JP2001515482A - フルクトース−１，６−ビスホスファターゼの新規なベンズイミダゾールインヒビター - Google Patents
フルクトース−１，６−ビスホスファターゼの新規なベンズイミダゾールインヒビターInfo
- Publication number
- JP2001515482A JP2001515482A JP53888798A JP53888798A JP2001515482A JP 2001515482 A JP2001515482 A JP 2001515482A JP 53888798 A JP53888798 A JP 53888798A JP 53888798 A JP53888798 A JP 53888798A JP 2001515482 A JP2001515482 A JP 2001515482A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- group
- aryl
- cyclic
- alicyclic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 38
- 102000012195 Fructose-1,6-bisphosphatases Human genes 0.000 title abstract description 7
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 title abstract description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title description 151
- -1 C 1 -C 5 alkyl Chemical group 0.000 claims abstract description 313
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 304
- 125000003118 aryl group Chemical group 0.000 claims abstract description 223
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 144
- 125000002723 alicyclic group Chemical group 0.000 claims abstract description 114
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 105
- 239000000651 prodrug Substances 0.000 claims abstract description 55
- 229940002612 prodrug Drugs 0.000 claims abstract description 55
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims abstract description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 47
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 39
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 35
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 33
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 32
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 30
- 125000005843 halogen group Chemical group 0.000 claims abstract description 26
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 20
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 20
- 150000003462 sulfoxides Chemical class 0.000 claims abstract description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 19
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims abstract description 15
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims abstract description 14
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims abstract description 14
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001409 amidines Chemical class 0.000 claims abstract description 11
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 11
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims abstract description 10
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims abstract description 10
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims abstract description 10
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims abstract description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 30
- 150000001875 compounds Chemical class 0.000 claims description 230
- 238000000034 method Methods 0.000 claims description 102
- 150000002148 esters Chemical class 0.000 claims description 99
- 125000002541 furyl group Chemical group 0.000 claims description 54
- 229910052720 vanadium Inorganic materials 0.000 claims description 50
- 101710099475 3'-phosphoadenosine 5'-phosphate phosphatase Proteins 0.000 claims description 41
- 101710196411 Fructose-1,6-bisphosphatase Proteins 0.000 claims description 41
- 101710186733 Fructose-1,6-bisphosphatase, chloroplastic Proteins 0.000 claims description 41
- 101710109119 Fructose-1,6-bisphosphatase, cytosolic Proteins 0.000 claims description 41
- 101710198902 Fructose-1,6-bisphosphate aldolase/phosphatase Proteins 0.000 claims description 41
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 40
- 239000008103 glucose Substances 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000008280 blood Substances 0.000 claims description 37
- 210000004369 blood Anatomy 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims description 35
- 206010012601 diabetes mellitus Diseases 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000004423 acyloxy group Chemical group 0.000 claims description 32
- 125000002947 alkylene group Chemical group 0.000 claims description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 30
- 125000004429 atom Chemical group 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 27
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 24
- 239000001301 oxygen Substances 0.000 claims description 23
- 125000003107 substituted aryl group Chemical group 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 125000004104 aryloxy group Chemical group 0.000 claims description 20
- 229910052698 phosphorus Inorganic materials 0.000 claims description 20
- 239000011574 phosphorus Substances 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 230000004110 gluconeogenesis Effects 0.000 claims description 17
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 16
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 13
- 102000004877 Insulin Human genes 0.000 claims description 12
- 108090001061 Insulin Proteins 0.000 claims description 12
- 229940125396 insulin Drugs 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 9
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 150000003457 sulfones Chemical class 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 150000002596 lactones Chemical class 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 241000699670 Mus sp. Species 0.000 claims description 4
- 208000007345 glycogen storage disease Diseases 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229920005556 chlorobutyl Polymers 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 125000005429 oxyalkyl group Chemical group 0.000 claims description 2
- 150000003008 phosphonic acid esters Chemical group 0.000 claims description 2
- 241000065675 Cyclops Species 0.000 claims 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical class O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 abstract description 2
- 125000005343 heterocyclic alkyl group Chemical group 0.000 abstract description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 abstract 2
- 125000006598 aminocarbonylamino group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 57
- 239000000203 mixture Substances 0.000 description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 229910001868 water Inorganic materials 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 36
- 241000700159 Rattus Species 0.000 description 34
- 238000000921 elemental analysis Methods 0.000 description 34
- 239000000047 product Substances 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 102000004190 Enzymes Human genes 0.000 description 28
- 108090000790 Enzymes Proteins 0.000 description 28
- 229940088598 enzyme Drugs 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 27
- 238000004519 manufacturing process Methods 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 25
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 19
- 210000004185 liver Anatomy 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 230000000704 physical effect Effects 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 150000001299 aldehydes Chemical class 0.000 description 16
- 238000000605 extraction Methods 0.000 description 16
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 230000029936 alkylation Effects 0.000 description 14
- 238000005804 alkylation reaction Methods 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- 238000010168 coupling process Methods 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 210000003494 hepatocyte Anatomy 0.000 description 11
- 230000007062 hydrolysis Effects 0.000 description 11
- 238000006460 hydrolysis reaction Methods 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 230000009229 glucose formation Effects 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 239000006188 syrup Substances 0.000 description 9
- 235000020357 syrup Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 150000004985 diamines Chemical class 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 201000001421 hyperglycemia Diseases 0.000 description 8
- 239000002798 polar solvent Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 150000000185 1,3-diols Chemical class 0.000 description 7
- 229940035437 1,3-propanediol Drugs 0.000 description 7
- CZMRCDWAGMRECN-UHFFFAOYSA-N 2-{[3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 150000005690 diesters Chemical class 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000007429 general method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 102100032534 Adenosine kinase Human genes 0.000 description 6
- 229920002527 Glycogen Polymers 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 6
- 229940100389 Sulfonylurea Drugs 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical group 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 235000003599 food sweetener Nutrition 0.000 description 6
- 229940096919 glycogen Drugs 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 239000000375 suspending agent Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4062797P | 1997-03-07 | 1997-03-07 | |
| US60/040,627 | 1997-03-07 | ||
| PCT/US1998/004498 WO1998039343A1 (en) | 1997-03-07 | 1998-03-06 | Novel benzimidazole inhibitors of fructose-1,6-bisphosphatase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001515482A true JP2001515482A (ja) | 2001-09-18 |
| JP2001515482A5 JP2001515482A5 (https=) | 2005-11-10 |
Family
ID=21912034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP53888798A Pending JP2001515482A (ja) | 1997-03-07 | 1998-03-06 | フルクトース−１，６−ビスホスファターゼの新規なベンズイミダゾールインヒビター |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6110903A (https=) |
| EP (1) | EP0970095B1 (https=) |
| JP (1) | JP2001515482A (https=) |
| AT (1) | ATE253073T1 (https=) |
| AU (1) | AU6691498A (https=) |
| DE (1) | DE69819311T2 (https=) |
| DK (1) | DK0970095T3 (https=) |
| ES (1) | ES2210728T3 (https=) |
| PT (1) | PT970095E (https=) |
| WO (1) | WO1998039343A1 (https=) |
| ZA (1) | ZA981936B (https=) |
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| JP2012506432A (ja) * | 2008-10-22 | 2012-03-15 | メルク・シャープ・エンド・ドーム・コーポレイション | 抗糖尿病剤として有用な新規な環状ベンゾイミダゾール誘導体 |
| JP2012507536A (ja) * | 2008-10-31 | 2012-03-29 | メルク・シャープ・エンド・ドーム・コーポレイション | 糖尿病用剤として有用な新規環状ベンゾイミダゾール誘導体 |
| JP4986853B2 (ja) * | 2005-07-13 | 2012-07-25 | 大鵬薬品工業株式会社 | プロスタグランジンｄ合成酵素を阻害するベンゾイミダゾール化合物 |
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| US20250152658A1 (en) | 2023-11-14 | 2025-05-15 | Merck Sharp & Dohme Llc | Cyclic peptide for trapping interleukin-1 beta |
| TW202542176A (zh) | 2023-12-15 | 2025-11-01 | 美商默沙東有限責任公司 | 用於治療動脈粥樣硬化及發炎病症之環狀肽IL-1β捕捉劑 |
| WO2026019977A1 (en) | 2024-07-19 | 2026-01-22 | Merck Sharp & Dohme Llc | Pyrrolopyridazine vegfr inhibitors |
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| US4000305A (en) * | 1972-09-27 | 1976-12-28 | Imperial Chemical Industries Limited | 15-, 16- AND 17-Indolyl or indolinyl nor prostanoic acid derivatives |
| DE2855659A1 (de) * | 1978-12-22 | 1980-07-03 | Bayer Ag | Benzimidazolyl-2-alkan-phosphonsaeuren |
| IE56605B1 (en) * | 1983-01-28 | 1991-10-09 | Schering Corp | Phosphorous containing amide compounds,pharmaceutical compositions containing them,and processes for their preparation |
| ES2038692T4 (es) * | 1986-11-21 | 2012-02-10 | Novartis Ag | Procedimiento para la obtencion de acidos alcanodifosfonicos substituidos. |
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| US6054587A (en) | 1997-03-07 | 2000-04-25 | Metabasis Therapeutics, Inc. | Indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
| DE69819311T2 (de) * | 1997-03-07 | 2004-07-29 | Metabasis Therapeutics Inc., San Diego | Neue benzimidazol inhibitoren der fructose-1,6-bisphosphatase |
| KR20010033811A (ko) * | 1997-12-31 | 2001-04-25 | 토마스 안 빅토리아 | 2차 및 3차 아민을 함유하는 약제의 물에 용해가능한프로드럭 및 그것의 제조방법 |
-
1998
- 1998-03-06 DE DE69819311T patent/DE69819311T2/de not_active Expired - Fee Related
- 1998-03-06 EP EP98909031A patent/EP0970095B1/en not_active Expired - Lifetime
- 1998-03-06 ZA ZA9801936A patent/ZA981936B/xx unknown
- 1998-03-06 AT AT98909031T patent/ATE253073T1/de not_active IP Right Cessation
- 1998-03-06 DK DK98909031T patent/DK0970095T3/da active
- 1998-03-06 ES ES98909031T patent/ES2210728T3/es not_active Expired - Lifetime
- 1998-03-06 PT PT98909031T patent/PT970095E/pt unknown
- 1998-03-06 WO PCT/US1998/004498 patent/WO1998039343A1/en not_active Ceased
- 1998-03-06 AU AU66914/98A patent/AU6691498A/en not_active Abandoned
- 1998-03-06 US US09/036,329 patent/US6110903A/en not_active Expired - Fee Related
- 1998-03-06 JP JP53888798A patent/JP2001515482A/ja active Pending
-
2000
- 2000-04-11 US US09/547,282 patent/US6399782B1/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4986853B2 (ja) * | 2005-07-13 | 2012-07-25 | 大鵬薬品工業株式会社 | プロスタグランジンｄ合成酵素を阻害するベンゾイミダゾール化合物 |
| JP2012506432A (ja) * | 2008-10-22 | 2012-03-15 | メルク・シャープ・エンド・ドーム・コーポレイション | 抗糖尿病剤として有用な新規な環状ベンゾイミダゾール誘導体 |
| JP2012507536A (ja) * | 2008-10-31 | 2012-03-29 | メルク・シャープ・エンド・ドーム・コーポレイション | 糖尿病用剤として有用な新規環状ベンゾイミダゾール誘導体 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0970095B1 (en) | 2003-10-29 |
| AU6691498A (en) | 1998-09-22 |
| DE69819311D1 (de) | 2003-12-04 |
| US6399782B1 (en) | 2002-06-04 |
| DE69819311T2 (de) | 2004-07-29 |
| ATE253073T1 (de) | 2003-11-15 |
| DK0970095T3 (da) | 2004-03-08 |
| ES2210728T3 (es) | 2004-07-01 |
| EP0970095A1 (en) | 2000-01-12 |
| ZA981936B (en) | 1999-09-06 |
| US6110903A (en) | 2000-08-29 |
| PT970095E (pt) | 2004-03-31 |
| WO1998039343A1 (en) | 1998-09-11 |
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