CA2664413A1 - Treatment for non-alcoholic-steatohepatitis - Google Patents

Info

Publication number

CA2664413A1

CA2664413A1 CA002664413A CA2664413A CA2664413A1 CA 2664413 A1 CA2664413 A1 CA 2664413A1 CA 002664413 A CA002664413 A CA 002664413A CA 2664413 A CA2664413 A CA 2664413A CA 2664413 A1 CA2664413 A1 CA 2664413A1

Authority

CA

Canada

Prior art keywords

substituted

group

aryl

nitrogen

independently selected

Prior art date

2006-10-04

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 title claims abstract description 97
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 title claims description 62
• 238000011282 treatment Methods 0.000 title claims description 32
• 238000000034 method Methods 0.000 claims abstract description 180
• 150000001875 compounds Chemical class 0.000 claims abstract description 105
• 150000003839 salts Chemical class 0.000 claims abstract description 58
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 25
• 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 22
• 208000008589 Obesity Diseases 0.000 claims abstract description 15
• 235000020824 obesity Nutrition 0.000 claims abstract description 15
• 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 12
• -1 nitro, carboxy Chemical group 0.000 claims description 134
• 125000003118 aryl group Chemical group 0.000 claims description 90
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 83
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 60
• 125000000217 alkyl group Chemical group 0.000 claims description 58
• 239000003795 chemical substances by application Substances 0.000 claims description 54
• 125000000623 heterocyclic group Chemical group 0.000 claims description 47
• DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims description 45
• 210000004369 blood Anatomy 0.000 claims description 43
• 239000008280 blood Substances 0.000 claims description 43
• 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 42
• 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 39
• 239000008103 glucose Substances 0.000 claims description 39
• 125000001072 heteroaryl group Chemical group 0.000 claims description 39
• 229910052757 nitrogen Inorganic materials 0.000 claims description 37
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 33
• 229910052739 hydrogen Inorganic materials 0.000 claims description 33
• 125000002757 morpholinyl group Chemical group 0.000 claims description 33
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 33
• 125000004193 piperazinyl group Chemical group 0.000 claims description 33
• 125000003386 piperidinyl group Chemical group 0.000 claims description 32
• 125000003107 substituted aryl group Chemical group 0.000 claims description 31
• 239000003814 drug Substances 0.000 claims description 30
• 229910052736 halogen Inorganic materials 0.000 claims description 30
• 150000002367 halogens Chemical class 0.000 claims description 30
• 231100000240 steatosis hepatitis Toxicity 0.000 claims description 30
• 125000004429 atom Chemical group 0.000 claims description 28
• 150000002632 lipids Chemical class 0.000 claims description 25
• 108090001061 Insulin Proteins 0.000 claims description 24
• 102000004877 Insulin Human genes 0.000 claims description 24
• 229940124597 therapeutic agent Drugs 0.000 claims description 24
• 125000003545 alkoxy group Chemical group 0.000 claims description 23
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims description 22
• 229940125396 insulin Drugs 0.000 claims description 21
• 229960003562 phentermine Drugs 0.000 claims description 21
• 125000001424 substituent group Chemical group 0.000 claims description 21
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 18
• 208000004930 Fatty Liver Diseases 0.000 claims description 17
• 206010016654 Fibrosis Diseases 0.000 claims description 17
• 206010019708 Hepatic steatosis Diseases 0.000 claims description 17
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 17
• 208000010706 fatty liver disease Diseases 0.000 claims description 17
• 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 17
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 16
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 16
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 16
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 16
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 16
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 16
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 16
• 125000002541 furyl group Chemical group 0.000 claims description 16
• 125000001188 haloalkyl group Chemical group 0.000 claims description 16
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
• 125000002883 imidazolyl group Chemical group 0.000 claims description 16
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 16
• 125000001041 indolyl group Chemical group 0.000 claims description 16
• 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 16
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 16
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 16
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 16
• 125000002971 oxazolyl group Chemical group 0.000 claims description 16
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 16
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 16
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 16
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 16
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 16
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 16
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 16
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 16
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 16
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 16
• 125000000335 thiazolyl group Chemical group 0.000 claims description 16
• 125000001544 thienyl group Chemical group 0.000 claims description 16
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 16
• 125000004306 triazinyl group Chemical group 0.000 claims description 16
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
• 230000007863 steatosis Effects 0.000 claims description 15
• MFOCDFTXLCYLKU-CMPLNLGQSA-N Phendimetrazine Chemical compound O1CCN(C)[C@@H](C)[C@@H]1C1=CC=CC=C1 MFOCDFTXLCYLKU-CMPLNLGQSA-N 0.000 claims description 14
• 125000004423 acyloxy group Chemical group 0.000 claims description 14
• 239000003963 antioxidant agent Substances 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 229960001243 orlistat Drugs 0.000 claims description 14
• 229960000436 phendimetrazine Drugs 0.000 claims description 14
• 238000002360 preparation method Methods 0.000 claims description 14
• 229960004425 sibutramine Drugs 0.000 claims description 14
• 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 14
• 125000004963 sulfonylalkyl group Chemical group 0.000 claims description 14
• 230000003078 antioxidant effect Effects 0.000 claims description 13
• 230000007882 cirrhosis Effects 0.000 claims description 13
• HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 13
• 208000011580 syndromic disease Diseases 0.000 claims description 13
• 208000007082 Alcoholic Fatty Liver Diseases 0.000 claims description 12
• 208000026594 alcoholic fatty liver disease Diseases 0.000 claims description 12
• 235000006708 antioxidants Nutrition 0.000 claims description 12
• 229960003512 nicotinic acid Drugs 0.000 claims description 12
• 235000001968 nicotinic acid Nutrition 0.000 claims description 12
• 239000011664 nicotinic acid Substances 0.000 claims description 12
• 229930003827 cannabinoid Natural products 0.000 claims description 11
• 239000003557 cannabinoid Substances 0.000 claims description 11
• GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
• 208000007788 Acute Liver Failure Diseases 0.000 claims description 10
• 206010000804 Acute hepatic failure Diseases 0.000 claims description 10
• YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 10
• 231100000836 acute liver failure Toxicity 0.000 claims description 10
• 229940121363 anti-inflammatory agent Drugs 0.000 claims description 10
• 239000002260 anti-inflammatory agent Substances 0.000 claims description 10
• 208000035475 disorder Diseases 0.000 claims description 10
• SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims description 9
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• 229940100389 Sulfonylurea Drugs 0.000 claims description 9
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• 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 9
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• RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims description 9
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 8
• DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 claims description 7
• RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 7
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