WO2010100139A1 - Derivatives of benzothiazines, preparation thereof and application thereof as drugs - Google Patents
Derivatives of benzothiazines, preparation thereof and application thereof as drugs Download PDFInfo
- Publication number
- WO2010100139A1 WO2010100139A1 PCT/EP2010/052609 EP2010052609W WO2010100139A1 WO 2010100139 A1 WO2010100139 A1 WO 2010100139A1 EP 2010052609 W EP2010052609 W EP 2010052609W WO 2010100139 A1 WO2010100139 A1 WO 2010100139A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzo
- dioxo
- methyl
- thiazin
- methanone
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 9
- 229940079593 drug Drugs 0.000 title claims description 8
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical class C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 254
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 28
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 16
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical group C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 11
- 239000004305 biphenyl Chemical group 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- JVZRCNQLWOELDU-UHFFFAOYSA-N gamma-Phenylpyridine Chemical group C1=CC=CC=C1C1=CC=NC=C1 JVZRCNQLWOELDU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- -1 [ 1, 2 ] thiazin- 3-yl Chemical group 0.000 claims description 177
- 238000000034 method Methods 0.000 claims description 61
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 56
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 33
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 claims description 29
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- UWDMKTDPDJCJOP-UHFFFAOYSA-N 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-ium-4-carboxylate Chemical compound CC1(C)CC(O)(C(O)=O)CC(C)(C)N1 UWDMKTDPDJCJOP-UHFFFAOYSA-N 0.000 claims description 15
- 206010012601 diabetes mellitus Diseases 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 12
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- 230000007170 pathology Effects 0.000 claims description 10
- 125000000565 sulfonamide group Chemical group 0.000 claims description 10
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 235000020824 obesity Nutrition 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 8
- 101710088194 Dehydrogenase Proteins 0.000 claims description 7
- 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 7
- 239000008103 glucose Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 6
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 6
- 208000037849 arterial hypertension Diseases 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- RZCJYMOBWVJQGV-UHFFFAOYSA-N 2-naphthyloxyacetic acid Chemical compound C1=CC=CC2=CC(OCC(=O)O)=CC=C21 RZCJYMOBWVJQGV-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 201000001421 hyperglycemia Diseases 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 4
- 230000003449 preventive effect Effects 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 241000223783 Glaucoma Species 0.000 claims description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
- 206010033645 Pancreatitis Diseases 0.000 claims description 3
- 206010038923 Retinopathy Diseases 0.000 claims description 3
- 206010003230 arteritis Diseases 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- 210000003141 lower extremity Anatomy 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 125000006012 2-chloroethoxy group Chemical group 0.000 claims description 2
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims description 2
- KFYRPLNVJVHZGT-UHFFFAOYSA-N Amitriptyline hydrochloride Chemical class Cl.C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KFYRPLNVJVHZGT-UHFFFAOYSA-N 0.000 claims description 2
- 229940123208 Biguanide Drugs 0.000 claims description 2
- 102000011145 Hydroxysteroid Dehydrogenases Human genes 0.000 claims description 2
- 108010062875 Hydroxysteroid Dehydrogenases Proteins 0.000 claims description 2
- 102000004877 Insulin Human genes 0.000 claims description 2
- 108090001061 Insulin Proteins 0.000 claims description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 2
- 101001032756 Rattus norvegicus Granzyme-like protein 1 Proteins 0.000 claims description 2
- 229940100389 Sulfonylurea Drugs 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000000883 anti-obesity agent Substances 0.000 claims description 2
- 239000003472 antidiabetic agent Substances 0.000 claims description 2
- 229940125710 antiobesity agent Drugs 0.000 claims description 2
- 150000004283 biguanides Chemical class 0.000 claims description 2
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 2
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 229940125396 insulin Drugs 0.000 claims description 2
- 229950004994 meglitinide Drugs 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 claims description 2
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 2
- 229960001243 orlistat Drugs 0.000 claims description 2
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004425 sibutramine Drugs 0.000 claims description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims 6
- 235000010233 benzoic acid Nutrition 0.000 claims 5
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims 4
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 claims 3
- GHRYSOFWKRRLMI-UHFFFAOYSA-N 1-naphthyloxyacetic acid Chemical compound C1=CC=C2C(OCC(=O)O)=CC=CC2=C1 GHRYSOFWKRRLMI-UHFFFAOYSA-N 0.000 claims 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- FKXMWPFESIFWMS-UHFFFAOYSA-N (4-methylphenyl)methanone Chemical compound CC1=CC=C([C+]=O)C=C1 FKXMWPFESIFWMS-UHFFFAOYSA-N 0.000 claims 2
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 claims 2
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims 2
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 claims 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 2
- ZWUSBSHBFFPRNE-UHFFFAOYSA-N 3,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1Cl ZWUSBSHBFFPRNE-UHFFFAOYSA-N 0.000 claims 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims 2
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 claims 2
- SLBRSTXWIBNAOM-UHFFFAOYSA-N 4-cyanobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(C#N)C=C1 SLBRSTXWIBNAOM-UHFFFAOYSA-N 0.000 claims 2
- DZULQZKFBAHSRX-UHFFFAOYSA-N adamantane-1-carbaldehyde Chemical compound C1C(C2)CC3CC2CC1(C=O)C3 DZULQZKFBAHSRX-UHFFFAOYSA-N 0.000 claims 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims 2
- UOJOLJBVVPLEMF-UHFFFAOYSA-N methyl 2-[[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-1$l^{6},2-benzothiazin-4-yl]oxy]acetate Chemical compound C1=CC=CC2=CC(C(=O)C3=C(C4=CC=C(F)C=C4S(=O)(=O)N3C)OCC(=O)OC)=CC=C21 UOJOLJBVVPLEMF-UHFFFAOYSA-N 0.000 claims 2
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 claims 1
- SNVPTYOYPYSYAS-UHFFFAOYSA-N 2-[[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-1$l^{6},2-benzothiazin-4-yl]oxy]-1-piperidin-1-ylethanone Chemical compound C12=CC=C(F)C=C2S(=O)(=O)N(C)C(C(=O)C=2C=C3C=CC=CC3=CC=2)=C1OCC(=O)N1CCCCC1 SNVPTYOYPYSYAS-UHFFFAOYSA-N 0.000 claims 1
- 125000006016 2-bromoethoxy group Chemical group 0.000 claims 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 claims 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 claims 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 claims 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims 1
- ABGPPNVNKDFWOI-UHFFFAOYSA-N C(C)(=O)O.C1(=CC=C(C=C1)C=O)C Chemical compound C(C)(=O)O.C1(=CC=C(C=C1)C=O)C ABGPPNVNKDFWOI-UHFFFAOYSA-N 0.000 claims 1
- RNNZMDKCSKMDJL-UHFFFAOYSA-N ClC1=C(C(=O)O)C=CC(=C1)Cl.CN1S(C2=C(C(=C1C(=O)C1=CC3=CC=CC=C3C=C1)OC(C)=O)C=CC=C2)(=O)=O Chemical compound ClC1=C(C(=O)O)C=CC(=C1)Cl.CN1S(C2=C(C(=C1C(=O)C1=CC3=CC=CC=C3C=C1)OC(C)=O)C=CC=C2)(=O)=O RNNZMDKCSKMDJL-UHFFFAOYSA-N 0.000 claims 1
- CHZZLXQTFXRCIL-UHFFFAOYSA-N [2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-1$l^{6},2-benzothiazin-4-yl] propanoate Chemical compound CN1S(=O)(=O)C2=CC=CC=C2C(OC(=O)CC)=C1C(=O)C1=CC=C(C)C=C1 CHZZLXQTFXRCIL-UHFFFAOYSA-N 0.000 claims 1
- BSKKEYHQWPQKHN-UHFFFAOYSA-N [2-methyl-4-(2-naphthalen-1-yloxyethoxy)-1,1-dioxo-1$l^{6},2-benzothiazin-3-yl]-(4-methylphenyl)methanone Chemical compound C=1C=CC2=CC=CC=C2C=1OCCOC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)C1=CC=C(C)C=C1 BSKKEYHQWPQKHN-UHFFFAOYSA-N 0.000 claims 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims 1
- 229940125708 antidiabetic agent Drugs 0.000 claims 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims 1
- 230000002255 enzymatic effect Effects 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 abstract description 3
- 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 155
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 136
- 238000005160 1H NMR spectroscopy Methods 0.000 description 93
- 238000004128 high performance liquid chromatography Methods 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 73
- 238000006243 chemical reaction Methods 0.000 description 70
- 238000001819 mass spectrum Methods 0.000 description 69
- 229910001868 water Inorganic materials 0.000 description 69
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 68
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- 239000012429 reaction media Substances 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000007787 solid Substances 0.000 description 38
- 239000000243 solution Substances 0.000 description 38
- 239000012074 organic phase Substances 0.000 description 37
- 239000000377 silicon dioxide Substances 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 29
- 235000019341 magnesium sulphate Nutrition 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 24
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 239000012298 atmosphere Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000002244 precipitate Substances 0.000 description 16
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 150000007529 inorganic bases Chemical class 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- 229960000890 hydrocortisone Drugs 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 11
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 230000000875 corresponding effect Effects 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 239000006188 syrup Substances 0.000 description 10
- 235000020357 syrup Nutrition 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 150000007530 organic bases Chemical class 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000007429 general method Methods 0.000 description 8
- 239000003862 glucocorticoid Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 229940081974 saccharin Drugs 0.000 description 8
- 235000019204 saccharin Nutrition 0.000 description 8
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 8
- 238000002821 scintillation proximity assay Methods 0.000 description 8
- 229940126657 Compound 17 Drugs 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 150000001805 chlorine compounds Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 7
- 229940037128 systemic glucocorticoids Drugs 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000006911 enzymatic reaction Methods 0.000 description 6
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- 230000001131 transforming effect Effects 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 4
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 241000287219 Serinus canaria Species 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000011948 assay development Methods 0.000 description 4
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 4
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 description 4
- 229960004544 cortisone Drugs 0.000 description 4
- 238000009509 drug development Methods 0.000 description 4
- 150000002085 enols Chemical class 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 210000001589 microsome Anatomy 0.000 description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 4
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 description 4
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 3
- YHXHHGDUANVQHE-UHFFFAOYSA-N 2-bromo-1-naphthalen-2-ylethanone Chemical compound C1=CC=CC2=CC(C(=O)CBr)=CC=C21 YHXHHGDUANVQHE-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 0 CN(C(C(c1ccc(cccc2)c2c1)=O)=C(c(cc1)c2cc1F)OCC(N(*)*)=O)S2(=O)=O Chemical compound CN(C(C(c1ccc(cccc2)c2c1)=O)=C(c(cc1)c2cc1F)OCC(N(*)*)=O)S2(=O)=O 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- IOSLINNLJFQMFF-XMMPIXPASA-N [(2R)-1-[[4-[[3-[(4-fluorophenyl)methylsulfanyl]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound FC1=CC=C(CSC=2C=C(OCC3=CC=C(CN4[C@H](CCC4)CO)C=C3)C=CC=2)C=C1 IOSLINNLJFQMFF-XMMPIXPASA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000001837 anti-cortisol effect Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229940125900 compound 59 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- PKAUVIXBZJUYRV-UHFFFAOYSA-N methane;hydroiodide Chemical compound C.I PKAUVIXBZJUYRV-UHFFFAOYSA-N 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VCHOFVSNWYPAEF-UHFFFAOYSA-N 1-(3-acetylphenyl)ethanone Chemical compound CC(=O)C1=CC=CC(C(C)=O)=C1 VCHOFVSNWYPAEF-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- PAOBXXMBVWFWMR-UHFFFAOYSA-N 2-naphthalen-2-yloxyacetyl chloride Chemical compound C1=CC=CC2=CC(OCC(=O)Cl)=CC=C21 PAOBXXMBVWFWMR-UHFFFAOYSA-N 0.000 description 2
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 2
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- 208000004611 Abdominal Obesity Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 2
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- SUKXKLNDBLNTSW-UHFFFAOYSA-N N-(4-hydroxycyclohexyl)-6-phenylhexanamide Chemical compound OC1CCC(CC1)NC(CCCCCC1=CC=CC=C1)=O SUKXKLNDBLNTSW-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 2
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 2
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 150000001351 alkyl iodides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 229950011260 betanaphthol Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000005620 boronic acid group Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- JEAVBVKAYUCPAQ-UHFFFAOYSA-N ethyl 2-chloropropanoate Chemical compound CCOC(=O)C(C)Cl JEAVBVKAYUCPAQ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- YPSSCICDVDOEAI-UHFFFAOYSA-N methyl 2-amino-4-chlorobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C=C1N YPSSCICDVDOEAI-UHFFFAOYSA-N 0.000 description 2
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 1
- WPRAXAOJIODQJR-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)ethanone Chemical compound CC(=O)C1=CC=C(C)C(C)=C1 WPRAXAOJIODQJR-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- XXLDSONYUGRTQS-UHFFFAOYSA-N 1-[3-(2,2,2-trifluoro-1-trimethylsilyloxyethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(O[Si](C)(C)C)C(F)(F)F)=C1 XXLDSONYUGRTQS-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- ZHFURHRJUWYDKG-UHFFFAOYSA-N 1-phenylcyclopropane-1-carbonitrile Chemical compound C=1C=CC=CC=1C1(C#N)CC1 ZHFURHRJUWYDKG-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- SNHVYTASQNOIGA-UHFFFAOYSA-N 2-(2-naphthalen-2-yl-2-oxoethyl)-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=CC2=CC(C(CN3S(C4=CC=CC=C4C3=O)(=O)=O)=O)=CC=C21 SNHVYTASQNOIGA-UHFFFAOYSA-N 0.000 description 1
- XSAYZAUNJMRRIR-UHFFFAOYSA-N 2-acetylnaphthalene Chemical compound C1=CC=CC2=CC(C(=O)C)=CC=C21 XSAYZAUNJMRRIR-UHFFFAOYSA-N 0.000 description 1
- LGNVAEIITHYWCG-UHFFFAOYSA-N 2-amino-4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C(N)=C1 LGNVAEIITHYWCG-UHFFFAOYSA-N 0.000 description 1
- LTCYMNSEASALNB-UHFFFAOYSA-N 2-bromo-1-(3,4-dimethylphenyl)ethanone Chemical compound CC1=CC=C(C(=O)CBr)C=C1C LTCYMNSEASALNB-UHFFFAOYSA-N 0.000 description 1
- KJVRURZDIOVSSQ-UHFFFAOYSA-N 2-bromo-1-(3-chlorophenyl)ethanone Chemical compound ClC1=CC=CC(C(=O)CBr)=C1 KJVRURZDIOVSSQ-UHFFFAOYSA-N 0.000 description 1
- ITAQNNGDCNFGID-UHFFFAOYSA-N 2-bromo-1-(3-fluorophenyl)ethanone Chemical compound FC1=CC=CC(C(=O)CBr)=C1 ITAQNNGDCNFGID-UHFFFAOYSA-N 0.000 description 1
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical compound C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 1
- QVNFUJVNBRCKNJ-UHFFFAOYSA-N 3-acetylbenzaldehyde Chemical compound CC(=O)C1=CC=CC(C=O)=C1 QVNFUJVNBRCKNJ-UHFFFAOYSA-N 0.000 description 1
- JHIDHTQDDZCASD-UHFFFAOYSA-N 3-chloro-2-methylbenzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(N)(=O)=O JHIDHTQDDZCASD-UHFFFAOYSA-N 0.000 description 1
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 1
- NIHMMULLFBKTOK-UHFFFAOYSA-N 4-chloro-3-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC(C=O)=CC=C1Cl NIHMMULLFBKTOK-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- NNYVGGHJPLSSRQ-UHFFFAOYSA-N 4-fluoro-2-methylbenzenesulfonamide Chemical compound CC1=CC(F)=CC=C1S(N)(=O)=O NNYVGGHJPLSSRQ-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- FXNSWDXUWUJLLI-UHFFFAOYSA-N 5-bromo-2-methylbenzenesulfonamide Chemical compound CC1=CC=C(Br)C=C1S(N)(=O)=O FXNSWDXUWUJLLI-UHFFFAOYSA-N 0.000 description 1
- NPEWBMJAUUSBLE-UHFFFAOYSA-N 5-fluoro-2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=C(F)C=C1S(Cl)(=O)=O NPEWBMJAUUSBLE-UHFFFAOYSA-N 0.000 description 1
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 description 1
- OVTOPAMDBHJZNS-UHFFFAOYSA-N 5-tert-butyl-2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=C(C(C)(C)C)C=C1S(Cl)(=O)=O OVTOPAMDBHJZNS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical class CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- BGGALFIXXQOTPY-NRFANRHFSA-N C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC Chemical compound C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC BGGALFIXXQOTPY-NRFANRHFSA-N 0.000 description 1
- IRSCIOWGYPAVLD-UHFFFAOYSA-N CN(C(C(c1cc(cccc2)c2cc1)=O)=C(c(cc1)c2cc1F)O)S2(=O)=O Chemical compound CN(C(C(c1cc(cccc2)c2cc1)=O)=C(c(cc1)c2cc1F)O)S2(=O)=O IRSCIOWGYPAVLD-UHFFFAOYSA-N 0.000 description 1
- PGJIINJAOPGBKV-UHFFFAOYSA-N CN(C(C(c1ccc(cccc2)c2c1)=O)=C(c(cc1)c2cc1N1CCCCC1)O)S2(=O)=O Chemical compound CN(C(C(c1ccc(cccc2)c2c1)=O)=C(c(cc1)c2cc1N1CCCCC1)O)S2(=O)=O PGJIINJAOPGBKV-UHFFFAOYSA-N 0.000 description 1
- BQENDLAVTKRQMS-SBBGFIFASA-L Carbenoxolone sodium Chemical compound [Na+].[Na+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](OC(=O)CCC([O-])=O)C1(C)C BQENDLAVTKRQMS-SBBGFIFASA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000919811 Collyria Species 0.000 description 1
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 206010022491 Insulin resistant diabetes Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- VSINKJYXCBCZDH-UHFFFAOYSA-N [2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-1$l^{6},2-benzothiazin-4-yl] acetate Chemical compound C1=CC=C2S(=O)(=O)N(C)C(C(=O)C=3C=C4C=CC=CC4=CC=3)=C(OC(C)=O)C2=C1 VSINKJYXCBCZDH-UHFFFAOYSA-N 0.000 description 1
- HMGCRQKVECKPQY-UHFFFAOYSA-N [2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-1$l^{6},2-benzothiazin-4-yl] benzoate Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C(=O)C=2C=C3C=CC=CC3=CC=2)=C1OC(=O)C1=CC=CC=C1 HMGCRQKVECKPQY-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- IYKFYARMMIESOX-SPJNRGJMSA-N adamantanone Chemical compound C([C@H](C1)C2)[C@H]3C[C@@H]1C(=O)[C@@H]2C3 IYKFYARMMIESOX-SPJNRGJMSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical compound OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000530 carbenoxolone Drugs 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- ZYXBIOIYWUIXSM-UHFFFAOYSA-N furo[2,3-c]pyridine Chemical compound C1=NC=C2OC=CC2=C1 ZYXBIOIYWUIXSM-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960001764 glibornuride Drugs 0.000 description 1
- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004132 lipogenesis Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 230000000512 lipotoxic effect Effects 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- LPOIGVZLNWEGJG-UHFFFAOYSA-N n-benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 LPOIGVZLNWEGJG-UHFFFAOYSA-N 0.000 description 1
- XNLBCXGRQWUJLU-UHFFFAOYSA-N naphthalene-2-carbonyl chloride Chemical compound C1=CC=CC2=CC(C(=O)Cl)=CC=C21 XNLBCXGRQWUJLU-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- JBDKAABFESSFMV-UHFFFAOYSA-N pyrrolo[1,2-a]pyrimidine Chemical compound N1=CC=CN2C=CC=C21 JBDKAABFESSFMV-UHFFFAOYSA-N 0.000 description 1
- RIEKLTCRUGDAPM-UHFFFAOYSA-N pyrrolo[1,2-c]pyrimidine Chemical compound C1=CN=CN2C=CC=C21 RIEKLTCRUGDAPM-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 238000011680 zucker rat Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- 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
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
Definitions
- the object of the present invention is derivatives of benzothiazine, the method for making them, the pharmaceutical compositions which contain them and their use as drugs intended for treating and/or preventing diabetes of type 2, obesity, dyslipidemias, arterial hypertension and atherosclerosis.
- These compounds may also find use in treating and/or preventing hyperglycemias, intolerance to glucose, insulin resistance, hypertriglyceridemias, hypercholesterolemias, restenoses, pancreatitises, retinopathies, nephropathies, neuropathies (Reichard et al., N. Engl. J. Med. 1993, 329:304-309), certain types of cancer (Strickler et al . , Diabetes Technology & Therapeutics 2001, 3(2) : 263-274) or glaucomas (Pascale et al., Ophtalmology 2006, 113(7) : 1081-86) .
- the present invention also relates to the combinations between the described compounds and other agents used in the treatment of these pathologies.
- the treatment of pathologies such as diabetes of type 2 often requires the combined use of several classes of compounds in order to attain the recommended values of glycemia and to keep it balanced (Nathan et al., Diabetes Care 2009 32:193-203) .
- These associations may also relate to combined treatments of obesity and diabetes of type 2 (Grundy et al . , Circulation 2005, 112: 2735-2752) .
- the metabolic syndrome is an early stage of several serious cardiovascular pathologies. It develops as a consequence of insulin-resistance and is characterized by visceral obesity (Despres et al . , Nature 2006 444(14) : 881-87), associated with certain risk factors such as intolerance to glucose and certain dyslipidemias which may be associated with arterial hypertension (Grundy, Nat. Rev. Drug Discov. 2006, 5:295-309) .
- Diabetes of type 2 is a well-documented pathology since the glycemic disorders are explained by three main mechanisms: a deficiency of the function of the Langerhans ⁇ islets at the pancreas, a decrease in the use of glucose at the peripheral tissues and excess production of glucose by the liver (Monnier et al . , Diabetes & Metabolism 2008, 34: 207-216) .
- many patients affected with diabetes of type 2 do not reach the recommended glycemia target values (notably HbAi c ) . Therefore, there is always a strong demand for treatments of this pathology based on new mechanisms.
- Obesity is an ailment affecting an increasing number of persons worldwide. It is often associated with an increased risk of diabetes of type 2, of cardiovascular diseases, of cerebro-vascular strokes and of certain types of cancer. Obesity therefore represents a major risk factor for pathologies associated with a high level of morbidity or mortality.
- Glucocorticoids are ubiquitous hormones which play a predominant role in the regulation of energy metabolism. They promote gluconeogenesis and inhibit insulin secretion by beta pancreatic cells as well as peripheral recapture of glucose (Dallman et al., Front Neuroendocrinol . 1993, 14: 303-347) .
- ll ⁇ -HSDs ll ⁇ - hydroxysteroid dehydrogenases
- target tissues liver, adipous tissue, kidney, brain ....
- this mechanism may cause a local increase in Cortisol.
- this may lead to an increase in the visceral fatty mass due to the effect of glucocorticoids on the differentiation of pre- adipocytes into adipocytes and lipogenesis; in certain situations, glucocorticoids promote lipolysis and deleterious impacts of free plasma fatty acids at the liver, pancreas, skeletal muscle for example (lipotoxicity) .
- this generation of Cortisol may cause an increase in glycemia which may develop into diabetes of type 2.
- ll ⁇ -HSD2 Two isoforms of ll ⁇ -HSD are known: type 1 and type 2.
- ll ⁇ -HSD2 is mainly localized in the kidneys. It catalyses the transformation of active glucocorticoids into inactive glucocorticoids (Cortisol into cortisone in humans) and consequently it is essentially involved in the protection of the mineralocorticoid receptors (MR) towards activation by Cortisol (Edwars et al . , Lancet, 1988, 2: 986-989) .
- MR mineralocorticoid receptors
- ll ⁇ -HSDl predominantly acts like an 11-keto-reductase and transforms inactive glucocorticoids into active glucocorticoids in the tissues where it is strongly expressed (liver and adipous tissue) .
- the inhibition of this enzyme at a hepatic and adipocyte level should therefore be expressed by a reduction of the effects mentioned earlier.
- Several studies conducted in animals have confirmed the implication of ll ⁇ -HSDl in models of obesity and/or diabetes.
- the expression of ll ⁇ - HSDl is increased in diabetic Zucker rats and this increase was correlated with the progression of the pathology (Duplomb et al . , Biochem. Biophys. Res. Commun., 2004, 313: 594-599) .
- mice without any gene coding for ll ⁇ -HSDl (KO mice) have proved to be resistant to hyperglycemia caused by obesity or stress (Kotelevtsev Y. et al. PNAS 1997, 94: 14924-14929) .
- transgenic mice selectively over-expressing ll ⁇ -HSDl at the adipous tissue developed visceral obesity, insulin-resistant diabetes and hyperlipidemia (Masuzika et al . , Science, 2001, 294: 2166-2170) .
- These experimental data emphasize the inhibition advantage of ll ⁇ -HSDl as a therapeutic target (Wamil et al . , Drug Discovery Today, 2007, 12: 504-520)
- the compounds of the present invention have the capability of selectively inhibiting ll ⁇ -HSDl relatively to ll ⁇ -HSD2 which should be expressed in human by beneficial action on diabetes of type 2, obesity, hyperlipidemias, arterial hypertension, atherosclerosis and the whole of the pathologies which are associated therewith such as coronary strokes, cerebro-vascular strokes or arteritis of the lower limbs (Wilcox et al . , Stroke, 2007, 38: 865-873; Wilcox et al., Am. Heart J. 2008, 155:712-7) . These compounds are distinguished from the prior art by their different chemical structure and their remarkable biological property.
- the object of the present invention is benzothiazine derivatives having the capability of inhibiting ll ⁇ -HSDl not only at an enzyme level but also at a cell level.
- the compounds of the present invention are of the general formula (I) :
- n represents:
- R 2 represents:
- R 3 represents:
- R 4 and R' 4 either identical or different, represent:
- R 5 represents: Ci-C 6 alkyl; phenyl either non-substituted or substituted with one or more groups selected from a halogen, Ci-C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe; a naphthyl either non-substituted or substituted with one or more groups selected from halogen or Ci-C 6 alkyl, CN, OH,
- CF 3 , OCF 3 , SMe a cycloalkyl either non-substituted or substituted with a CONH 2 , SO 2 Me, SO 2 NH 2 , heteroaryl either non-substituted or substituted with one or more groups selected from halogen, Ci-C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe
- R 6 represents:
- Ci-C 6 alkyl phenyl either non- substituted or substituted with one or more groups selected from halogen, C x -C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe; a naphthyl or heterocycle, either non-substituted or substituted with one or more groups selected from halogen or C x -C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe; a cycloalkyl either non-substituted or substituted with CONH 2 , SO 2 Me, SO 2 NH 2
- R 7 represents:
- Ci-C 6 alkyl phenyl either non- substituted or substituted with one or more groups selected from halogen, C x -C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe; a naphthyl or heterocycle, either non-substituted or substituted with one or more groups selected from halogen, Ci-C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe; a cycloalkyl either non-substituted or substituted with CONH 2 , SO 2 Me, SO 2 NH 2
- R 7 and Rs taken together may form a cycle of 4-6 members with the nitrogen atom to which they are bound and which may contain one or more heteroatoms selected from N, S or 0 and may be either non-substituted or substituted with one or more groups selected from Ci-C 6 alkyl, Ci-C 6 alkyl aryl or aryl .
- Rg represents:
- Rn represents:
- Ci-C 6 alkyl Ci-C 6 alkyl cycloalkyl, cycloalkyl, aryl, Ci-C 6 alkyl aryl
- halogen » represents fluorine, chlorine, bromine or iodine.
- alkyl » represents saturated or unsaturated linear or branched, aliphatic hydrocarbon chains and comprising the specified number of carbon atoms .
- cycloalkyl » represents cyclic or polycyclic hydrocarbon chains comprising from 3-12 carbon atoms.
- aryl » represents any monocyclic or bicyclic carbon ring which may contain up to 7 atoms per ring and in which at least one of the rings is an aromatic ring.
- heteroaryl » either represents a stable monocycle containing 5-7 atoms or a stable bicycle containing 8-11 atoms, unsaturated and consisting of carbon atoms and of one to four heteroatoms selected from N, O or S.
- heterocycle » either represents a stable monocycle containing from 5-7 atoms or a stable bicycle containing 8-11 atoms which may be either saturated or unsaturated, and consisting of carbon atoms and of one to four heteroatoms selected from N, O or S.
- taht Ri represents: Ci-C 6 alkyl or COR 5 or CO (CH 2 ) m R 6 or CO (CH 2 ) m 0R 6 or (CH 2 ) m R 6 or (CH 2 ) m CONR 7 R 8 or (CH 2 ) n NR 7 R 8 or (CH 2 ) n 0R 6 or CHR 7 ORg or (CH 2 ) m Rio, as defined earlier.
- the salts acceptable for therapeutic use of the compounds of the present invention comprise the conventional non-toxic salts of the compounds of the invention such as those formed from organic or inorganic acids or from organic or inorganic bases.
- the salts derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acids, and those derived from organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic acids.
- the salts derived from inorganic bases such as soda, potash or calcium hydroxide and the salts derived from organic bases such as lysine or arginine.
- salts may be synthesized from the compounds of the invention containing a basic of acid portion and the corresponding acids or bases according to conventional chemical methods.
- the solvates acceptable for therapeutic use of the compounds of the present invention comprise conventional solvates such as those formed during the last step of preparation of the compounds of the invention because of the presence of solvents.
- solvates due to the presence of water or ethanol.
- the compounds of general formula (I) are those for which:
- R 2 represents: A phenyl substituted with one or more groups selected from halogen, Ci-C 6 alkyl, CN, OH, CF 3 , OCF 3 , SMe; a naphthyl, 1, 2, 3, 4-tetrahydro- naphthalene, biphenyl, or heterocycle different from indole in the case when Ri, R 4 and R' 4 represent a hydrogen atom, either non-substituted or substituted with one or more groups selected from a halogen or Ci- C 6 alkyl, CN, OH, CF 3 , OCF 3 , OMe, SMe; a cycloalkyl either non-substituted or substituted with CONH 2 , SO 2 Me, SO 2 NH 2 ;
- the group R 2 is always bound to the carbonyl through a carbon atom.
- R 4 and R' 4 either identical or different, represent: hydrogen; halogen; Ci-C 6 alkyl; CN; CF 3; OCF 3; SMe; OMe; NR 7 R 8 ;
- R 7 and Rs taken together may form a ring with 4-6 members with the nitrogen atom to which they are bound and which may contain one or more heteroatoms selected from N, S or 0 and may either be non-substituted or substituted with one or more groups selected from a Ci- C 6 alkyl or aryl,
- the compounds of general formula (I) are those for which Ri represents a hydrogen.
- the compounds of general formula (I) are those for which ORi represents an ester or an ether, with Ri representing a Ci-C 6 alkyl or COR 5 or CO (CH 2 ) m R 6 or CO (CH 2 ) m 0R 6 or (CH 2 ) m R 6 or (CH 2 ) m CONR 7 R 8 or (CH 2 ) n NR 7 R 8 or
- ORi represents an ester, with Ri representing COR 5 or CO (CH 2 ) m R 6 or CO (CH 2 ) m 0R 6 .
- the object of the present invention also relates to the compounds of general formula (I) for which R 2 repreesents a naphthyl or a 1, 2, 3, 4-tetrahydro- naphthalene or biphenyl or a phenyl pyridine either non-substituted or substituted with one or more groups selected from a halogen, C x -C 6 alkyl, CN, OH, CF 3 , OCF 3 , OMe, SMe; or a phenyl substituted with one or more halogens, CN, CF 3 or Ci-C 6 alkyl.
- R 2 repreesents a naphthyl or a 1, 2, 3, 4-tetrahydro- naphthalene or biphenyl or a phenyl pyridine either non-substituted or substituted with one or more groups selected from a halogen, C x -C 6 alkyl, CN, OH, CF 3
- the compounds of general formula (I) are those for which R 4 and R' 4 represent a hydrogen.
- an appreciated class of compounds corresponds to the compounds of general formula (I) wherein Ri is a hydrogen and R 2 is a naphthyl or else a 1, 2, 3, 4-tetrahydro-naphthalene .
- the present invention relates to the compounds of general formula (I) wherein ORi represents an ester or an ether and R 2 is a naphthyl or else a 1,2,3, 4-tetrahydro-naphthalene .
- ORi represents an ester or an ether and R 2 is a naphthyl or else a 1,2,3, 4-tetrahydro-naphthalene .
- Another appreciated class of compounds corresponds to the compounds of general formula (I) wherein Ri is a hydrogen and R2 is a phenyl substituted with one or more halogens, CN, CF 3 or Ci-C ⁇ alkyl.
- Another appreciated class of compounds corresponds to the compounds of general formula (I) wherein Ri is a hydrogen and R2 is a biphenyl or a phenyl pyridine, either non-substituted or substituted as defined in the description of general formula (I) .
- the present invention relates to the compounds of general formula (I) wherein ORi represents an ester or an ether and R2 is a phenyl substituted with one or more halogen, CN, CF 3 or Ci-C ⁇ alkyl.
- Another appreciated class of compounds corresponds to the compounds of general formula (I) wherein ORl represents an ester or an ether and R2 is a biphenyl or a phenyl pyridine non-substituted or substituted as defined in the description of the general formula (I) .
- the present invention also relates to the preparation of the compounds of general formula (I) by general methods described in the following synthesis schemes if necessary completed with all the standard manipulations described in the literature or well-known to one skilled in the art or else still exemplified in the experimental part.
- Scheme 1 illustrates the first general method which may be used for preparing the compounds of general formula (Ia) .
- R 2 , R3, R4 and R' 4 are defined as in the previous description of the general formula (I) and Ri is equal to hydrogen.
- X may represent a leaving group such as for example Cl, Br, I, OSO 2 CH 3 , OSO 2 CF 3 or O-tosyl.
- the reaction with the compound of general formula (II) will be conducted in the presence of an inorganic base such as for example NaH in a polar anhydrous solvent such as THF or DMF at a temperature comprised between - 20° and 100 0 C.
- the intermediate of general formula (III) is transformed into an intermediate of general formula
- reaction with the compound of general formula (IV) will be conducted in the presence of an inorganic base such as for example NaH in a polar anhydrous solvent such as THF or DMF at a temperature comprised between - 20° and 100 0 C.
- an inorganic base such as for example NaH in a polar anhydrous solvent such as THF or DMF at a temperature comprised between - 20° and 100 0 C.
- Scheme 2 illustrates the general method which may be used for preparing the compounds of general formula
- R' 4 are defined as in the previous description of the general formula (I) except that Ri is different from a hydrogen .
- the intermediate of general formula (Ia) is transformed into a compound of general formula (Ib) by reaction with Ri-Z.
- Ri represents a Ci-C 6 alkyl, (CH 2 ) m R 6 , (CH 2 UCONR 7 R 8 , (CH 2 ) n NR 7 R 8 , (CH 2 ) n OR 6 , CHR 7 OR 9 or (CH 2 ) m Ri 0 with R ⁇ , R 7 , R 8 , Rg, Rio, in and n defined as in the previous description of the general formula (I), except that Rio does not represent an acid, and Z is a leaving group such as for example Cl, Br, I, OSO 2 CH 3 , OSO 2 CF 3 or O-tosyl, the reaction with the enol of general formula
- (Ia) may be conducted in the presence of an organic or inorganic base such as for example Et3N, iPr 2 NEt, NaH, pyridine, CS2CO3, K2CO3 in a polar anhydrous solvent such as THF, DMF, DMSO, acetone at a temperature comprised between -20° and 140 0 C, either in the presence or not of a salt as a catalyst and which may be KI, BU4NI, LiI, AgBF 4 , AgClO 4 , Ag 2 CO 3 , KF, Bu 4 NF or
- the reaction may also be conducted in a « sealed or threaded tube » heated by heat energy or microwave energy, at temperatures comprised between 80 and 180 0 C.
- Z may also represent an alcohol.
- the reaction with the intermediate (Ia) will be of the « Mitsunobu » type and may be conducted in the presence of diethylazodicarboxylate (DEAD) and of triphenylphosphine in a polar anhydrous solvent such as THF at a temperature comprised between 0 and 60 0 C.
- DEAD diethylazodicarboxylate
- THF polar anhydrous solvent
- reaction with the enol of general formula (Ia) boils down to the reaction between an acid chloride and a sulfonyl chloride and an alcohol.
- This reaction may be conducted in the presence of an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, pyridine, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, dichloromethane at a temperature comprised between -20° and 140 0 C.
- an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, pyridine, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, dichloromethane at a temperature comprised between -20° and 140 0 C.
- a particularly appreciated method consists of producing this condensation in the presence of 1- (3- dimethylaminopropyl) -3-ethyl-carbodiimide (EDC), of 3- hydroxy-1, 2, 3-benzotriazin-4 (3H) -one, of a tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane, at a temperature comprised between -15°C and 40 0 C.
- EDC 1- (3- dimethylaminopropyl) -3-ethyl-carbodiimide
- EDC 3- hydroxy-1, 2, 3-benzotriazin-4 (3H) -one
- a tertiary amine such as diisopropylethylamine
- Scheme 3 illustrates the general method which may be used for preparing the compounds of general formula (Ic) wherein R 1 represents (CH 2 J n NR 7 R 8 or (CH 2 ) n OR 6 with Re, R 7 , R 8 , n and R 2 , R3, R 4 and R' 4 defined as in the previous description of general formula (I) .
- the intermediate of general formula (Ia) is transformed into an intermediate of general formula (V) by reaction with a reagent of general formula X (CH 2 ) n X' wherein X and X' represent a leaving group either identical or different such as for example Cl, Br, I, OSO 2 CH 3 , OSO 2 CF 3 or O-tosyl and n is defined as earlier.
- the reaction between this reagent and the enol of general formula (Ia) for leading to the intermediate of general formula (V) may be conducted in the presence of an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, pyridine, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, acetone at a temperature comprised between -20° and 140 0 C, either in the presence or not of a salt as a catalyst and which may be KI, BU4NI, LiI, AgBF 4 , AgClO 4 , Ag 2 CO 3 , KF, Bu 4 NF or CsF.
- an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, pyridine, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, acetone at a temperature comprised between
- This reaction may also be conducted without any solvent, with a large excess of reagent X (CH 2 ) n X' •
- the reaction may also be conducted in a « sealed or threaded tube » heated by heat energy or microwave energy, at temperatures comprised between 80 and 180 0 C.
- X or X' may also represent an alcohol.
- the reaction with the intermediate (V) will be of the « Mitsunobu » type and may be conducted in the presence of diethylazodicarboxylate (DEAD) and of triphenylphosphine in a polar anhydrous solvent such as THF at a temperature comprised between 0 and 60 0 C.
- DEAD diethylazodicarboxylate
- THF polar anhydrous solvent
- the intermediate of general formula (V) is transformed into a product of general formula (Ic) by reaction with HNR 7 Rg or HOR ⁇ wherein R ⁇ , R 7 and Rs are defined as in the previous description of the general formula (I) .
- This reaction may be conducted in the presence of an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, pyridine, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, acetone at a temperature comprised between -20° and 140 0 C, either in the presence or not of a solvent as a catalyst and which may be KI, BU4NI, LiI, AgBF 4 , AgClO 4 , Ag 2 CO 3 , KF, Bu 4 NF or CsF.
- the selection of the experimental conditions and of the reagents for conducting this reaction of course depends on the nature of the substituents Re, R 7 and Rs and will be performed according to the methods
- Scheme 4 illustrates the general method which may be used for preparing the compounds of general formula
- Ri represents (CH 2 ) m CONR 7 R 8 with R 7 , R 8 , m and R2, R3, R4 and R' 4, defined as in the previous description of general formula (I) .
- the intermediate of general formula (Ia) is transformed into an intermediate of general formula (VI) by reaction with a reagent of general formula Y(CH 2 ) m COOY' wherein Y represents a leaving group such as for example Cl, Br, I, OSO 2 CH 3 , OSO 2 CF 3 or O-tosyl, m is defined as earlier and Y' represents a Ci-C 4 alkyl radical.
- This reaction may be conducted in the presence of an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, pyridine, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, acetone at a temperature comprised between -20° and 140 0 C, either in the presence or not of a salt as a catalyst and which may be KI, BU4NI, LiI, AgBF 4 , AgClO 4 , Ag 2 CO 3 , KF, Bu 4 NF or CsF.
- the reaction may also be conducted in a « sealed or threaded tube » heated by heat energy or microwave energy, to temperatures comprised between 80 and 180°C.
- the intermediate of general formula (VI) is transformed into an intermediate of general formula (VII) by reaction with an inorganic base such as for example NaOH, KOH, LiOH in a polar solvent such as methanol, ethanol, THF and water, at a temperature comprised between 20° and 80 0 C.
- an inorganic base such as for example NaOH, KOH, LiOH in a polar solvent such as methanol, ethanol, THF and water, at a temperature comprised between 20° and 80 0 C.
- the obtained carboxylic acid (VII) may react with an amine in order to lead to the compounds of general formula (Id) . This reaction may be conducted by the methods and techniques well- known to one skilled in the art.
- a particularly appreciated method consists of condensing these 2 entities in the presence of 1- (3-dimethylaminopropyl) - 3-ethyl-carbodiimide (EDC), of 3-hydroxy-l, 2, 3- benzotriazin-4 (3H) -one, of a tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane or DMF, at a temperature comprised between -15°C and 50 0 C.
- EDC 1- (3-dimethylaminopropyl) - 3-ethyl-carbodiimide
- EDC 3-hydroxy-l
- 2, 3- benzotriazin-4 (3H) -one of a tertiary amine such as diisopropylethylamine
- a polar aprotic solvent such as dichloromethane or DMF
- BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate
- Another particularly appreciated method consists of transforming the carboxylic acid into an acid chloride by reaction with oxalyl chloride or thionyl chloride in the absence or in the presence of a base such as pyridine or triethylamine with or without a solvent such as toluene or dichloromethane at a temperature comprised between 20 and 100 0 C.
- This acid chloride may then react with the amine HNR 7 R 8 in the presence of a base such as pyridine or triethylamine in a solvent such as dichloromethane at a temperature comprised between 0 and 100 0 C.
- Scheme 5 illustrates the general method which may be used for transforming the compounds of general formula (Ie) wherein R 4 represents a fluorine and R2, R3 and R' 4 are defined as in the previous description of the general formula (I) into compounds of general formula (If) wherein R 4 represents NR 7 Rg with R 7 , Rg and R2, R3 and R' 4 defined as in the previous description of the general formula (I) .
- the compounds of general formula (Ie) may be transformed into compounds of general formula (If) by reaction with an amine of general formula HNR 7 Rg in the presence of an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such a DMF, DMSO at a temperature comprised between 20° and 140 0 C.
- an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, NaH, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such a DMF, DMSO at a temperature comprised between 20° and 140 0 C.
- Scheme 6 illustrates the general method which may be used for transforming the compounds of general formula
- the compounds of general formula (Ig) may be transformed into compounds of general formula (Ih) by a Suzuki type reaction with a boronic acid in the presence of an organic or inorganic base such as for example Et 3 N, NMP, iPr 2 NEt, NaH, Cs 2 CO 3 , K 2 CO 3 , K 3 PO 4 with a catalyst such as for example palladium acetate, palladium tetrakis triphenylphosphine, tris (dibenzilideneacetone) dipalladium in a polar solvent such as for example acetone, methyl ethyl ketone, ethanol, DME, water, dioxane, and optionally in the presence of a phosphine such as triphenylphosphine or tricyclohexylphosphine at a temperature comprised between 20° and 140 0 C.
- an organic or inorganic base such as for example Et 3 N, NMP, iPr 2 NEt,
- Scheme 7 illustrates the general method which may be used for transforming the compounds of general formula
- R 2 represents a phenyl substituted with a CN group in the ortho or meta position into compounds of general formula (Ij) wherein R 2 represents a phenyl substituted with a carboxylic acid in the ortho or meta position and then into compounds of general formula (Ik) wherein R 2 represents a phenyl substituted with an amide of formula CONR 7 Rn and wherein R 3 , R 4 , R 7 , Rn and R' 4 are defined as in the previous description of the general formula (I) .
- the comounds of general formula (Ii) may be transformed into compounds of general formula (Ij) by treatment with an inorganic base such as for example NaOH, KOH, LiOH in a polar solvent such as ethanol, methanol, THF, water at a temperature comprised between 20° and 140 0 C followed by acidification by treatment with an acid such as HCl, H 2 SO 4 , HCOOH.
- the compounds of general formula (Ij) may be transformed into compounds of general formula (Ik) by reaction with an amine of formula HNR 7 Rn. This reaction may be conducted with methods and techniques well-known to one skilled in the art.
- a particularly appreciated method consists of condensing these 2 entities in the presence of 1- (3- dimethylaminopropyl) -3-ethyl-carbodiimide (EDC), of 3- hydroxy-1, 2, 3-benzotriazin-4 (3H) -one, of a tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane or DMF, at a temperature comprised between -15°C and 50 0 C.
- EDC 1- (3- dimethylaminopropyl) -3-ethyl-carbodiimide
- EDC 3- hydroxy-1, 2, 3-benzotriazin-4 (3H) -one
- a tertiary amine such as diisopropylethylamine
- BOP benzotriazol-1-yloxy- tris (dimethylamino) phosphonium hexafluorophosphate
- Another particularly appreciated method consists of transforming the carboxylic acid into an acid chloride by reaction with oxalyl chloride or thionyl chloride in the absence or in the presence of a base such as pyridine or triethylamine with or without a solvent such as toluene or dichloromethane at a temperature comprised between 20 and 100 0 C.
- This acid chloride may then react with the amine HNR 7 Rn in the presence of a base such as pyridine or triethylamine in a solvent such as dichloromethane at a temperature comprised between 0 and 100°C.
- the saccharin (25 g, 136 mmol) and DMF (350 mL) are introduced into a three-neck flask equipped with a thermometer and a condenser.
- the medium is inertized by a vacuum/nitrogen succession (3x) .
- Example IB (4-hydroxy-l, l-dioxo-2H- benzo[e] [ 1, 2 ] thiazin-3-yl) (naphthalen-2-yl) methanone.
- ethanol 165 mL
- heptane 8 g, 347 mmol
- the reaction medium is heated to 70 0 C until complete reaction of the sodium.
- the reaction is then cooled to room temperature, and the compound IA (47 g, 131 mmol) is added rapidly.
- An intense vermilion red and then blood red coloration appears as well as a thick precipitate.
- the reaction medium is heated briefly to 60 0 C where it solidifies. It is then cooled to room temperature and diluted in 500 mL of ethyl acetate.
- a fraction of the compound 1 is dissolved and methanol and treated at room temperature with 1.05 equivalents of an aqueous IN soda solution.
- the reaction medium is concentrated and the solid residue rinsed with a mixture of dichloromethane and ethyl ether.
- the thereby obtained canary yellow solid is dried in vacuo for several days .
- the compounds 2_ to ⁇ 2_ were synthesized according to the procedure used for preparing the derivative 1, from saccharin and various 2-bromo-l- (alkyl or aryl) ethanones in the first step and from methyl iodide or ethyl iodide in the third step.
- the rearrangement protocol in the second step is unchanged.
- Example 13A 2-Chloro-6-sulfamoylbenzoic acid.
- the compound 13A (12.87 g, 54.6 mmol) is introduced into a flask followed by 38.8 mL of concentrated sulfuric acid.
- the reaction mixture is stirred at room temperature for 1.5 hours and then poured on a mixture of water and ice.
- the formed precipitate is filtered, rinsed with water and dried until its weight is constant in order to obtain the compound 13B as a white solid (9.16 g; 77%) .
- Example 13C 4-chloro-2- (2- (naphthalen-2-yl) -2- oxoethyl) benzo [d] isothiazol-3 (2H) -one-1, 1-dioxide.
- the compound 13C was synthesized from the compound 13B
- the compound 13D was synthesized from the compound 13C
- Example 13 - The compound L3 was synthesized from the compound 13D (3 g, 7.7 mmol) according to the procedure used for preparing the derivative I ⁇ in order to obtain the compound L3 as a yellow solid (2.3 g; 70%) .
- the compound 14. was synthesized from the compound 13D (1 g, 2.6 mmol) and from iodoethane according to the procedure used for preparing the derivative I ⁇ in order to obtain 805 mg (60%) of the desired product.
- Example 15A 6-fluoro-4-hydroxy-l, l-dioxo-2H- benzo[e] [ 1, 2 ] thiazin-3-yl) (naphthalen-2-yl) methanone .
- the compound 15A was synthesized from the compound 4- fluoro-2-methylbenzenesulfonamide according to the same sequence of steps involved in preparing the compound 13D.
- the product is obtained as a yellow solid with an overall yield of 79%.
- the compound L5 was synthesized from the compound 15A (1.5 g, 4 mmol) according to the procedure used for preparing the derivative I ⁇ in order to obtain 1.47 g (89%) of the desired product as a yellow solid.
- the compound 1_6 was synthesized from the compound 15A (1.5 g, 4 mmol) and from iodoethane according to the procedure used for preparing the derivative I ⁇ in order to obtain 520 mg (29%) of the desired product as a yellow solid.
- Example 17B (7-Fluoro-4-hydroxy-l, l-dioxo-2H- benzo [e] [ 1, 2 ] thiazin-3-yl) (naphthalen-2-yl) methanone .
- the compound 17B was synthesized from the compound 17A according to the same sequence of steps involved in preparing the compound 13D.
- the product is obtained as a yellow solid with an overall yield of 73%.
- Example 17 (7-Fluoro-4-hydroxy-2-methyl-l, l-dioxo-2H- benzo[e] [ 1, 2 ] thiazin-3-yl) (naphthalen-2-yl) methanone .
- the compound 3/7 was synthesized from the compound 17B (4.00 g, 10.8 mmol) according to the procedure used for preparing the derivative I ⁇ in order to obtain two batches of the desired product with different purities.
- First batch: 3.79 g; pale brown solid; HPLC: RT 5.65 min, 94%.
- the compound 18 was synthesized from the compound 17A
- the compound 1 (86 mg, 0.18 mmol) is dissolved under an inert atmosphere in 0.5 mL of dichloromethane and 0.5 mL of pyridine.
- the reaction medium is cooled to 0 0 C and then benzoyl chloride (33 ⁇ l, 0.27 mmol) is added.
- the cold bath is removed and the reaction is stirred for 4 hours at room temperature.
- 16 ⁇ l (0.14 mmol) of benzoyl chloride are further added and the reaction medium is stirred at room temperature for a further 20 hours before being concentrated.
- the residue is taken up in ethyl acetate, washed once with water and once with an aqueous NaCl saturated solution, dried on sodium sulfate, filtered and concentrated.
- This second residue is co-evaporated three times with toluene in order to remove the remaining pyridine.
- the thereby obtained yellow syrup is purified on a column of 12 g of spherical silica (flow rate 12 mL/min, CH2Cl2/heptane gradient from 20 to 100% (30 min) ) , in order to obtain the compound 1_9 as a yellow foam (38 mg; 44%) .
- the compound 1_ (86 mg, 0.18 mmol) is st dissolved under an inert atmosphere in 0.5 mL de pyridine.
- the reaction medium is cooled to 0 0 C and then cyclohexanecarbonyl chloride (62 ⁇ l, 0.46 mmol) is added.
- the cold bath is removed and the reaction is stirred for 18 hours at room temperature, and then heated to 60 0 C for 8 hours.
- the reaction mixture is concentrated and co-evaporated three times with toluene.
- the thereby obtained residue is purified on a column of 12 g of spherical silica (flow rated 12 mL/min, CH2Cl2/heptane gradient from 20 to 100% (20 min) ) , in order to obtain the compound £0_ as a yellow foam (65 mg; 28%) .
- the compound 1_ (86 mg, 0.18 mmol) is dissolved under inert atmosphere in 0.5 mL of pyridine.
- the reaction medium is cooled to 0 0 C and then tertbutylcarbonyl chloride (57 ⁇ l, 0.46 mmol) is added.
- the cold bath is removed and the reaction is stirred for 18 hours at room temperature.
- the reaction medium is concentrated and co-evaporated three times with toluene.
- the thereby obtained residue is purified on a column of 12 g of spherical silica (flow rate 12 mL/min, CH 2 Cl2/heptane gradient from 20 to 100% (20 min) ) , in order to obtain the compound 2 ⁇ _ as a yellow foam (47 mg; 53%) .
- the compound 22 was synthesized according to the same procedure as for compound Z ⁇ _ from the compound I ⁇ (86 mg, 0.18 mmol) and from 4-methylbenzoyl chloride (62 ⁇ l, 0.46 mmol) .
- the product is obtained as a yellow foam (27 mg; 31%) .
- the reaction medium is concentrated and co-evaporated three times with toluene.
- the thereby obtained residue is purified on a column of 12 g of spherical silica (flow rate 12 mL/min, CH 2 Cl 2 /heptane gradient from 20 to 100% (20 min) ) , in order to obtain the compound 23 as a yellow foam (51 mg; 42%) .
- HPLC : RT 5 . 92 min , 97 %
- the compounds 2 ⁇ _ to 21_ were synthesized according to the procedure described for preparing the compound 21, from the compound 15 and from various acid chlorides.
- the compounds 28 to 31 were synthesized according to the procedure described for preparing compound 2 ⁇ _, from the compound 16 and various acid chlorides.
- the compounds 3£ and 3_3 were synthesized according to the procedure described for preparing the compound 23, from 4-chlorobenzoic acid and from the compounds L5 and 16, respectively.
- the compound 3 ⁇ (150 mg, 0.455 mmol) is dissolved under an inert atmosphere in 3 mL of tetrahydrofurane .
- Sodium hydride (27 mg, 0.68 mmol) is added, followed by naphthalen-2-ylcarbonyl chloride (105 ⁇ l, 0.68 mmol) 30 minutes later.
- the reaction is stirred for 4 horus at room temperature.
- the reaction medium is neutralized with water and the aqueous phase is extracted twice with ethyl acetate.
- the organic phases are combined, dried on magnesium sulfate, filtered and concentrated.
- the compounds 3_5 to 4_5 were synthesized according to the procedure described for preparing the compound 34, from the compound 3 or from the compound 5 and from various acid chlorides.
- 2-naphthol (3.0 g, 20 mmol) is dissolved in 95 mL of methylethylketone (MEK) in the presence of soda (40 g, 93 mmol) , and then heated to 50 0 C for 30 minutes.
- MEK methylethylketone
- the acid formed earlier (3.04 g, 15 mmol) is partly dissolved under an inert atmosphere and at room temperature in 34 mL of dichloromethane .
- Oxalyl chloride (1.35 mL, 15.7 mmol) is added followed by 100 ⁇ l of DMF. Caution, a violent reaction occurs upon adding DMF.
- the reaction mixture is stirred for 1 hour and then concentrated, co-evaporated twice with toluene and dried until it has constant weight in order to obtain 3.4 g (100%) of (naphthalen-2-yloxy) acetyl chloride as an orangey solid.
- the thereby formed acid chloride was used as such in preparing the compounds 4_0_ and 41.
- the compound 1 (100 mg, 0.274 mmol) is dissolved under an inert atmosphere in 2 mL of dichloromethane .
- Triethylamine (230 ⁇ l, 1.64 mmol) is added at 0 0 C, followed by acetyl chloride (78 ⁇ l, 1.09 mmol) .
- the reaction medium is stirred at room temperature for 18 hours and then concentrated.
- the thereby obtained residue is purified on a column of 12 g of spherical silica in order to obtain the compound 4_6 (21 mg; 30%) .
- the compounds 47 to 54 were synthesized according to the procedure described for preparing the compound 46, from the compound 1 and from various acid chlorides.
- the compound 1_ (159 mg, 0.435 mmol) is dissolved under an inert atmosphere in 2 mL of DMF. Sodium hydride (26 mg, 0.65 mmol) is added, followed by methane iodide
- the compounds 5J> to 5JJ were prepared according to the following procedure:
- the compound 1_ (150 mg, 0.42 mmol) is dissolved under an inert atmosphere in 0.3 mL of DMF.
- Cesium carbonate (201 mg, 0.61 mmol) and the require alkyl iodide (4 mmol) are added.
- the reaction medium is stirred for 18 hours at room temperature, for 4 hours at 50 0 C and then neutralized with water, and the aqueous phase is extracted twice with ethyl acetate.
- the organic phases are combined, dried on magnesium sulfate, filtered and concentrated.
- the thereby obtained residues are purified on columns of 12 g of spherical silica (flow rate 12 mL/min, gradient of 20 to 60% dichloromethane in heptane), in order to obtain the desired products.
- the compound 3 ⁇ (100 mg, 0.3 mmol) is dissolved in 3 mL of THF, under an inert atmosphere and in the presence of 2-chloroethanol (100 ⁇ l, 1.5 mmol) .
- the reaction mixture is cooled to 0 0 C, and then triphenylphosphine (318 mg, 1.2 mmol) and diethyldiazene-1, 2-dicarboxylate (DEAD, 211 mg, 1.2 mmol) are successively added dropwise. Stirring is continued for 20 hours at room temperature, and then the reaction is neutralized with an aqueous solution saturated with ammonium chloride. This aqueous phase is extracted twice with ethyl acetate.
- the compound ⁇ £ (70 mg, 0.17 mmol) is dissolved in 2 mL of DMF, under an inert atmosphere and in the presence of potassium carbonate (64 mg, 0.53 mmol), potassium iodide (31 mg, 0.19 mmol) and 2-naphthol (38 mg, 0.27 mmol) .
- the reaction medium is heated to 65°C, for 22 hours, and then neutralized with water and extracted twice with ethyl acetate. The organic phases are combined, dried on magnesium sulfate, filtered and concentrated.
- the thereby obtained residue is purified by semi-preparative HPLC on a Waters Sunfire column (19x100 mm, 5 ⁇ m) , with a flow of 20 mL/min and a 15 minute gradient of 10 to 100% acetonitrile in water (0.1% TFA buffer), in order to obtain the compound (>0_ (30 mg; 29%) .
- the compound 1_ (100 mg, 0.274 mmol) is dissolved in 0.5 mL of DMF in presence of potassium carbonate (90 mg, 0.55 mmol) and 2-phenoxyethyl bromide (110 mg, 0.55 mmol) .
- the reaction medium is heated in a sealed tube, to 80 0 C for 16 hours.
- the medium is taken up in ethyl acetate and then washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the thereby obtained residue is purified on a column of 12 g of silica (flow rate 20 mL/min, gradient of 0 to 10% dichloromethane in heptane) , in order to obtain the compound Sl_ as a yellow syrup (45 mg; 34%) .
- the compound 62_ was synthesized according to the same procedure as the compound b ⁇ _ from the compound 3_ (300 mg, 0.91 mmol) and from methyl glycolate (350 ⁇ l, 4.5 mmol) in order to obtain 300 mg (79%) of the desired product as a yellow syrup.
- the compound 62 (75 mg, 0.18 mmol) is dissolved in 1 mL of THF, and lithium hydroxide (1M/H 2 O, 0.37 mmol) is added.
- the reaction medium is stirred at room temperature for 2 hours, and then diluted in water and extracted twice with dichloromethane .
- the yield of this operation is 30%.
- the compound 63 (110 mg, 0.28 mmol) is dissolved in 3 mL of DMF. Different amines (0.23 mmol), DIEA (82 ⁇ l, 0.472 mmol), HOOBT (35 mg, 0.26 mmol) EDCI (50 mg, 0.26 mmol) are added. The reaction medium is stirred for 18 hours at room temperature. The medium is taken up in dichloromethane and then washed with IN soda, water, and a saturated NaCl solution. The organic phases are combined, dried on magnesium sulfate, filtered and concentrated. The thereby obtained residues are purified on columns of 12 g of spherical silica (flow rate 12 mL/min, 0 to 50% AcOEt in heptane), in order to obtain the desired products.
- the compound 1_ (1.0 g, 2.74 mmol) is dissolved in 2 mL of DMF in the presence of potassium carbonate (682 mg, 4.1 mmol) and methyl bromoacetate (1.26 mL, 13.68 mmol) .
- the reaction medium is stirred at room temperature for 5 hours and then the same amount of methyl bromoacetate is added again. After one night at room temperature, the mixture is taken up in ethyl acetate and then washed with water and with a saturated NaCl solution. The organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the thereby obtained residue is purified on a column of 90 g of silica (flow rate 32 mL/min, gradient of 40 to 100% dichloromethane in heptane) , in order to obtain the compound 61_ as a yellow syrup (486 mg; 41%) .
- the compound 61_ (480 mg, 1.1 mmol) is dissolved in THF/water 5:1 mixture (6 mL) and then treated with LiOH
- the medium is taken up in ethyl acetate and then washed with IN HCl, water and with a saturated NaCl solution.
- EDCI 50 mg, 0.26 mmol
- the reaction mixture is stirred for 24 hours at room temperature and then amine in excess is added (0.07 mmol) and the medium is stirred for a further 5 hours.
- the medium is taken up in dichloromethane and washed with IN soda, water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the thereby obtained residues are purified on columns of 12 g of spherical silica (flow rate 12 mL/min, 1% of a methanol/ammonia 9:1 mixture in dichloromethane) , in order to obtain the desired products .
- the compounds 72 to 74 were synthesized according to the procedure described for preparing the compound 46, from the compound 1 and from various acid chlorides.
- the compounds 75 anc ⁇ ZU were synthesized according to the procedure described for preparing the compound 60, from the compound 59 and various alcohols.
- the compounds 11_ and 1%_ were synthesized according to the procedure described for preparing the compound 34, from the compound 3_ and from acetyl chloride and propanoyl chloride respectively.
- the compounds 7_9 et JH) were synthesized according to the procedure described for preparing the compound 59, from the compound ⁇ and from methanol and ethanol respectively.
- the compound 1 (150 mg, 0.41 mmol) is dissolved in methylethylketone (3 mL) and then treated with dibromoethane (71 ⁇ l, 0.82 mmol) in the presence of K2CO3 (170 mg, 1.02 mmol) .
- the reaction is heated with microwave energy in a sealed tube at 130 0 C for 4h 30min.
- the medium is taken up in ethyl acetate and then washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated. The thereby obtained residue (brown syrup, 197 mg) is directly engaged into the next reaction.
- the compound 81 (197 mg, 0.41 mmol) is dissolved in methylethylketone (1.5 mL) and then treated with 4- chlorophenol (107 ⁇ l, 0.82 mmol) in the presence of K2CO3 (173 mg, 1.04 mmol) .
- the reaction is heated with microwave energy in a sealed tube at 130 0 C for 2 hours.
- the medium is taken up in ethyl acetate and then washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the thereby obtained residue is purified on a column of 12 g of silica (flow rate 12 mL/min, gradient of 10 to 100% dichloromethane in heptane) , in order to obtain the compound JJ£ as a yellow syrup (21 mg; 14%) .
- the compound 1 (100 mg, 0.27 mmol) is dissolved in DMF (1 mL) and then treated with ethyl 2-chloropropanoate (110 ⁇ l, 0.82 mmol) in the presence of K 2 CO 3 (91 mg, 0.55 mmol) .
- the reaction is heated in a sealed to 60 0 C overnight and then the same amount of ethyl 2- chloropropanoate is added and the reaction is stirred for a further 24 hours.
- the medium is taken up into ethyl acetate and then washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the thereby obtained residue is purified on a column of 12 g of silica (flow rate 12 mL/min, gradient of 25 to 80% dichloromethane in heptane), in order to obtain the compound JJ3_ as a yellow syrup (100 mg; 76%) .
- the compound 1_ (100 mg, 0.27 mmol) is dissolved in methylethylketone (0.5 mL) and then treated with 1- (2- chloroethyl) piperidine (252 mg, 1.37 mmol) in the presence of K2CO3 (159 mg, 0.96 mmol) .
- the reaction is heated to 8O 0 C overnight.
- the medium is further taken up with ethyl acetate and then washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the compounds L3, r5, or 3/7 are dissolved under an inert atmosphere in 2 mL of dichloromethane in the presence or triethylamine (6 eq.) and then treated with various acid chlorides (4 eq.) at 0 0 C.
- the reaction mixtures are stirred for 2 hours at 0 0 C and then at room temperature for 20 hours.
- the media are taken up in ethyl acetate and then washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on sodium sulfate, filtered and concentrated.
- the thereby obtained residues are purified on a column of 12 g of silica (flow rate 12 mL/min, gradient of 0 to 20% ethyl acetate in heptane) , in order to obtain the expected compounds .
- the compounds 91_ to 104 were synthesized according to the procedure used for preparing examples 56 to 58 from the compound L3, L5, or 3/7 and from corresponding alkyl iodides or sulfates.
- the compound 105 was synthesized according to the procedure used for preparing example 67 from the compound 17 (1 g, 2.61 mmol) .
- the product is obtained as a yellow syrup (810 mg; 68%) .
- the compound 106 was synthesized according to the procedure used for preparing example 68 from the compound 105 (598 mg, 1.31 mmol) .
- the product is obtained as a beige powder (262 mg; 45%) .
- the compounds 107 to 109 were synthesized according to the procedure used for preparing examples 69 to 71 from the compound 106 and the corresponding amines.
- the compound 3/7 (200 mg, 0.52 mmol) is dissolved in dichloromethane (2 mL) and then treated at 0 0 C with benzene sulfonyl chloride (67 ⁇ l, 0.52 mmol) in the presence of Et 3 N (145 ⁇ l, 1.04 mmol) .
- the reaction is stirred from 0 0 C to room temperature for 4 hours and then the medium is taken up in dichloromethane and washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on magnesium sulfate, filtered and concentrated.
- the thereby obtained residue is purified on a column of 12 g of silica (flow rate 12 mL/min, gradient of 20 to 50% dichloromethane in heptane) , in order to obtain the compound 110 as a cream-colored powder (177 mg; 65%) .
- the compounds 111 to 117 were synthesized according to the procedure used for preparing example 110 from the compound 1 or 17 and the corresponding sulfonyl chlorides .
- the compound 17 (200 mg, 0.52 mmol) is dissolved in DMSO (2 mL) in the presence of K 2 CO 3 (144 mg, 1.04 mmol) and then treated at room temperature with piperidine (154 ⁇ l, 1.56 mmol) .
- the reaction is stirred at 100 0 C for 20 hours and then the medium is taken up in ethyl acetate and washed with water and with a saturated NaCl solution.
- the organic phases are combined, dried on magnesium sulfate, filtered and concentrated.
- the compounds 119 to 121 were synthesized according to the procedure used for preparing example 118 from the compound 17 and the corresponding amines.
- the compound 122 was synthesized from 2-methyl-5- tertbutylbenzenesulfonyl chloride according to the same sequence of steps involved in preparing the compound 17. The compound is obtained as a yellow solid with an overall yield of 10%.
- the compounds 123 to 130 were synthesized from saccharine and from corresponding 2-bromo-l- arylethanones according to the same sequence of steps described for preparing the compound 1_ (for 123, 125, 127 and 128) from the compound Q_ (for 124 and 126) and from the compound 17 (for 129 and 130)
- the compounds 144 to 146 were synthesized from saccharine and from the corresponding 2-bromo-l- arylethanones according to the same sequence of steps described for the preparation of the compound 1_.
- the 2-bromo-l-arylethanones were prepared by bromination of the corresponding arhylethanones, according to the procedure described for preparing the compound 144A: 1- (3, 4-dimethylphenyl) ethanone (2.5 g, 16.9 mmol) is dissolved under a nitrogen atmosphere in 42 mL of THF at room temperature. Trifluoroacetic acid (1.5 mL, 16.9 mmol) is added followed by pyridinium tribromide (6.5 g, 20.2 mmol) . The solution turns vermilion red and a white precipitate gradually appears. After three hours of stirring at room temperature, the reaction is neutralized by adding 50 mL of water, and then extracted with 100 mL of ethyl acetate.
- the organic phase is washed with 40 mL of a saturated CuSO 4 solution, 40 mL of a saturated NaCl solution, and then dried on magnesium sulfate, filtered and concentrated under reduced pressure.
- the residue is purified on a column of 130 of silica with a gradient of 0% to 5% ethyl acetate in heptane in order to obtain two batches of 2-bromo-l- (3, 4-dimethyl-phenyl) -ethanone (144A, 57%) .
- Example 147B - l-Adamantan-2-yl-ethanone .
- the compound 147A (4.63 g, 28.7 mmol) is dissolved under a nitrogen atmosphere in 61 mL of ether, and then cooled with an ice bath.
- Methyllithium (27 mL, 1.6 M / Et 2 O, 43 mmol) is added dropwise while maintaining the reaction medium between 5°C and 12°C. As soon as the addition is finished, the cold bath is removed and stirring is continues for 30 minutes at room temperature.
- the reaction medium is then neutralized with 46 ml of water.
- the organic phase is recovered, dried on magnesium sulfate, dried and concentrated under reduced pressure.
- the compound 147B (500 mg, 2.8 mmol) is dissolved in 8.6 mL of methanol under a nitrogen atmosphere, and then cooled to 0 0 C. Bromine (151 ⁇ l, 2.94 mmol) is slowly added. The reaction medium is stirred for Ih 40min at 0 0 C and then neutralized with water and extracted twice with ethyl acetate. The organic phases are combined, dried on magnesium sulfate, filtered and concentrated.
- the thereby obtained residue is purified on a column of 35 g of silica (20 mL / min, gradient of 0% to 15% ethyl acetate in heptane in 25 minutes) , in order to obtain the compound 147C (1.37 g, 85%) .
- the compound 147 was synthesized from saccharin and from the compound 147C according to the same sequence of steps described for preparing the compound I ⁇ with a yield of 11% for the three steps.
- the thereby obtained residue is purified on silica (gradient of 0% to 50% dichloromethane in heptane, and then 10% ethyl acetate in heptane) , in order to obtain the partly purified compound 148A (3.34 g, 61%) .
- the compound 148 was synthesized from saccharin and from the compound 148C according to the same sequence of steps described for preparing the compound 1_, with an overall yield of 36%.
- the thereby obtained residue is purified on a column of 120 g of silica (92 mL / min; gradient of 0% to 35% ethyl acetate in heptane in 40 min), in order to obtain the compound 149A (5.71 g, 62%) .
- the compound 149A (2.62 g, 11.7 mmol) is dissolved in
- the compound 149C was synthesized from the compound 149B according to the procedure for preparing the compound 144A, with a yield of 66%.
- Example 149 (4-Chloro-3-trifluoromethyl-phenyl) - (4- hydroxy-2-methyl-l, 1-dioxo-l, 2-dihydro-2H- benzo[e] [l,2]thiazin-3-yl) -methanone .
- the compound 149 was synthesized from saccharin and from the compound 149C according to the same sequence of steps described for preparing the compound ⁇ _, with an overall yield of 20%.
- the compound 150A (1.59 g, 5.56 mmol) is dissolved in 6 mL of concentrated sulfuric acid at room temperature and the reaction medium is stirred for 3 hours before being poured over ice. The suspension is filtered. The precipitate is rinsed three times with water, and then dried for 24 hours at 50 0 C and in vacuo.
- the compound 150B (1.33 g, 89%) is obtained as a white solid.
- Example 150 (7-Bromo-4-hydroxy-2-methyl-l, 1-dioxo- 1, 2-dihydro-2H-benzo [e] [1,2] thiazin-3-yl) -naphthalen- 2-yl-methanone .
- the compound 150 was synthesized from the compound 150B and from 2-bromo-l- (naphthalen-2-yl) ethanone according to the same sequence of steps described for preparing the compound ⁇ _, with an overall yield of 55%.
- Methyl 2-amino-4-chlorobenzoate (5 g, 26.9 mmol) is heated in 18 mL of HCl (20% in water) until complete dissolution, and then cooled to 0 0 C.
- a solution of NaN ⁇ 2 (1.85 g, 26.9 mmol) in 4.5 mL of water is added dropwise while maintaining the temperature between 2 0 C and 6°C.
- the reaction medium is then stirred for 1 hour at room temperature.
- about 15 g of SO2 gas is bubbled in 22 mL of acetic acid and 2.3 mL of water at 0 0 C.
- CuCl (666 mg, 6.7 mmol) is then added.
- the first reaction medium is then added to this blue- green solution between 1°C and 3°C. Gas evolvement is observed; Stirring at low temperature is continued for 45 minutes before removing the cold bath, and then the reaction medium is poured over 100 g of ice and extracted three times with ethyl acetate. The organic phases are collected, washed with a saturated NaHCC>3 solution, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up into 5 mL of THF at 0 0 C and 2.8 mL of a concentrated ammonia solution are added slowly. The cold bath is removed and stirring is continued for 1 hour.
- the formed precipitate is filtered, rinsed with water and dried under reduced pressure at 50 0 C in order to obtain the compound 151A (896 mg, 15%) .
- the compound 151 was synthesized from the compound 151A and from 2-bromo-l- (naphthalen-2-yl) ethanone according to the same sequence of steps described for preparing the compound ⁇ _, with an overall yield of 39%.
- 2-amino-4-methyl-benzonitrile (2.5 g, 18.9 mmol) is heated in 12 mL of HCl (20% in water) until complete dissolution), and then cooled to 0 0 C.
- a solution of NaN ⁇ 2 (1.3 g, 18.9 mmol) in 3.2 mL of water is added dropwise while maintaining the temperature between 2 0 C and 6°C.
- the reaction medium is then stirred for 1 hour at room temperature.
- about 15.7 g of SO2 gas is bubbled in 15 mL of acetic acid and 1.6 mL of water at 0 0 C.
- CuCl (468 mg, 4.7 mmol) is then added.
- the first reaction medium is then added to this blue- green solution between 1°C and 3 0 C. Gas evolvement is observed. Stirring at low temperature is continued for 45 minutes before removing the cold bath, and then the reaction mixture is poured over 70 g of ice and extracted three times with a mixture of 20% methanol in DCM. The organic phases are collected, washed with a saturated NaHCC>3 solution, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up into 5 mL of THF at 0 0 C and 2.8 mL of a concentrated ammonia solution are added slowly. The cold bath is removed and stirring is continued for 1 hour.
- the formed precipitate is filtered, rinsed with water and dried under reduced pressure at 50 0 C in order to obtain the compound 152A (800 mg, 21%) .
- the compound 152A (620 mg, 3.15 mmol) is dissolved in 7.5 mL of KOH (30% in water) and 530 ⁇ l of hydrogen peroxide (30% in water) .
- the organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure, in order to obtain the compound 152B (428 g, 60%) .
- the compound 152B (428 mg, 1.94 mmol) is dissolved in 3 mL of concentrated sulfuric acid at room temperature. The reaction mixture is stirred for 2 hours and then poured over ice and filtered. The precipitate is abundantly rinsed with water and then dried in order to obtain the compound 152C (359 mg, 93%) as a pink solid.
- the compound 152 was synthesized from the compound 152C and from 2-bromo-l- (naphthalen-2-yl) ethanone according to the same sequence of steps described for preparing the compound ⁇ _, with an overall yield of 21%.
- the compound 142 (200 mg, 0.5 mmol) is dissolved under an inert atmosphere in 1.1 mL of acetone and 1.2 mL of water in the presence of benzene boronic acid (68 mg,
- the compounds 154 to 169 were synthesized from the compound 142 and from various boronic acids according to the same method described for preparing the
- Example 170 (4-Hydroxy-7-methanesulfonyl-2-methyl- 1 , 1-dioxo-l, 2-dihydro-2H-benzo [e] [1,2] thiazin-3-yl) - naphthalen-2-yl-methanone
- the compound 170 was synthesized from 5- methanesuIfonyl-2-methyl-benzenesulfonyl chloride according to the same sequence of steps described for preparing the compound 17, with an overall yield of 7%.
- the compound 171A was synthesized from 1-phenyl- cyclopropanecarbonitrile according to the same procedure described for preparing the compound 147B, with a yield of 40%.
- the compound 171 was synthesized from the compound 17IA according to the same sequence of steps described for preparing the compound 144, with an overall yield of
- Example 172 - 1- [3- (4-Hydroxy-2-methyl-l, 1-dioxo-l, 2- dihydro-2H-benzo [e] [1,2] thiazine-3-carbonyl) -phenyl ] - ethanone
- the compound 172 was synthesized from 1- (3-acetyl- phenyl) -ethanone according to the same sequence of steps described for preparing the compound 144, with an overall yield of 21%.
- Example 173A [3- (2, 2, 2 -Trifluoro-1 -hydroxy- 1- methy1-ethyl) -phenyl] -ethanone
- the thereby obtained residue is purified on silica (gradient of 0% to 50% ethyl acetate in heptane in 20 min) , in order to obtain the partly purified compound 173A (2.87 g) . It is used as such in the next step .
- the compound 173B was synthesized from the compound 173A according to the procedure for preparing the compound 144A, with a yield of 57%.
- Example 173 (4-Hydroxy-2-methyl-l, 1-dioxo-l, 2- dihydro-2H-benzo [e] [1,2] thiazin-3-yl) - [3- (2,2,2- trifluoro-1-hydroxy-l-methyl-ethyl) -phenyl] -methanone.
- the compound 173 was synthesized from saccharin and from the compound 173B according to the same sequence of steps described for preparing the compound 1_, with an overall yield of 52%.
- HPLC: RT 6.05 min, 95% (XBridge column;
- 3-acetylbenzaldehyde (1.27 g, 8.57 mmol) is dissolved in 30 mL of DMF under a nitrogen atmosphere in the presence of potassium carbonate (59 mg, 0.42 mmol) and of TMS-CF 3 (1.52 mL, 10.3 mmol) .
- the reaction mixture is stirred for 30 minutes at room temperature and then neutralized with 1 mL of a saturated NH 4 Cl solution and concentrated under reduced pressure. The residue is taken up in ethyl acetate and then washed once with HCl
- the compound 174B was synthesized from the compound 174A according to the procedure for preparing the compound 144A, with a yield of 60%.
- the compound 174 was synthesized from saccharin and from the compound 174B according to the same sequence of steps described for preparing the compound ⁇ _, with an overall yield of 33%.
- the compound 143 (100 mg, 0.29 mmol) is dissolved in 1 mL of KOH (30% in water) in the presence of 330 ⁇ l of ethanol, and then heated to 70 0 C for 18 hours.
- the organic phases are combined, dried on magnesium sulfate, filtered and concentrated in order to obtain the compound 175 as a yellow solid (99 mg, 93%) .
- the compound 175 (150 mg, 0.41 mmol) is dissolved in 3 mL of DMF under an inert atmosphere in the presence of (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (120 mg, 0.62mmol), of 3-hydroxy- 3H- benzo[d] [ 1, 2, 3] triazin-4-one (102 mg, 0.62 mmol) and iPr 2 NEt (162 mg, 1.25 mmol) , and then stirred at room temperature for 72 hours. The reaction mixture is concentrated under reduced pressure, diluted with 20 mL of DCM and washed twice with HCl (IN in water) . The aqueous phases are collected and extracted DCM.
- the compounds 177 to 183 were synthesized from the compound 175 and from various amines according to the same procedure described for preparing the compound 176.
- the compound 175 (150 mg, 0.42 mmol) is dissolved in 3 mL of THF in the presence of PyBOP (239 mg, 0.46 mmol), of ammonia (152 ⁇ l, 1.25 mmol) and of DIEA (80 ⁇ l, 0.46 mmol) and stirred at room temperature for 4 hours.
- the reaction medium is diluted with 20 mL of DCM and washed with HCl (IN in water) .
- the aqueous phase is extracted four times with DCM.
- the organic phases are combined, dried on magnesium sulfate, filtered and concentrated in order to obtain the compound 184 as a yellow solid (71 mg, 46%) .
- Example 185 3- (4-Hydroxy-2-methyl-l, 1-dioxo-l, 2- dihydro-2H-benzo [e] [1,2] thiazine-3-carbonyl) -benzoic acid ethyl ester.
- the compound 175 (150 mg, 0.42 mmol) is dissolved in 6 mL ethanol in the presence of pTsOH (8 mg, 0.04 mmol), and refluxed with stirring for 18 hours.
- the reaction medium is concentrated under reduced pressure.
- the thereby obtained residue is purified on a column of 12 g of silica (12 mL/min, DCM) , in order to obtain the compound 185 as a yellow solid (138 mg, 84%) .
- Example 186 (4-Hydroxy-2-methyl-l, 1-dioxo-l, 2- dihydro-2H-benzo [e] [1, 2] thiazin-3-yl) -(3 -pyridin-3-yl - phenyl) -methanone .
- the compound 142 (200 mg, 0.5 mmol) is dissolved under an inert atmosphere in 1.5 mL of 1,4-dioxane in the presence of pyridin-3-ylboronic acid (104 mg, 0.76 mmol) , of tripotassium orthophosphate (1.27 mol/1, 679 ⁇ l, 0.86 mmol) , of tris (dibenzylideneacetone) dipalladium (23 mg, 0.025 mmol) and of tricyclo-hexylphosphine (21 mg, 0.076 mmol) .
- the reaction medium is heated to 100 0 C for 18 hours and then brought back to room temperature, diluted with DCM and washed with a saturated NH 4 Cl solution.
- the compounds 187 to 195 were synthesized from the compound 144 and from various boronic acids according to the same method as described for preparing the compound 186.
- the compounds 196 and 197 were synthesized from saccharin and from 2-bromo-l- (3-chlorophenyl) ethanone and 2-bromo-l- (3-fluorophenyl) ethanone respectively according to the same method described for preparing the compound 1.
- the derivatives of the present invention are selective 5 inhibitors of 11 -HSDl relatively to 11 -HSD2 as shown by the results of the models described below: 1) Human enzymatic activity of llfi-HSDl from liver microsomes after treatment with inhibitor compounds (inhibition %) .
- the enzymatic test is based on the conversion of cortisone into Cortisol by ll ⁇ -HSDl.
- the enzymatic reaction is started by adding 1 ⁇ g of human hepatic microsome (Xenotech) to wells (half volume 96-well plates, reaction volume of 50 ⁇ L) containing 160 nM of cortisone in a Tris 20 mM buffer (pH 7.4) with 5 mM EDTA, 200 ⁇ M NADPH and the inhibitor compound or the carrier (1% DMSO) .
- a calibration curve of known Cortisol concentrations is produced simultaneously under the same experimental conditions. The plates are incubated for 2 hours at 37°C (enzymatic phase) .
- the enzymatic reaction may be stopped and after incubation of 2 hours at room temperature the formed Cortisol (detection phase) may be quantified by HTRF ® (CIS bio international, reference 62CO2PEC) .
- the fluorescence measurements are conducted with a FusionTM ⁇ (Perkin Elmer) reader. For each well, fluorescence is measured at 620 nm and at 665 nm. A ratio ( ⁇ 6 65 nm/ ⁇ 620 nm ) and a specific FRET signal are calculated, with which an inhibition percentage may be determined for each concentration of evaluated inhibitor compound.
- the enzymatic test is based on the conversion of [ 3 H] cortisone into [ 3 H] Cortisol by ll ⁇ -HSDl.
- the enzymatic reaction is stated by adding 1 ⁇ g (standardization of this amount in order to obtain 80% of the substrate conversion maximum under hte experimental conditions) of human hepatic microsomes (Xenotech) to wells (OptiplateTM 96-well plates, reaction volume of 50 ⁇ L) containing 20 nM of [1,2- 3 H] cortisone (specific activity of 40-50 Ci/mmol, Amersham-GE Healthcare) in a 50 mM HEPES buffer at (pH 7.4) with 100 mM KCl, 5 mM NaCl, 2 mM MgCl 2 , 1 mM NADPH and the inhibitor compound or the carrier (1% DMSO) .
- the sealed plates are centrifuged at low speed for mixing the components and then incubated for 2 hours at 37°C (enzymatic phase) .
- the enzymatic reaction is stopped by adding 70 ⁇ l/well of complex [10 mg/mL of yttrium silicate SPA beads associated with the protein A (GE Healthcare) and pre- incubated with an anti-cortisol monoclonal antibody (East Coast Biologies, ME) ] containing 10 ⁇ M of 18 ⁇ - glycerrhitinic acid.
- the plates are sealed and then incubated under slow orbital stirring for 2 hours at room temperature (detection phase) . After centrifugation, measurements are conducted with a scintillation counter (TopCount NXT (Perkin Elmer) .
- a percentage of inhibition for each evaluated compound concentration is calculated relatively to the standard enzymatic activity (carrier 1% DMSO) with which the potential of each compound may then be determined (EC 5 O obtained by the software SigmaPlot v.ll, a logistic equation with 4 parameters) .
- SPA scintillation proximity assay
- the enzymatic test is based on the conversion of [ H] Cortisol into [ 3 H] cortisone by ll ⁇ -HSD2.
- the enzymatic reaction is started by adding 0.75 ⁇ g (standardization of this amount in order to obtain 80% of the conversion maximum of the substrate under the experimental conditions) of human kidney microsomes (Xenotech) to wells (OptiplateTM 96-well plates, a reaction volume of 50 ⁇ L) containing 8 nM [1,2,6,7- 3 H] Cortisol (specific activity of 70-75 Ci/mmol, Amersham-GE Healthcare) in a 50 mM HEPES buffer (pH 7.4) with 100 mM KCl, 5 mM NaCl, 2 mM MgCl2, 1 mM NAD + and the inhibitor compound or the carrier (1% DMSO) .
- the sealed plates are centrifuged at low speed in order to mix the components and then incubated for 2 hours at 37°C (enzymatic phase) .
- the enzymatic reaction is stopped by adding 70 ⁇ l/well of complex [10 mg/mL of yttrium silicate SPA beads associated with protein A (GE Healthcare) and pre- incubated with an anti-cortisol monoclonal antibody (East Coast Biologies, ME) ] containing 10 ⁇ M of 18 ⁇ - glycerrhitinic acid.
- the plates are sealed and then incubated under slow orbital stirring for 2 hours at room temperature (detection phase) . After centrifugation, the measurements are conducted with a scintillation counter TopCount NXT (Perkin Elmer) .
- An inhibition percentage for each evaluated compound concentration is calculated relatively to the standard enzymatic activity (carrier 1% DMSO) .
- SPA scintillation proximity assay
- the object of the present invention is the compounds of general formula (I) or one of their stereoisomers or one of their salts acceptable for pharmaceutical use, for their use as a drug.
- the object of the present invention is also the pharmaceutical compositions containing as an active ingredient a compound of general formula (I) or one of its stereoisomers, or one of its salts acceptable for pharmaceutical use in association with a pharmaceutically acceptable carrier, as drugs.
- These compositions may for example assume the form of solid, liquid compositions, emulsions, lotions or creams.
- compositions containing as an active ingredient a compound of general formula (I) or one of their stereoisomers or one of their salts acceptable for pharmaceutical use may be used for inhibiting ll ⁇ -hydroxysteroid dehydrogenase type 1 (ll ⁇ HSDl) .
- compositions containing as an active ingredient a compound of general formula (I) or one of its stereoisomers or one of its salts acceptable for pharmaceutical use for both curative and preventive treatment of diabetes of type 2.
- compositions containing as an active ingredient a compound of general formula (I) or one of its stereoisomers or one of its salts acceptable for pharmaceutical use for both curative and preventive treatment of disorders related to the type 1 ll ⁇ -hydroxysteroid dehydrogenase (ll ⁇ HSDl); or obesity; or dyslipidemias; or arterial hypertension; or atherosclerosis and clinical pathologies which result therefrom such as coronary strokes, or cerebro-vascular strokes, or arteritis of the lower limbs; or hyperglycemias; of intolerance to glucose; or insulin- resistance; or hypertriglyceridemias; or hypercholesterolemias; or restenoses, or pancreatitises; or retinopathies; or nephropathies; or neuropathies; or certain types of cancer or glaucomas.
- compositions may be administered in association with an anti-diabetic such as biguanides
- sulfonylureas for example carbutamide, glibornuride, glipizide, gliclazide, glibenclamide, glimepiride
- meglitinides for example nateglinide, repaglinide, mitiglinide
- PPAR modulators for example pioglitazone
- inhibitors of alpha-glucosidase for example acarbose, miglitol, voglibose
- amyline for example pramLintide
- compositions may also be administered in association with an anti-obesity agent such as for example orlistat or sibutramine.
- an anti-obesity agent such as for example orlistat or sibutramine.
- compositions for oral administration tablets, pills, powders (gelatin capsules, tablets) or granules may be used.
- the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, saccharose, lactose or silica, under an argon stream.
- these compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring agent, a coating (dragees) or a varnish.
- compositions for oral administration pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil may be used.
- inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil
- These compositions may comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavoring agents or stabilizers.
- the sterile compositions for parenteral administration may preferably aqueous or non-aqueous solutions, suspensions or emulsions.
- a solvent or carrier water, propyleneglycol, polyethyleneglycol, vegetable oils, in particular olive oil, injectable organic esters for example ethyl oleate or other suitable organic solvents may be used.
- These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization may be accomplished in several ways, for example by aseptizing filtration, by incorporating to the composition sterilizing agents, by irradiation or by heating. They may also be prepared as sterile solid compositions which may be dissolved at the moment of use in sterile water or any other injectable sterile medium.
- compositions for rectal administration are suppositories or rectal capsules which contain in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethyleneglycols .
- compositions for topical administration may for example be creams, lotions, collyria, collutories, nasal drops or aerosols.
- the doses depend on the sought effect, on the duration of the treatment and on the administration route used; they are generally comprised between
- 0.001 g and 1 g preferably comprised between 0.005 g and 0.75 g
- unit doses ranging from 0.1 mg to 500 mg of active substance.
- the physician will determine the suitable dosage depending on the age, the weight and all the other factors specific to the subject to be treated.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cosmetics (AREA)
Abstract
Description
Claims
Priority Applications (21)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011552415A JP5650139B2 (en) | 2009-03-03 | 2010-03-02 | Benzothiazine derivatives, their manufacture and their application as drugs |
KR1020117022812A KR101701531B1 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
AU2010220335A AU2010220335B2 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
NZ595276A NZ595276A (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
US13/254,473 US9187438B2 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
RU2011139014/04A RU2523791C2 (en) | 2009-03-03 | 2010-03-02 | Benzothiazine derivatives, production and use thereof as medical drugs |
MX2011008942A MX2011008942A (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs. |
ES10706624.3T ES2483516T3 (en) | 2009-03-03 | 2010-03-02 | Benzothiazine derivatives, their preparation and application as drugs |
EP10706624.3A EP2403840B1 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
BRPI1010243A BRPI1010243A2 (en) | 2009-03-03 | 2010-03-02 | benzothiazine derivatives, preparation thereof and application thereof as drugs |
GEAP201012398A GEP20135832B (en) | 2009-03-03 | 2010-03-02 | Benzothiazines derivatives, preparation thereof, and their application as drugs |
PL10706624T PL2403840T3 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
CN201080010207.7A CN102341379B (en) | 2009-03-03 | 2010-03-02 | Benzothiazine derivative, its preparation method and the application as medicine thereof |
UAA201111590A UA105040C2 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
CA2753630A CA2753630C (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
MA34191A MA33138B1 (en) | 2009-03-03 | 2010-03-02 | Benzotiaziazine derivatives prepared and used as drugs |
SG2011063146A SG174208A1 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
TN2011000429A TN2011000429A1 (en) | 2009-03-03 | 2011-08-19 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
IL214907A IL214907A (en) | 2009-03-03 | 2011-08-31 | Derivatives of benzothiazines, method of preparation thereof and pharmaceutical compositions comprising them |
ZA2011/07104A ZA201107104B (en) | 2009-03-03 | 2011-09-29 | Derivatives of benzothiazines,preparation thereof and application thereof as drugs |
HK12106611.2A HK1165802A1 (en) | 2009-03-03 | 2012-07-06 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0951336 | 2009-03-03 | ||
FR0951336A FR2942797B1 (en) | 2009-03-03 | 2009-03-03 | BENZOTHIAZINE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010100139A1 true WO2010100139A1 (en) | 2010-09-10 |
Family
ID=40790339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2010/052609 WO2010100139A1 (en) | 2009-03-03 | 2010-03-02 | Derivatives of benzothiazines, preparation thereof and application thereof as drugs |
Country Status (29)
Country | Link |
---|---|
US (1) | US9187438B2 (en) |
EP (1) | EP2403840B1 (en) |
JP (1) | JP5650139B2 (en) |
KR (1) | KR101701531B1 (en) |
CN (1) | CN102341379B (en) |
AR (1) | AR075777A1 (en) |
AU (1) | AU2010220335B2 (en) |
BR (1) | BRPI1010243A2 (en) |
CA (1) | CA2753630C (en) |
CL (1) | CL2011002171A1 (en) |
CO (1) | CO6501175A2 (en) |
ES (1) | ES2483516T3 (en) |
FR (1) | FR2942797B1 (en) |
GE (1) | GEP20135832B (en) |
HK (1) | HK1165802A1 (en) |
IL (1) | IL214907A (en) |
MA (1) | MA33138B1 (en) |
MX (1) | MX2011008942A (en) |
MY (1) | MY160819A (en) |
NZ (1) | NZ595276A (en) |
PL (1) | PL2403840T3 (en) |
RU (1) | RU2523791C2 (en) |
SA (1) | SA110310181B1 (en) |
SG (1) | SG174208A1 (en) |
TN (1) | TN2011000429A1 (en) |
TW (1) | TWI495636B (en) |
UA (1) | UA105040C2 (en) |
WO (1) | WO2010100139A1 (en) |
ZA (1) | ZA201107104B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8524894B2 (en) | 2009-06-04 | 2013-09-03 | Laboratorios Salvat, S.A. | Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1 |
WO2016169983A1 (en) * | 2015-04-21 | 2016-10-27 | Pierre Fabre Medicament | Use of (4-hydroxy-2-methyl-1,1-dioxido-2h-benzo[e][1,2]thiazine-3-yl)(naphthalene-2-yl) methanone in the prevention and/or treatment of non-alcoholic steatohepatitis |
CN106243046A (en) * | 2016-08-02 | 2016-12-21 | 南京工业大学 | A kind of preparation method of mesosulfuron |
WO2018185266A1 (en) | 2017-04-06 | 2018-10-11 | Inventiva | New compounds inhibitors of the yap/taz-tead interaction and their use in the treatment of malignant mesothelioma. |
EP3632908A1 (en) | 2018-10-02 | 2020-04-08 | Inventiva | Inhibitors of the yap/taz-tead interaction and their use in the treatment of cancer |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103271923B (en) * | 2013-06-28 | 2014-11-26 | 安徽中医学院 | Medical application of benzothiazine derivative |
CN103304513B (en) * | 2013-06-28 | 2015-02-04 | 安徽中医学院 | One-class 1,2-benzothiazine compound as well as preparation method and application thereof |
CN103275035B (en) * | 2013-06-28 | 2014-11-26 | 安徽中医学院 | Benzothiazine compound, and preparation method and anti-tumor purpose thereof |
WO2023154412A1 (en) * | 2022-02-12 | 2023-08-17 | Miralogx Llc | Anti-inflammatory compounds, pharmaceutical compositions, and treatment methods |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060160870A1 (en) * | 2005-01-20 | 2006-07-20 | Adamed, Sp. Z.O.O. | 3-phenylpropionic acid derivatives |
JP2007197369A (en) * | 2006-01-26 | 2007-08-09 | Sankyo Co Ltd | Benzothiadiazine derivative |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
US3808205A (en) * | 1971-09-10 | 1974-04-30 | Warner Lambert Co | Process for the preparation of 4-hydroxy-3-carbamyl-2h-1,2-benzothiazine 1,1-dioxides and 4-hydroxy-3(2h)-1,2-benzothiazine carboxylate-1,1-dioxides |
US4289879A (en) * | 1980-09-29 | 1981-09-15 | Pfizer Inc. | Synthetic method and intermediate for piroxicam |
FR2694295B1 (en) * | 1992-07-28 | 1994-09-02 | Adir | New peptides derived from trifluoromethyl ketones, their preparation process and the pharmaceutical compositions containing them. |
US5599811A (en) * | 1995-02-21 | 1997-02-04 | Warner-Lambert Company | Benzothiazine dioxides as endothelin antagonists |
AU2002212672A1 (en) * | 2000-10-12 | 2002-04-22 | Dr. Reddy's Research Foundation | Salts of benzothiazine and benzoxazine derivatives and pharmaceutical compositions containing them |
GB0224830D0 (en) * | 2002-10-24 | 2002-12-04 | Sterix Ltd | Compound |
DE602004025220D1 (en) * | 2003-04-11 | 2010-03-11 | High Point Pharmaceuticals Llc | PHARMACEUTICAL USES OF CONDENSED 1,2,4-TRIAZOLENE |
CN103724335A (en) * | 2005-10-20 | 2014-04-16 | 默沙东公司 | Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
RU2443689C2 (en) * | 2005-11-21 | 2012-02-27 | Сионоги Энд Ко., Лтд. | HETEROCYCLIC COMPOUNDS HAVING 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITING ACTIVITY |
-
2009
- 2009-03-03 FR FR0951336A patent/FR2942797B1/en not_active Expired - Fee Related
-
2010
- 2010-03-02 MY MYPI2011004096A patent/MY160819A/en unknown
- 2010-03-02 US US13/254,473 patent/US9187438B2/en not_active Expired - Fee Related
- 2010-03-02 CA CA2753630A patent/CA2753630C/en not_active Expired - Fee Related
- 2010-03-02 WO PCT/EP2010/052609 patent/WO2010100139A1/en active Application Filing
- 2010-03-02 BR BRPI1010243A patent/BRPI1010243A2/en not_active Application Discontinuation
- 2010-03-02 SG SG2011063146A patent/SG174208A1/en unknown
- 2010-03-02 MX MX2011008942A patent/MX2011008942A/en active IP Right Grant
- 2010-03-02 UA UAA201111590A patent/UA105040C2/en unknown
- 2010-03-02 MA MA34191A patent/MA33138B1/en unknown
- 2010-03-02 KR KR1020117022812A patent/KR101701531B1/en active IP Right Grant
- 2010-03-02 RU RU2011139014/04A patent/RU2523791C2/en not_active IP Right Cessation
- 2010-03-02 SA SA110310181A patent/SA110310181B1/en unknown
- 2010-03-02 NZ NZ595276A patent/NZ595276A/en not_active IP Right Cessation
- 2010-03-02 CN CN201080010207.7A patent/CN102341379B/en not_active Expired - Fee Related
- 2010-03-02 GE GEAP201012398A patent/GEP20135832B/en unknown
- 2010-03-02 AR ARP100100618A patent/AR075777A1/en active IP Right Grant
- 2010-03-02 AU AU2010220335A patent/AU2010220335B2/en not_active Ceased
- 2010-03-02 PL PL10706624T patent/PL2403840T3/en unknown
- 2010-03-02 EP EP10706624.3A patent/EP2403840B1/en active Active
- 2010-03-02 ES ES10706624.3T patent/ES2483516T3/en active Active
- 2010-03-02 JP JP2011552415A patent/JP5650139B2/en not_active Expired - Fee Related
- 2010-03-03 TW TW099106123A patent/TWI495636B/en not_active IP Right Cessation
-
2011
- 2011-08-19 TN TN2011000429A patent/TN2011000429A1/en unknown
- 2011-08-31 IL IL214907A patent/IL214907A/en active IP Right Grant
- 2011-09-02 CL CL2011002171A patent/CL2011002171A1/en unknown
- 2011-09-29 CO CO11128125A patent/CO6501175A2/en active IP Right Grant
- 2011-09-29 ZA ZA2011/07104A patent/ZA201107104B/en unknown
-
2012
- 2012-07-06 HK HK12106611.2A patent/HK1165802A1/en not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060160870A1 (en) * | 2005-01-20 | 2006-07-20 | Adamed, Sp. Z.O.O. | 3-phenylpropionic acid derivatives |
JP2007197369A (en) * | 2006-01-26 | 2007-08-09 | Sankyo Co Ltd | Benzothiadiazine derivative |
Non-Patent Citations (26)
Title |
---|
C. TOKUDA ET AL., SCREENTECH, March 2004 (2004-03-01) |
DALLMAN ET AL., FRONT NEUROENDOCRINOL., vol. 14, 1993, pages 303 - 347 |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1 January 1990 (1990-01-01), YOON, MINJOONG ET AL: "Novel transition-metal catalyzed rearrangement of piroxicam, a benzothiazine carboxamide derivative", XP002534572, retrieved from STN Database accession no. 1991:607295 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 19 May 1957 (1957-05-19), ABE, KYUJI ET AL: "A new method for the preparation of secondary amines. VIII. Syntheses of phenylalkanolamines", XP002534571, retrieved from STN Database accession no. 1957:17098 * |
DESPRÉS ET AL., NATURE, vol. 444, no. 14, 2006, pages 881 - 87 |
DUPLOMB ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 313, 2004, pages 594 - 599 |
EDWARS ET AL., LANCET, vol. 2, 1988, pages 986 - 989 |
GRUNDY ET AL., CIRCULATION, vol. 112, 2005, pages 2735 - 2752 |
GRUNDY, NAT. REV. DRUG DISCOV., vol. 5, 2006, pages 295 - 309 |
K. SOLLY ET AL., ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, vol. 3, no. 4, 2005, pages 377 - 384 |
KOTELEVTSEV Y. ET AL., PNAS, vol. 94, 1997, pages 14924 - 14929 |
LAZER E S ET AL: "EFFECT OF STRUCTURAL MODIFICATION OF ENOL-CARBOXYMIDE-TYPE NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON COX-2/COX-1 SELECTIVITY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 40, 1 January 1997 (1997-01-01), pages 980 - 989, XP000974272, ISSN: 0022-2623, [retrieved on 19970101] * |
M. AMORAVAIN ET AL.: "SBS", September 2006, 12TH ANNUAL CONFERENCE |
MASUZIKA ET AL., SCIENCE, vol. 294, 2001, pages 2166 - 2170 |
MONNIER ET AL., DIABETES & METABOLISM, vol. 34, 2008, pages 207 - 216 |
NATHAN ET AL., DIABETES CARE, vol. 32, 2009, pages 193 - 203 |
PASCALE ET AL., OPHTALMOLOGY, vol. 113, no. 7, 2006, pages 1081 - 86 |
REICHARD ET AL., N. ENGL. J. MED., vol. 329, 1993, pages 304 - 309 |
S. MUNDT ET AL., ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, vol. 3, no. 4, 2005, pages 367 - 375 |
STRICKLER ET AL., DIABETES TECHNOLOGY & THERAPEUTICS, vol. 3, no. 2, 2001, pages 263 - 274 |
WAMIL ET AL., DRUG DISCOVERY TODAY, vol. 12, 2007, pages 504 - 520 |
WILCOX ET AL., AM. HEART J., vol. 155, 2008, pages 712 - 7 |
WILCOX ET AL., STROKE, vol. 38, 2007, pages 865 - 873 |
YAKUGAKU ZASSHI , 76, 1058-63 CODEN: YKKZAJ; ISSN: 0031-6903, 1 January 1956 (1956-01-01) * |
YONGU NONMUNJIP - CHUNGNAM TAEHAKKYO KICHO KWAHAK YONGUSO , 10, 54-7 CODEN: YNCYEZ, 1990 * |
ZINNES H ET AL: "1,2-BENZOTHIAZINES. 6.1 3-CARBAMOYL-4-4HYDROXY-2H-1, 1,2-BENZOTHIAZINE 1, 1-DIOXIDES AS ANTIINFLAMMATORY AGENTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 16, no. 1, 1 January 1973 (1973-01-01), pages 44 - 48, XP002047510, ISSN: 0022-2623, [retrieved on 19730101] * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8524894B2 (en) | 2009-06-04 | 2013-09-03 | Laboratorios Salvat, S.A. | Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1 |
US8822452B2 (en) | 2009-06-04 | 2014-09-02 | Laboratorios Salvat, S.A. | Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1 |
WO2016169983A1 (en) * | 2015-04-21 | 2016-10-27 | Pierre Fabre Medicament | Use of (4-hydroxy-2-methyl-1,1-dioxido-2h-benzo[e][1,2]thiazine-3-yl)(naphthalene-2-yl) methanone in the prevention and/or treatment of non-alcoholic steatohepatitis |
FR3035326A1 (en) * | 2015-04-21 | 2016-10-28 | Pf Medicament | USE OF (4-HYDROXY-2-METHYL-1,1-DIOXIDO-2H-BENZO [E] [1,2] THIAZIN-3-YL) (NAPHTHALEN-2-YL) METHANONE IN THE PREVENTION AND / OR TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS |
CN106243046A (en) * | 2016-08-02 | 2016-12-21 | 南京工业大学 | A kind of preparation method of mesosulfuron |
CN106243046B (en) * | 2016-08-02 | 2019-07-05 | 南京工业大学 | A kind of preparation method of mesosulfuron |
WO2018185266A1 (en) | 2017-04-06 | 2018-10-11 | Inventiva | New compounds inhibitors of the yap/taz-tead interaction and their use in the treatment of malignant mesothelioma. |
EP3632908A1 (en) | 2018-10-02 | 2020-04-08 | Inventiva | Inhibitors of the yap/taz-tead interaction and their use in the treatment of cancer |
WO2020070181A1 (en) | 2018-10-02 | 2020-04-09 | Inventiva | Inhibitors of the yap/taz-tead interaction and their use in the treatment of cancer |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2753630C (en) | Derivatives of benzothiazines, preparation thereof and application thereof as drugs | |
JP5844376B2 (en) | Development of potent urate transporter inhibitors: compounds designed for their uric acid excretion effect | |
WO2006093801A1 (en) | Thiadiazine derivatives useful as anti-infective agents | |
KR100791252B1 (en) | Glycogen synthase kinase 3beta inhibitor, composition and process for the preparation thereof | |
WO2002046129A2 (en) | Inhibitors of histone deacetylase | |
DK2484669T3 (en) | Fenolderivat | |
US20080193413A1 (en) | Anti-Infective Agents | |
Supuran et al. | Carbonic anhydrase inhibitors. Part 36. Inhibition of isozymes I and II with Schiff bases derived from chalkones and aromatic/heterocyclic sulfonamides | |
AU2003237787A1 (en) | Substituted phenylacetic acids | |
CA2703718A1 (en) | Inhibitors of histone deacetylase | |
US4116964A (en) | 2-[(N-2-pyridylcarbamoyl)methyl]saccharin | |
JP2003532730A (en) | Indazole having 1,1-dioxoisothiazolidine useful as a cell growth inhibitor | |
WO2005019191A2 (en) | 1, 1-dioxido-4h-1,2,4-benzothiadiazine derivate und verwandte verbindungen als inhibitoren der hcv polymerase zur behandlung von hepatitis c | |
CN109942505A (en) | Isothiazolinone compound and corresponding uses | |
IE64657B1 (en) | Pharmaceutical compositions 2-benzothiazolamine derivatives and their preparation | |
JPH04173782A (en) | 2-sulfonamide-4,5-diphenylthiazole derivative | |
IL178066A (en) | Process for producing 1,2-benzisoxazole-3-methanesulfonamide, a one pot process for producing 1,2-benzisoxazole-3-methanesulfonamide and a process for producing 1,2-benzisoxazole-3-acetic acid | |
Tagliabue | Synthesis of enantiomerically pure polyfluorobenzo [d] sultams | |
IE901414A1 (en) | Naphthalene derivatives | |
JPH0333713B2 (en) | ||
CA2203921A1 (en) | Hypolipidemic benzothiazepines | |
ZA200506904B (en) | Process for the production of imidazopyridin-8-ones | |
NO166446B (en) | NAFTOTIAZEPINON-DERIVATIVES. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080010207.7 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10706624 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12011501685 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2753630 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/008942 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 214907 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011002171 Country of ref document: CL Ref document number: 2011552415 Country of ref document: JP Ref document number: 13254473 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010220335 Country of ref document: AU Ref document number: 595276 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 7244/DELNP/2011 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 20117022812 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11128125 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12398 Country of ref document: GE |
|
ENP | Entry into the national phase |
Ref document number: 2011139014 Country of ref document: RU Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010706624 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2010220335 Country of ref document: AU Date of ref document: 20100302 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: PI1010243 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: PI1010243 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110905 |