of the intermediate ethyl enol ether can be utilized to effect this conversion (Synthesis 1997, 1446-1450).
- the compounds of formula X wherein R 4 is an acetyl substituent and wherein the amino group is protected as the trimethylacetyl amide can be converted to the compounds of formula X wherein R 4 is a methylhydantoin substituent and wherein the amino group is protected as the trimethylacetyl amide using the Bucherer-Bergs reaction conditions (Bioorg. Med. Chem, Lett. 2001, 11(6), 777-780). Deprotection of the trimethylacetyl amide under standard basic conditions can provide the desired amino heteroaromatic compounds of formula X wherein R 4 is methylhydantoin.
- the bromo substituent can be directly converted to the compounds of formula X wherein R 4 is the aforementioned unsubstituted or mono-substituted five- or six-membered heteroaromatic rings.
- Any conventional method for the palladium-mediated coupling of an aromatic bromo substituent with a heteroaromatic boronic acid (such as the Suzuki coupling reaction) or with a heteroaromatic stannyl reagent (such as the Stille coupling reaction) can be utilized to effect this conversion.
- the resulting compounds of formula X wherein R 4 is the desired unsubstituted or mono-substituted five- or six-membered heteroaromatic ring can then be condensed with the compounds of formula DC via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is the desired unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to position 5 of the pyridine or pyrazine ring, with said five- or six-membered heteroaromatic ring containing one heteroatom selected from sulfur, oxygen or nitrogen; said mono-substituted heteroaromatic ring being mono-substituted at a position on a ring carbon atom other than the said connecting carbon atom with a substituent selected from the group consisting of cyano, chloro, bromo, nitro, amino, methyl, methoxy or hydroxy.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- R is a nine- or ten-membered bicyclic heteroaromatic ring having one heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur and connected by a ring carbon atom
- these compounds can be prepared according to the reaction sequence described above using the desired fused heteroaromatic boronic acid or fused heteroaromatic stannyl reagents.
- R 4 is an unsubstituted or mono-substituted aryl ring connected by a ring carbon atom to position 5 of the pyridine or pyrazine ring, with said aryl ring containing six carbon atoms; said mono-substituted aryl ring being mono-substituted at a position on a ring carbon atom other than the said connecting carbon atom with a substituent selected from the group consisting of cyano, chloro, bromo, nitro, amino, methyl, methoxy or hydroxy, the aforementioned known amino heteroaromatic compounds of formula X wherein R 4 is bromo can also be used as starting materials.
- the bromo substituent can be directly converted to the compounds of formula X wherein R 4 is the aforementioned unsubstituted or mono-substituted aryl ring.
- Any conventional method for the palladium-mediated coupling of an aromatic bromo substituent with a heteroaromatic boronic acid, such as the Suzuki coupling reaction, can be utilized to effect this conversion.
- amino heteroaromatic compounds of formula X wherein R 4 is a (tetrahydro-furan-2-yl) substituent are available, they can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is a (tetrahydro-furan-2-yl) substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- Any conventional method for the nucleophilic addition of ethylenediamine to an aromatic cyano group can be utilized to effect this conversion (Bioorg. Med. Chem. 2001, 9(3), 585-592).
- the compounds of formula X wherein R is an imidazoline substituent can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is an imidazoline substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the 5-[chloro]heteroaromatic-2- carboxylic acid tert-butyl ester can then be converted to the conesponding 5- [fluoro]heteroaromatic-2-carboxylic acid tert-butyl ester using silver(I) fluoride in acetonitrile (J. Med. Chem. 1995, 38, 3902-3907).
- the 5-[fluoro]heteroaromatic-2- carboxylic acid tert-butyl ester can then be converted to the compounds of formula X wherein R 4 is a tert-butyl carboxylate substituent.
- Any conventional method for the nucleophilic displacement of an aromatic fluoro group with ammonia to afford an aromatic amino group can be utilized to effect this conversion.
- the resulting compounds of fonnula X wherein R 4 is a tert-butyl carboxylate substituent can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is a tert-butyl carboxylate substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- any conventional method for reacting a carboxylic acid with the commercially available O-(tert-butyl)hydroxylamine hydrochloride to from the conesponding carboxylic acid tert-butoxy amide analog can be utilized to effect this conversion.
- the nitro substituent can be converted to the amino heteroaromatic compounds of formula X wherein R 4 is the desired (malonic acid dialkyl ester) substituent. Any conventional method for the reduction of a nitro substituent to an amino substituent can be utilized to effect this conversion.
- These compounds of formula X wherein R 4 is a (malonic acid dialkyl ester) substituent can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is a (malonic acid dialkyl ester) substituent.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- the (malonic acid dialkyl ester) substituent can then be converted to the compounds of formula I wherein R 4 is a (bis-hydroxymethyl)methyl substituent.
- Any conventional method for the reduction of an ester to an alcohol can be utilized to effect this conversion.
- the chloro substituent on the resulting 5-[chloro]heteroaromatic-2- carboxylic acid (bis-benzyloxymethyl)methyl ester can be directly displaced with 1,3- dibenzyloxy-2-propanol to produce the conesponding 5-[(bis- benzyloxymethyl)methoxy]heteroaromatic-2-carboxylic acid (bis- benzyloxymethyl)methyl ester
- Any conventional method for the nucleophilic displacement of an aromatic chloro substituent with a secondary alcohol can be utilized to effect this conversion.
- Curtius reanangement involving pyrolysis of the resulting acyl azide in the presence of tert-butyl alcohol can provide the compounds of formula X wherein R 4 is (bis-benzyloxymethyl)methoxy and wherein the amino group is protected as the tert-butyl carbamate.
- Deprotection of the tert-butyl carbamate under standard conditions can provide the desired amino heteroaromatic compounds of formula X wherein R 4 is (bis-benzyloxymethyl)methoxy.
- the resulting compounds of formula X wherein R 4 is (bis-benzyloxymethyl)methoxy can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R 4 is (bis- benzyloxymethyl)methoxy.
- any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
- Deprotection of the benzyl ethers under standard hydrogenation conditions can provide the desired compounds of formula I wherein R is a (bis- hydroxymethyl)methoxy substituent.
- the compounds of formula I have an asymmetric carbon atom through which the group -CH R 3 and the amide substituents are connected. In accordance with this invention, the prefened stereoconfiguration at this carbon is "R.”
- the compounds of formula V where R 20 is lower alkyl thio and R 2 is as described above are first converted to the pseudoephedrine amides using lR,2R-(-)-pseudoephedrine as the desired enantiomer of pseudoephedrine.
- Any conventional method for converting a carboxylic acid to a carboxamide can be utilized to effect this conversion.
- the pseudoephedrine amides can undergo highly diastereoselective alkylations with alkyl halides to afford the ⁇ -substituted amide products conesponding to formula DC.
- R carboxylic acids of formula DC where R 20 is lower alkyl thio and R 2 is as described above by conventional acidic hydrolysis methods for converting a carboxamide to a carboxylic acid.
- R carboxylic acids of formula IX where R is lower alkyl thio and R 2 is as described above can be converted to the R isomers of formula I where R 20 is lower alkyl thio and R 2 is as described above.
- any conventional method of condensing a primary amine with a carboxylic acid, without racemization can be utilized to effect this conversion.
- R carboxylic acids of formula IX where R 20 is lower alkyl thio and R 2 is as described above can first be oxidized to the R compounds of formula DC where R is lower alkyl sulfonyl and R is as described above. Any conventional method of oxidizing an alkyl thio substituent to the conesponding sulfone group can be utilized to effect this conversion. These compounds can be then converted to the corresponding R compounds of formula I where R 20 is lower alkyl sulfonyl and R 2 is as described above. In canying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid, without racemization, can be utilized to effect this conversion.
- Another chemical means to produce the R or S isomer of the compounds of formula I is to react the compound of formula IX with an optically active base.
- Any conventional optically active base can be utilized to carry out this resolution.
- the prefened optically active bases are the optically active amine bases such as alpha- methylbenzylamine, quinine, dehydroabietylamine, and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
- the compound of formula IX is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula IX.
- temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure.
- the R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula IX in the R and S configuration by hydrolysis with an acid.
- prefened acids are dilute aqueous acids, i.e., from about 0.00 IN to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid.
- aqueous acids such as aqueous sulfuric or aqueous hydrochloric acid.
- the configuration of formula IX which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomers of formula I.
- the resolution of racemates of the compounds of the formula DC can also be achieved via the formation of conesponding diastereomeric esters or amides.
- These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula IX with a chiral alcohol or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine.
- the corresponding diastereomers of compounds of the formula IX can then be separated using any conventional separation methods.
- the resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the conesponding pure R or S isomers.
- the hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ester or an amide without racemization.
- the separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters conesponding to the compound of the formula VIII (Tetrahedron Lett. 1989, 30, 7053-7056), which results in the formation of conesponding chiral acid and chiral ester.
- the ester and the acid can be separated by any conventional method of separating an acid from an ester.
- the configuration of formula VIII which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomers of formula I.
- the resolution of racemates of the compounds of the formula IX can also be achieved via the formation of conesponding diastereomeric esters or amides.
- These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula IX with a chiral alcohol or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine.
- the conesponding diastereomers of compounds of the formula IX can then be separated using any conventional separation methods.
- the resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the conesponding pure R or S isomers.
- the hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ester or an amide without racemization.
- the separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters conesponding to the compound of the formula VIII (Tetrahedron Lett. 1989, 30, 7053-7056), which results in the formation of conesponding chiral acid and chiral ester.
- the ester and the acid can be separated by any conventional method of separating an acid from an ester.
- the configuration of formula VIII which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomers of formula I. [000113]
- 6,320,050 is directed to 2, 3-di-substituted N- heteroaromatic propionamides as glucokinase activators.
- U.S. Patent No. 6,320,050 is incorporated by reference herein.
- Substituent designations for functional groups of formula I of the present invention are as provided herein.
- medicaments containing a compound of formula I are also an aspect of the present invention, as is a process for the manufacture of such medicaments, said process comprising bringing one or more compounds of formula I and, if desired, one or more therapeutically valuable substances into a galenical administration form, e.g., by combining a compound of formula I with a pharmaceutically acceptable carrier and/or adjuvant.
- the present invention encompasses pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- Prefened pharmaceutical compositions of the present invention comprise a compound listed above as having prefened glucokinase activator in vivo activity, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical compositions of the present invention can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example, in the form of suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathethecally, or transdermally, using for example, injection solutions. Furthermore, administration can be carried out sublingually or as an aerosol, for example, in the form of a spray.
- compositions of the present invention comprising compounds of formula I, and/or the salts thereof, may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, dragee-making, or lyophilizing processes.
- These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, steric acid or its salts can be used as such caniers for tablets, coated tablets, dragees and hard gelatin capsules.
- Suitable carriers for soft gelatin capsules include for example vegetable oils, waxes and fats, semi-solid or liquid polyols, etc. Depending on the nature of the active substance, no caniers are generally required in the case of soft gelatin capsules. In such cases, pharmaceutically acceptable caniers are considered to include soft gelatin capsules.
- Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose.
- Suitable carriers for injection solutions are water, alcohols, polyols, glycerine, vegetable oils, phospholipids and surfactants.
- Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols.
- the pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they can also contain other therapeutically valuable substances, including additional active ingredients other than those of formula I.
- a therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to treat obesity and/or type II diabetes. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art.
- Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated.
- a daily dosage of about 100 mg to about 1,000 mg should be appropriate.
- the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
- Prefened forms of use are intravenous, intramuscular or oral administration, most prefened is oral administration.
- reaction mixture was then diluted with water (50 mL), and the reaction mixture was further extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concenfrated in vacuo at 25°C. The resulting solid was washed with pentane (4 x 50 mL) and filtered through a silica gel plug. The filtrate was concenfrated in vacuo at 25°C to afford iodomethylcyclopentane (18.48 g, 88%) as a clear colorless liquid: EI-HRMS m/e calcd for C 6 H n I (M + ) 209.9906, found 209.9911.
- reaction mixture was then slowly poured onto ice (700 mL).
- the resulting yellow mixture was stined for 15 min and then was filtered through celite to remove the aluminum salts.
- the filtrate was then extracted with methylene chloride (3 x 50 mL).
- the combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1 x 50 mL).
- the reaction was then stined at 25°C until the reaction temperature cooled back to 80°C. At this time, another portion of potassium hydroxide (2.09 g, 31.7 mmol) was added. Again, an exotherm was observed, and the resulting reaction mixture was allowed to cool back to 80°C. Once at 80°C, a third portion of potassium hydroxide (2.09 g, 31.7 mmol) was added to the reaction mixture. Another exotherm was observed, and after cooling back to 80°C, the fourth and final portion of potassium hydroxide (2.09 g, 31.7 mmol) was added. At this point, the heating element was added, and the reaction mixture was heated at 100°C for 16 h.
- the resulting homogenous reaction mixture was cooled to 25°C and then diluted with water (12 mL). The reaction mixture was then transfened to a separatory funnel, rinsing with additional water (12 mL) and diethyl ether (40 mL). The layers were separated, and the aqueous layer was transfened to a flask. The organic layer was extracted with water (2 x 15 mL). The aqueous layers were combined and treated with heptane (20 mL), and the resulting reaction mixture was vigorously stined. This stined solution was then treated dropwise with concentrated hydrochloric acid (26 mL) over 30 min while the temperature was kept under 50°C with an ice bath.
- reaction mixture was stined at -10°C for 10 min and then warmed to 25°C where it was stined for 1 h. After such time, thin layer chromatography analysis indicated that the reaction was complete.
- the reaction mixture was then quenched with water (50 mL) and then extracted with ethyl acetate (1 x 100 mL). The organic layer was washed with water (2 x 40 mL). The aqueous layers were combined and back-extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concenfrated in vacuo.
- reaction mixture was stined at -78°C for 15 min and then slowly treated with a solution of 2-(3-chloro-4-methylsulfanyl- phenyl)-N-[2(R)-hydroxy-l(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-acetamide (13.75 g, 37.8 mmol) in tetrahydrofuran (90 mL) while maintaining the temperature below -65°C.
- the resulting yellow-orange reaction mixture was stined at -78°C for 15 min and then allowed to warm to 0°C where it was stined for 20 min.
- reaction mixture was then re-cooled to -78°C and then treated with a solution of iodomethylcyclopentane (11.9 g, 56.7 mmol) in l,3-dimethyl-3 5 4,5,6-tetrahydro-2(lH)-pyrimidinone (9.6 mL, 79.3 mmol).
- the resulting reaction mixture was stined at -78°C for 30 min and then allowed to warm to 25°C where it was stined for 16 h.
- the reaction mixture was diluted with ethyl acetate (200 mL) and then washed with a saturated aqueous ammonium chloride solution (1 x 100 mL).
- aqueous layer was then extracted with ethyl acetate (2 x 50 mL).
- the combined organic layers were washed with a saturated aqueous sodium chloride solution (1 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- the resulting material was then re-dissolved in ethyl acetate.
- This organic phase was washed with a 10% aqueous sulfuric acid solution (2 x 100 mL) and a 10% aqueous sodium bicarbonate solution (2 x 100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo.
- the solid material was dissolved in hot glacial acetic acid (15 mL), and the hot solution was treated with water (10 mL) to initiate crystallization. The mixture was allowed to cool to 25°C and then treated with an additional amount of water (20 mL). After stirring at 25°C for 1 h, the solid was collected by filtration.
- the reaction mixture was stined at 0°C for 30 min and at 25°C for 30 min.
- the reaction mixture was then treated with additional trifluoroacetic acid (1.0 mL, 12.99 mmol) and stined at 25°C for 2 h.
- the reaction mixture was further treated with trifluoroacetic acid (1.0 mL, 12.99 mmol) and stined at 25°C for 2 h.
- the resulting orange reaction mixture was treated with pyridine (0.04 mL, 0.495 mmol) and then stined at 0°C for 30 min and then at 25°C for 22 h.
- the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
- reaction mixture was then stined at -10°C to -5°C for 30 min and then treated with (lR,2R)-(-)-pseudoephedrine (59.5 g, 353 mmol) in -portions over 15 min while maintaining the temperature of the reaction mixture between -10°C and -4°C.
- the reaction mixture was then stined at -7°C to 0°C for 3 h.
- the reaction mixture was then quenched at 0°C by the addition of water (150 mL). After vigorously stirring for 10 min, toluene (150 mL) was added, and the reaction mixture was stined for 5 min.
- the organic layer was separated and washed with water (2 x 100 mL).
- the combined aqueous layers were back-extracted with toluene (1 x 50 mL).
- the combined organic layers were washed sequentially with a IN aqueous sulfuric acid solution (1 x 200 mL), a saturated aqueous sodium bicarbonate solution (1 x 200 mL), and a solution of water/saturated aqueous sodium chloride solution (1:1, 1 x 50 mL).
- the resulting organic layer was then concentrated in vacuo to afford a white solid.
- reaction mixture was stined at -20°C for 30 min and then was treated with a solution of N-[2(R)-hydroxy-l(R)-methyl-2(R)-phenyl- ethyl]-N-methyl-2-(4-methylsulfanyl-phenyl)-acetamide (66.1 g, 201 mmol) in tefrahydrofuran (500 mL) over 50 min while maintaining the temperature between -20°C and -15°C.
- the organic phase was washed sequentially with a solution of water/saturated aqueous sodium chloride solution (1:1, 1 x 1000 mL), a solution of water/saturated aqueous sodium chloride solution (1:2, 1 x 1000 mL), a IM aqueous sulfuric acid solution (1 x 800 mL), water (1 x 200 mL), and a saturated aqueous sodium bicarbonate solution (1 x 1000 mL).
- the silica gel plug was then washed with a solution of hexanes/ethyl acetate (4:1, 1.5 L), and the combined organics were concentrated in vacuo.
- the resulting pale-yellow oil was dissolved in ethyl acetate (35 mL) and subsequently freated with hexanes (100 mL).
- the solution was stored in a refrigerator overnight.
- the resulting solid was collected by filtration, washed with cold hexanes (ca.
- Biotage chromatography (FLASH 75S, Silica, 2.5% to 5% gradient ethyl acetate/methylene chloride) afforded 2(R)-(4- methanesulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazin-2-yl-propionamide (6.12 g, 81 %) as a light yellow solid.
- the resulting solution was added dropwise via an addition funnel at 0°C to a solution of 5-methylsulfanyl-pyrazin-2-ylamine (1.0 g, 7.08 mmol) in methylene chloride (5 mL) and pyridine (0.86 mL, 10.6 mmol).
- the reaction mixture was stined at 0°C for 2 h and then at 25°C overnight.
- the reaction mixture was quenched with a IN aqueous citric acid solution (10 mL) and was stined for 10 min.
- the reaction was then diluted with water (50 mL), methylene chloride (100 mL), and a IN aqueous citric acid solution (25 mL).
- the resulting solution was added dropwise via an addition funnel at 0°C to a solution of 5-methylsulfanyl-pyrazin-2- ylamine (prepared as in Example 4, 0.58 g, 4.07 mmol) in methylene chloride (10 mL) and pyridine (0.36 mL, 4.48 mmol).
- the reaction mixture was stined at 0°C for 30 min and then was allowed to warm to 25°C where it was stined for 3 h.
- the reaction mixture was quenched with a IN aqueous citric acid solution (10 mL) and was stined for 15 min.
- the reaction was then diluted with ethyl acetate (75 mL) and a IN aqueous citric acid solution (50 mL). The layers were separated, and the organic layer was then washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo.
- the reaction was treated with 2-amino-5-bromopyrazine (7.92 g, 45.6 mmol) followed by pyridine (8.79 mL, 108.8 mmol). The mixture was allowed to stir at 25°C for 1.5 h. At this time, the reaction was diluted with methylene chloride and then was washed with a IN aqueous hydrochloric acid solution (200 mL) followed by a 10%) aqueous potassium carbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concenfrated in vacuo.
- the resulting reaction mixture was diluted with methylene chloride (15 mL), and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a IN aqueous citric acid solution (10 mL). The combined aqueous layers were back-extracted with methylene chloride (2 x 5 mL). The combined organic layers were then concenfrated in vacuo. Flash chromatography (Merck Silica gel 60, 75% ethyl acetate/hexanes) provided impure product.
- the impure product was re-purified by reverse phase high-performance liquid chromatography (C-18, acetonitrile/water, 0.1 % trifluoroacetic acid, 50% to 100% acetonitrile gradient).
- the fractions containing product were concentrated in vacuo and lyophilized to afford 2(R)- (3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfamoyl-pyrazin-2- yl)-propionamide (15 mg, ⁇ 9% overall yield) as a yellow gum: (ES) + -HRMS m/e calcd for C 2 oH 25 ClN 4 O 5 S 2 (M+Na) + 523.0847 found 523.0854.
- the reaction mixture was stined at 25°C overnight and then was charged with an additional aliquot of a 2.0M solution of dimethylamine in tetrahydrofuran (0.21 mL, 0.42 mmol).
- the resulting reaction mixture was stined at 25°C for 5-6 h and then was treated with a final aliquot of a 2.0M solution of dimethylamine in tetrahydrofuran (0.21, 0.42 mmol).
- the reaction mixture was stined at 25°C overnight, monitoring by low resolution mass spectrometry.
- the resulting reaction mixture was diluted with ethyl acetate (10 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (10 mL).
- the aqueous layer was back- extracted with ethyl acetate (10 mL).
- the combined organic layers were washed with a IN aqueous citric acid solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo onto silica gel (Merck Silica gel 60, 230-400 mesh).
- Biotage chromatography FLASH 40S, Silica, 40% ethyl acetate/hexanes
- the impure product was re-purified by reverse phase high-performance liquid chromatography (C-18, acetonitrile/water, 0.1% trifluoroacetic acid, 50% to 100% acetonitrile gradient).
- the resulting mixture was stined at 25°C for 1 h and was then heated to 60°C for 1 h. At this time, the reaction was concentrated in vacuo. The residue was extracted into ethyl acetate from a IN aqueous hydrochloric acid solution.
- reaction mixture was then treated with a solution of ⁇ -(6-amino-pyridin-3-yl)-methanesulfonamide (190 mg, 1.01 mmol) and pyridine (0.08 mL, 1.01 mmol) in tetrahydrofuran (3.38 mL).
- This solution was stined at 25°C for 18 h.
- the reaction was concenfrated in vacuo.
- the residue was dissolved in methylene chloride (50 mL), and the organic layer was washed consecutively with a IN aqueous hydrochloric acid solution (1 x 100 mL) and a saturated aqueous sodium bicarbonate solution (1 x 100 mL).
- This solution was treated with charcoal and was filtered through a pad of celite (90/10 methylene chloride/methanol wash). The filtrate was partitioned, and the aqueous layer was exfra'cted with a solution of 90/10 methylene chloride/methanol. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
- a sealed tube apparatus was charged with 2-bromo-5-nitropyridine (1.02 g, 5.02 mmol) and a 5.6M solution of dimethylamine in ethanol (5.0 mL, 28.0 mmol). The resulting solution was heated at 90°C for 3 days, allowed to cool to 0°C, and then diluted with acetone and ethyl acetate. A white solid was removed via filtration, and the filtrate was absorbed onto silica gel (Merck Silica gel 60, 230-400 mesh).
- the resulting solution was added dropwise via an addition funnel at 0°C to a solution of N 5 ,N 5 -dimethyl-pyridine-2,5-diamine (287 mg, 2.09 mmol) in methylene chloride (5 mL) and pyridine (0.3 mL).
- the reaction mixture was stined at 0°C and then was allowed to warm to 25°C overnight.
- the reaction mixture was then concenfrated in vacuo and treated with ethyl acetate (75 mL) and a IN aqueous citric acid solution (75 mL). The layers. were separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL).
- the organic layer was washed with a saturated aqueous sodium bicarbonate solution (210 mL), water (210 mL), and a saturated aqueous sodium chloride solution (210 mL), dried over sodium sulfate and decolorizing carbon, filtered through a pad of celite, and concentrated in vacuo onto a pad of celite.
- the reaction was freated with trihexylsilane (8.42 mL, 23.6 mmol) and was stined under carbon monoxide at 65 psi at 110°C for 4 h. The reaction was then allowed to cool to 25°C and was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3 x 50 mL) and water (3 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- the aqueous layer was then extracted with ethyl acetate (4 x 50 mL).
- the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concenfrated in vacuo to afford a red solid.
- the resulting solid was combined with trimethylorthoformate (15 mL) and methanol (40 mL) and then was treated with p -toluenesulfonic acid monohydrate (191 mg, 1 mmol).
- the reaction mixture was heated under reflux for 1.5 h and then cooled to 25°C.
- the reaction was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL).
- the resulting homogeneous solution was poured into water (100 mL) and was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and a saturated aqueous sodium chloride solution (1 x 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in benzyl alcohol (0.66 mL, 6.54 mmol) and heated at 93°C for 20 min.
- the organic layer was sequentially washed with water (1 x 25 mL), a saturated aqueous sodium bicarbonate solution (1 x 25 mL), water (1 x 25 mL), an aqueous copper(II) sulfate solution (1 x 25 mL), and a saturated aqueous sodium chloride solution (1 x 25 mL).
- the organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
- the mixture was partitioned between a saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (50 mL).
- the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL).
- the combined organic layers were washed with a saturated ammonium chloride solution (1 x 30 mL), a saturated aqueous sodium bicarbonate solution (1 x 30 mL), and a saturated aqueous sodium chloride solution (1 x 30 mL).
- the organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
- the organic layer was separated, and the aqueous layer was exfracted with ethyl acetate (3 x 25 mL).
- the combined organic layers were washed with water (3 x 30 mL) and a saturated aqueous sodium chloride solution (1 x 30 mL), dried over anhydrous magnesium sulfate, filtered, and concenfrated in vacuo.
- the reaction mixture was treated with an additional amount of trimethylacetyl chloride (4.3 mL, 34.48 mmol) and then stined at 25°C for 4 h.
- the reaction mixture was then concentrated in vacuo to remove methylene chloride.
- the resulting residue was diluted with ethyl acetate (700 mL).
- the organic layer was washed with a IN aqueous hydrochloric acid solution (2 x 200 mL) and a saturated aqueous sodium chloride solution (1 x 200 mL), dried over sodium sulfate, filtered, and concenfrated in vacuo.
- the reaction mixture was stined at 0°C for 30 min and then allowed to warm to 25°C where it was stined for 24 h.
- the resulting two layers were separated, and the organic layer was further diluted with ethyl acetate (100 mL).
- the organic layer was then diluted with a 10%) aqueous ammonium fluoride solution (100 mL), and the resulting mixture was stined at 25°C for 5 h.
- the solids were then filtered, and the filfrate layers were separated.
- the organic layer was washed with a saturated aqueous sodium chloride solution (1 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- Biotage chromatography (FLASH 40L, Silica, 30% ethyl acetate/hexanes) afforded l-(5-amino-pyrazin-2-yl)-ethanone O-tert- butyl-oxime (408.4 g, quant.) as a light yellow solid: mp 113-115°C; EI-HRMS m/e calcd for Ci 0 Hi 6 N 4 O (M 1 208.1324, found 208.1325.
- the reaction mixture was then diluted with ethyl acetate (300 mL) and a IN aqueous citric acid solution (300 mL), and the layers were shaken and separated.
- the organic layer was washed with a saturated aqueous sodium bicarbonate solution (1 x 300 mL), water (1 x 300 mL), and a saturated aqueous sodium chloride solution (1 x 300 mL).
- the organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo.
- reaction mixture was then heated at 60°C where it was stined for a second night.
- the reaction mixture was then allowed cool to 25°C.
- the reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (2 x 50 mL) and a saturated aqueous sodium chloride solution (1 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- the yellow sluny was dissolved in methylene chloride (15 mL) and then cooled to 0°C. To this solution was added a solution of 5-amino-pyrazine- 2-carboxylic acid tert-butyl ester (0.71 g, 3.64 mmol) and pyridine (295 ⁇ L, 3.65 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stined at 0°C and was slowly warmed to 25°C overnight. The reaction was then quenched with a IN aqueous citric acid solution (10 mL), stined at 25°C for 3 min, and then concenfrated in vacuo.
- the reaction material was partitioned between ethyl acetate (400 mL) and a IN aqueous citric acid solution (200 mL), and the layers were seperated.
- the organic layer was washed with a saturated aqueous sodium bicarbonate solution (200 mL), water (200 mL), and a saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo onto silica gel (Merck Silica gel 60, 230-400 mesh).
- the reaction was partitioned between ethyl acetate (300 mL) and a IN aqueous citric acid solution (250 mL), and the layers were seperated.
- the organic layer was washed with a saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over sodium sulfate, filtered, and concenfrated in vacuo.
- a large steel reaction vessel was charged with a solution of 5-fluoro- pyrazine-2-carboxylic acid methyl ester (17.45 g, 111.78 mmol) in tetrahydrofuran (200 mL).
- the reaction solution was cooled to 0°C and was saturated with ammonia gas over 2-3 h.
- the vessel was then tightly sealed.
- the reaction was then mechanically agitated and allowed to warm to 25°C overnight.
- the vessel was then cooled to -78°C for 15-20 min, the vessel was carefully vented, and the contents of the vessel were diluted with diethyl ether (100 mL).
- the reaction material was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (100 mL), a saturated aqueous sodium chloride solution (100 mL), a IN aqueous hydrochloric acid solution (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- reaction mixture was then diluted with ethyl acetate (75 mL), washed with a IN aqueous hydrochloric acid solution (3 x 75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- reaction was then diluted with ethyl acetate (50 mL), washed with water (2 x 25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- Biotage chromatography (FLASH 40S, Silica, 100% methanol) afforded impure 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl- pyrazin-2-yl)-propionamide as an orange oil.
- This impure product was re-purified by reverse phase high-performance liquid chromatography (Waters symmetry packing, acetonitrile/water with 0.05% frifluoroacetic acid, 2% to 45% acetonitrile gradient).
- reaction mixture was then concentrated in vacuo, diluted with ethyl acetate (250 mL), and washed with a IN aqueous hydrochloric acid solution (3 x 100 mL) and a saturated aqueous sodium chloride solution (1 x 300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo.
- reaction solution was concentrated in vacuo and then partitioned between ethyl acetate (210 mL) and water (150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
- Biotage chromatography (FLASH 40S, Silica, 40% ethyl acetate/hexanes) afforded impure 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3- methyl-[l,2,4]oxadiazol-5-yl)-pyrazin-2-yl]-propionamide as a light yellow foam (22.5 mg, 13%).
- the impure product was re-purified by reverse phase high-performance liquid chromatography (Waters symmefry packing, acetonitrile/water with 0.05% trifluoroacetic acid, 2% to 45% acetonitrile gradient).
- Biotage chromatography (FLASH 40L, Silica, 5% ethyl acetate/methylene chloride) afforded (5- methylsulfanylmethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester as a crude white solid (0.45 g, 49%) which was used without further purification.
- the resulting yellow slurry was dissolved in methylene chloride (7 mL) and then cooled to 0°C. To this solution was added a solution of 5- methylsulfanylmethyl-pyrazin-2-ylamine (267.2 mg, 1.721 mmol) and pyridine (174 ⁇ L, 2.151 mmol) in methylene chloride (8.6 mL), followed by a methylene chloride rinse (1.7 mL). The pH of the reaction was roughly 3-4, and a second aliquot of pyridine (50 ⁇ L, 0.618 mmol) was added to adjust the pH to roughly 5. The reaction mixture was stined at 0°C and slowly warmed to 25°C overnight.
- reaction was then quenched with water (10 mL), stined at 25°C for 10 min, and concentrated in vacuo.
- the reaction slurry was partitioned between ethyl acetate (250 mL) and a IN aqueous hydrochloric acid solution (250 mL).
- the organic layer was washed with a IN aqueous hydrochloric acid solution (250 mL), a saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo.
- the yellow slurry was dissolved in methylene chloride (10 mL) and then cooled to 0°C. To this solution was added a mixture of (5-amino-pyrazin-2-yl)-acetonifrile (268.9 mg, 2.004 mmol) and pyridine (324 ⁇ L, 4.009 mmol) in methylene chloride (10 mL). The reaction mixture was stined at 0°C for 30 min and then warmed to 25°C where it was stined for 16 h. The reaction mixture was then diluted with methylene chloride (100 mL) and water (50 mL).
- reaction was acidified to a pH of about 7 with a IN aqueous hydrochloric acid solution and was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo.
- the yellow slurry was dissolved in methylene chloride (24 mL) and then cooled to 0°C. To this solution was added a solution of 5-(l,l- dimethoxy-ethyl)-pyrazin-2-ylamine (880.4 mg, 4.805 mmol) and pyridine (466 ⁇ L, 5.766 mmol) in methylene chloride (24 mL). The reaction mixture was stined at 0°C for 1 h. The reaction was then quenched with a saturated aqueous sodium chloride solution (50 mL), and the layers were separated. The aqueous layer was back-extracted with methylene chloride (50 mL).
- Biotage chromatography (FLASH 40M, Silica, 50% ethyl acetate/hexanes) afforded the 2(R)- ⁇ 5-[2-(3-chloro-4-methanesulfonyl- phenyl)-3-cyclopentyl-propionylamino]-pyrazin-2-yl ⁇ -malonic acid diethyl ester (76.9 mg, 26%) as a pale yellow oil.
- This material was further purified by dissolving it in methylene chloride and washing with a IN aqueous hydrochloric acid solution (25 mL).
- reaction was re-cooled to 0°C and was treated with an additional amount of a 2.0M solution of diisobutylaluminum hydride in hexanes (0.92 mL, 0.92 mmol).
- the reaction was stined at 0°C for 15 min and then at 25 °C for 1 h.
- the reaction mixture was poured onto a mixture of ice, water, and ethyl acetate. The aqueous layer was extracted with ethyl acetate and diethyl ether.
- Biotage chromatography (FLASH 40M, Silica, 90%> ethyl acetate/acetonitrile) afforded 2(R)-(3- chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy-l-hydroxymethyl- ethyl)-pyrazin-2-yl]-propionamide (17.9 mg, 11%) as a pale yellow foam: mp 110- 120°C; (ES) + -HRMS m/e calcd for C 22 H 28 N 3 O 5 (M+H) + 482.1511, found 482.1512.
- the aqueous phase was further exfracted with ethyl acetate (2 x 50 mL), and each organic extract was washed with a portion of a saturated aqueous sodium chloride solution (25 mL).
- the combined organic extracts were dried over sodium sulfate, filtered, and concenfrated in vacuo to a dark oil.
- the residue was treated with a solution of diethyl ether/hexanes (50 mL, 3:2) to produce an orange solid.
- the aqueous phase was extracted with ethyl acetate (2 x 50 mL). Each of the organic extracts was washed with a saturated aqueous sodium chloride solution (25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concenfrated in vacuo to afford the crude aldehyde, 5-formyl-pyrazine-2-carboxylic acid methyl ester (180 mg), as an orange oil which was used without further characterization or purification.
- the salt was suspended in NN- dimethylformamide (10 mL) and freated while stirring with diphenylphosphoryl azide (0.35 mL, 1.62 mmol). The mixture was stined at 25°C for 18 h. The solution was then concenfrated in vacuo. and the residue was partitioned with ethyl acetate (50 mL) and water (25 mL). The aqueous phase was extracted with ethyl acetate (2 x 25 mL). Each organic extract was washed with a small portion of a saturated aqueous sodium chloride solution.
- the filfrate was concentrated in vacuo to dryness, and the residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, elution with various concenfrations of ethyl acetate/hexanes) to afford an additional amount of the carbamate (60 mg , 16 %>).
- the resulting acid chloride was dissolved in methylene chloride (5 mL), cooled to 5°C, and then treated with a solution of 5- [l,3]dioxolan-2-yl-pyrazin-2-ylamine (105 ⁇ L, 0.628 mmol), pyridine (100 ⁇ L, 1.23 mmol) in methylene chloride (5 mL). After 5 min, the cooling bath was removed, and the stining was continued for 18 h.
- reaction mixture was then diluted with methylene chloride (50 mL), and the solution was washed with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution (25 mL), and a saturated aqueous sodium chloride solution (25 mL). Each aqueous wash was extracted with a small portion of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow oil.
- the aqueous phase was back-extracted with ethyl acetate (25 mL), and each organic extract was washed with a small portion of a saturated aqueous sodium chloride solution.
- the combined organic layers were combined, dried over sodium sulfate, filtered, and concenfrated in vacuo to afford the acid azide as a pale yellow oil (263 mg).
- This oil was treasted with benzyl alcohol (160 ⁇ L, 1.55 mmol) and heated with stirring at 85°C for 35 min.
- the residue was stined with diethyl ether (10 mL) and filtered to give the carbamate as an off-white solid (138 mg, 36 % yield).
- the filtrate was purified by flash chromatography on (Merck Silica gel 60 (230-400 mesh, gradient mixtures of ethyl acetate/hexanes) to afford an additional amount of the 5-[l,3]Dioxolan-2-ylmethyl- pyrazin-2-yl-carbamic acid benzyl ester (21 mg, 5.5%>).
- the resulting acid chloride was dissolved in methylene chloride (10 mL), cooled to 5°C, and then freated with a solution of the 5-[l,3]dioxolan-2-ylmethylpyrazin-2yl-amine (0.49 mmol), pyridine (100 ⁇ L, 1.23 mmol) in methylene chloride (5 mL). The mixture was stined at 5°C for 30 min then at 25°C for 18 h.
- the mixture was diluted with methylene chloride (25 mL) and washed with a saturated aqueous sodium bicarbonate solution (20 mL), a 0.5M aqueous hydrochloric acid solution (20 mL), and a saturated aqueous sodium chloride solution (20 mL). Each aqueous was back-extracted with a small portion of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concenfrated in vacuo.
- the resulting acid chloride was dissolved in methylene chloride (10 mL), cooled to 5°C and then freated with a solution of 5-allyloxy-pyrazin-2- ylamine (238 mg, 1.57 mmol) and pyridine (0.32 mL, 3.96 mmol) in methylene chloride (15 mL). The mixture was further stined at 25°C for 16 h. The reaction mixture was then diluted with methylene chloride (25 mL) and washed with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution (25 mL), and a saturated aqueous sodium chloride solution (25 mL).
- reaction mixture was cooled to 0°C and then freated with a 0.2M solution of osmium tetroxide in toluene (20 ⁇ L, 0.004 mmol) followed by a mixture of N- (5-allyloxy-pyrazin-2-yl)-2(R)(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide (210 mg, 0.452 mmol) in water/tert-butyl alcohol (3 mL, 1:1). The heterogeneous mixture was stined for 5 min, the cooling bath was removed, and the stirring continued for 2 h.
- the mixture was then freated while stirring with ethyl acetate (20 mL) and sodium metabisulfite (150 mg, 0.79 mmol), and the stirring continued for 30 min.
- the color of the reaction mixture changed from yellow to colorless, and a defined aqueous phase developed.
- the phases were separated, and the aqueous was diluted with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The extracts were washed with a saturated aqueous sodium chloride solution (20 mL).
- the combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo.
- the resulting acid chloride was dissolved in methylene chloride (5 mL), cooled to 0°C, and then freated with a solution of 5-(2,2-dimethoxy-ethyl)-pyrazin-2-ylamine (75 mg, 0.41 mmol) and pyridine (85 ⁇ L, 1.05 mmol) methylene chloride (5 mL).
- the reaction mixture was stined at 0°C for 5 min, the cooling bath was removed, and the stining was continued for 18 h.
- the mixture was diluted with methylene chloride (25 mL), and the solution was washed consecutively with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution, and a saturated aqueous sodium chloride solution (25 mL). Each aqueous wash was back-extracted with another small portion of methylene chloride. The combined organic layers were dried over sod im sulfate, filtered, and concentrated in vacuo.
- the mixture was stined at 25°C overnight and an oily black precipitate was obtained.
- the top clear solution was decanted, and the oily precipitate was first rinsed with toluene (8 ml) and then rinsed with hexanes/ethyl acetate
- reaction mixture was cooled to 0°C and then freated with a 0.2M solution of osmium tefroxide in toluene (20 ⁇ L, 0.004 mmol) followed by a mixture of N- (5-allyloxy-pyrazin-2-yl)-2(R)(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- propionamide (prepared as in Example 44, 210 mg, 0.452 mmol) in water/tert-butyl alcohol (3 mL, 1:1). The heterogeneous mixture was stined for 5 min, the cooling bath was removed, and the stirring continued for 2 h.
- the mixture was stined at 25°C overnight, and an oily black precipitate was obtained.
- the top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL).
- the residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2 ⁇ aqueous hydrochloric acid solution.
- the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo.
- the mixture was stined at 25°C overnight, and an oily black precipitate was obtained.
- the top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL).
- the residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution.
- the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo.
- the mixture was stined at 25°C overnight, and an oily black precipitate was obtained.
- the top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL).
- the residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2 ⁇ aqueous hydrochloric acid solution.
- the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo.
- reaction mixture was cooled to 0°C and then freated with a 0.2M solution of osmium tefroxide in toluene (17 ⁇ L, 0.0034 mmol) followed by a mixture of 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazin-2-yl)-propionamide (175 mg, 0.374 mmol) in water/tert-butyl alcohol (2 mL, 1:1). The heterogeneous mixture was stined for 10 min, and the cooling bath was removed.
- Method B [000280] A solution of 2-amino-5-bromopyrazine (10.00 g, 57.47 mmol) and pyridine (5.6 mL, 68.96 mmol) in methylene chloride (144 mL) was cooled to 0°C and then was treated slowly with trimethylacetyl chloride (8.6 mL, 68.96 mmol). The resulting reaction mixture was stined at 0°C for 30 min and then was allowed to warm to 25°C where it was stined for 18 h. At this time, the reaction mixture still contained the starting material 2-amino-5-bromopyrazine.
- the reaction mixture was freated with an additional amount of trimethylacetyl chloride (4.3 mL, 34.48 mmol) and then stined at 25°C for 4 h.
- the reaction mixture was then concentrated in vacuo to remove methylene chloride.
- the resulting residue was diluted with ethyl acetate (700 mL).
- the organic layer was washed with a IN aqueous hydrochloric acid solution (2 x 200 mL) and a saturated aqueous sodium chloride solution (1 x 200 mL), dried over sodium sulfate, filtered, and concenfrated in vacuo.
- reaction mixture was allowed to cool to 25°C and then was concenfrated in vacuo.
- the resulting orange slurry was diluted with methylene chloride (200 mL).
- the organic layer was washed with a IN aqueous hydrochloric acid solution (2 x 200 mL), a saturated aqueous sodium bicarbonate solution (1 x 200 mL), and a saturated aqueous sodium chloride solution (1 x 200 mL).
- the combined aqueous layers were back-extrated with methylene chloride (1 x 200 mL).
- the combined organic layers were dried over magnesium chloride and decolorizing carbon, filtered, and concentrated in vacuo.
- the reaction mixture was cooled to 5°C, treated with a 0.2M solution of osmium tefroxide in toluene (7.5 mL, 1.5 mmol), and then treated with 2,2-dimethyl-N- (5-vinyl-pyrazin-2-yl)-propionamide (30.8 g, 150 mmol) which was partially dissolved in water/tert-butyl alcohol (150 mL, 1:1).
- the mixture was stined at 4-5°C for 18 h using a Neslab Endocal cooling system to control the temperature. While stirring at 4-5°C, the mixture was then slowly freated with sodium metabisulfite (35 g, 184 mmol) which resulted in effervescence.
- the reaction mixture was concenfrated in vacuo, and the residue was dissolved in methylene chloride (600 mL).
- the organic layer was washed with a saturated aqueous sodium chloride solution (250 mL) and a saturated aqueous sodium bicarbonate solution (250 mL). Each aqueous layer was back-extracted with methylene chloride (250 mL).
- the combined organic layers were stined with sodium sulfate (35 mg) and Norit A Charcoal (8 g) and then filtered through a pad of celite. The filtrate was concenfrated in vacuo to a weight of about 250 g.
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Abstract
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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EP03767788A EP1572670B1 (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or -pyridine glucokinase activators |
DE60315886T DE60315886T2 (en) | 2002-12-12 | 2003-12-11 | SUBSTITUTED PYRAZIN OR PYRIDINE DERIVATIVES AS GLUCOCINASE ACTIVATORS |
MXPA05006250A MXPA05006250A (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or pyridine glucokinase activators. |
SI200330967T SI1572670T1 (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or -pyridine glucokinase activators |
DK03767788T DK1572670T3 (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or pyridine-glucokinase activators |
NZ540298A NZ540298A (en) | 2002-12-12 | 2003-12-11 | 5-Substituted-pyrazine or pyridine glucokinase activators |
JP2004558065A JP4490285B2 (en) | 2002-12-12 | 2003-12-11 | 5-substituted pyrazine or pyridine glucokinase activator |
BR0317268-6A BR0317268A (en) | 2002-12-12 | 2003-12-11 | Pyrazine and 5-substituted pyridine glucokinase activating compounds, pharmaceutical composition, use and process for preparing same |
CA002506441A CA2506441C (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or pyridine glucokinase activators |
AU2003292229A AU2003292229B2 (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or pyridine glucokinase activators |
NO20052555A NO330139B1 (en) | 2002-12-12 | 2005-05-26 | 5-substituted pyrazine or pyridine derivatives, the preparation of such, pharmaceutical preparations containing such, such compounds as active substances and the use of such compounds for the preparation of drugs for the treatment or prevention of disease |
HR20050512A HRP20050512A2 (en) | 2002-12-12 | 2005-06-07 | 5-substituted-pyrazine or pyridine glucokinase activators |
HK06107607.4A HK1085481A1 (en) | 2002-12-12 | 2006-07-06 | 5-substituted-pyrazine or pyridine glucokinase activators |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US43280602P | 2002-12-12 | 2002-12-12 | |
US60/432,806 | 2002-12-12 | ||
US52453103P | 2003-11-24 | 2003-11-24 | |
US60/524,531 | 2003-11-24 |
Publications (1)
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WO2004052869A1 true WO2004052869A1 (en) | 2004-06-24 |
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ID=32511672
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PCT/EP2003/014055 WO2004052869A1 (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or pyridine glucokinase activators |
Country Status (27)
Country | Link |
---|---|
US (1) | US7132425B2 (en) |
EP (1) | EP1572670B1 (en) |
JP (1) | JP4490285B2 (en) |
KR (1) | KR100743890B1 (en) |
AR (1) | AR046244A1 (en) |
AT (1) | ATE370936T1 (en) |
AU (1) | AU2003292229B2 (en) |
BR (1) | BR0317268A (en) |
CA (1) | CA2506441C (en) |
CY (1) | CY1106989T1 (en) |
DE (1) | DE60315886T2 (en) |
DK (1) | DK1572670T3 (en) |
ES (1) | ES2291697T3 (en) |
HK (1) | HK1085481A1 (en) |
HR (1) | HRP20050512A2 (en) |
MX (1) | MXPA05006250A (en) |
MY (1) | MY141521A (en) |
NO (1) | NO330139B1 (en) |
NZ (1) | NZ540298A (en) |
PA (1) | PA8592001A1 (en) |
PE (1) | PE20040801A1 (en) |
PL (1) | PL377551A1 (en) |
PT (1) | PT1572670E (en) |
RU (1) | RU2310648C2 (en) |
TW (1) | TW200426139A (en) |
UY (1) | UY28121A1 (en) |
WO (1) | WO2004052869A1 (en) |
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-
2003
- 2003-12-10 PE PE2003001259A patent/PE20040801A1/en not_active Application Discontinuation
- 2003-12-10 US US10/732,838 patent/US7132425B2/en not_active Expired - Fee Related
- 2003-12-10 MY MYPI20034740A patent/MY141521A/en unknown
- 2003-12-11 AR ARP030104577A patent/AR046244A1/en unknown
- 2003-12-11 BR BR0317268-6A patent/BR0317268A/en not_active IP Right Cessation
- 2003-12-11 ES ES03767788T patent/ES2291697T3/en not_active Expired - Lifetime
- 2003-12-11 PA PA20038592001A patent/PA8592001A1/en unknown
- 2003-12-11 DK DK03767788T patent/DK1572670T3/en active
- 2003-12-11 PL PL377551A patent/PL377551A1/en not_active Application Discontinuation
- 2003-12-11 DE DE60315886T patent/DE60315886T2/en not_active Expired - Lifetime
- 2003-12-11 EP EP03767788A patent/EP1572670B1/en not_active Expired - Lifetime
- 2003-12-11 CA CA002506441A patent/CA2506441C/en not_active Expired - Fee Related
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