CA2664413A1

CA2664413A1 - Treatment for non-alcoholic-steatohepatitis

Treatment for non-alcoholic-steatohepatitis Download PDF

Info

Publication number: CA2664413A1
Authority: CA; Canada
Prior art keywords: substituted; group; aryl; nitrogen; independently selected
Prior art date: 2006-10-04
Legal status : Abandoned

Application number

CA002664413A

Other languages

English (en)

French (fr)

Inventor

Naiara Beraza

Michel Dreano

Christian Trautwein

Current Assignee

Ares Trading SA

Original Assignee

Individual

Priority date

2006-10-04

Filing date

2007-10-04

Publication date

2008-04-10

2007-10-04 Application filed by Individual filed Critical Individual

2008-04-10 Publication of CA2664413A1 publication Critical patent/CA2664413A1/en

Status Abandoned legal-status Critical Current

Links

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
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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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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
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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
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PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 claims description 7
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KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 claims description 7
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SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 claims description 7
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LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 7
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KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 7
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229960003015 rimonabant Drugs 0.000 claims description 7
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UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 claims description 7
229960002911 zonisamide Drugs 0.000 claims description 7
ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 6
YCOOGLSVZRCSMP-UHFFFAOYSA-N 1-[4-[4-[[4-(4-chlorophenyl)pyrimidin-2-yl]amino]benzoyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1C(=O)C(C=C1)=CC=C1NC1=NC=CC(C=2C=CC(Cl)=CC=2)=N1 YCOOGLSVZRCSMP-UHFFFAOYSA-N 0.000 claims description 6
VTAKZNRDSPNOAU-UHFFFAOYSA-M 2-(chloromethyl)oxirane;hydron;prop-2-en-1-amine;n-prop-2-enyldecan-1-amine;trimethyl-[6-(prop-2-enylamino)hexyl]azanium;dichloride Chemical compound Cl.[Cl-].NCC=C.ClCC1CO1.CCCCCCCCCCNCC=C.C[N+](C)(C)CCCCCCNCC=C VTAKZNRDSPNOAU-UHFFFAOYSA-M 0.000 claims description 6
229920001268 Cholestyramine Polymers 0.000 claims description 6
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HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 claims description 6
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XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 4
XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 4
TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 4
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