CA2569507A1

CA2569507A1 - Amido compounds and their use as pharmaceuticals

Amido compounds and their use as pharmaceuticals Download PDF

Info

Publication number: CA2569507A1
Authority: CA; Canada
Prior art keywords: cycloalkyl; heterocycloalkyl; heteroaryl; aryl; haloalkyl
Prior art date: 2004-06-24
Legal status : Abandoned

Application number

CA002569507A

Other languages

English (en)

French (fr)

Inventor

Wenqing Yao

Meizhong Xu

Jincong Zhuo

Colin Zhang

Brian W. Metcalf

Yun-Long Li

Current Assignee

Incyte Corp

Original Assignee

Individual

Priority date

2004-06-24

Filing date

2005-06-23

Publication date

2006-02-02

2005-06-23 Application filed by Individual filed Critical Individual

2006-02-02 Publication of CA2569507A1 publication Critical patent/CA2569507A1/en

Status Abandoned legal-status Critical Current

Links

239000003814 drug Substances 0.000 title description 8
125000003368 amide group Chemical group 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 182
-1 hydroxyl steroid Chemical class 0.000 claims abstract description 76
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 47
230000000694 effects Effects 0.000 claims abstract description 36
201000010099 disease Diseases 0.000 claims abstract description 34
229960002478 aldosterone Drugs 0.000 claims abstract description 27
PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 claims abstract description 26
PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 claims abstract description 26
230000014509 gene expression Effects 0.000 claims abstract description 13
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 265
125000000753 cycloalkyl group Chemical group 0.000 claims description 248
125000003118 aryl group Chemical group 0.000 claims description 209
125000001072 heteroaryl group Chemical group 0.000 claims description 182
125000003710 aryl alkyl group Chemical group 0.000 claims description 117
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 116
125000005843 halogen group Chemical group 0.000 claims description 84
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 75
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 74
125000001188 haloalkyl group Chemical group 0.000 claims description 74
125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 69
238000000034 method Methods 0.000 claims description 67
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 54
239000000203 mixture Substances 0.000 claims description 52
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 51
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 50
125000000304 alkynyl group Chemical group 0.000 claims description 42
125000004432 carbon atom Chemical group C* 0.000 claims description 41
125000003342 alkenyl group Chemical group 0.000 claims description 38
125000004429 atom Chemical group 0.000 claims description 36
229910052717 sulfur Inorganic materials 0.000 claims description 35
125000005466 alkylenyl group Chemical group 0.000 claims description 31
229910002091 carbon monoxide Inorganic materials 0.000 claims description 25
206010020772 Hypertension Diseases 0.000 claims description 24
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 24
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 23
101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 claims description 23
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 23
150000003839 salts Chemical class 0.000 claims description 23
125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 claims description 22
208000008589 Obesity Diseases 0.000 claims description 21
125000004663 dialkyl amino group Chemical group 0.000 claims description 21
235000020824 obesity Nutrition 0.000 claims description 21
206010022489 Insulin Resistance Diseases 0.000 claims description 20
125000003282 alkyl amino group Chemical group 0.000 claims description 20
208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 20
208000001145 Metabolic Syndrome Diseases 0.000 claims description 19
201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 19
125000002619 bicyclic group Chemical group 0.000 claims description 18
125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
239000000651 prodrug Substances 0.000 claims description 18
229940002612 prodrug Drugs 0.000 claims description 18
229910052760 oxygen Inorganic materials 0.000 claims description 17
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 13
229910052739 hydrogen Inorganic materials 0.000 claims description 13
208000031226 Hyperlipidaemia Diseases 0.000 claims description 12
201000001421 hyperglycemia Diseases 0.000 claims description 11
230000002401 inhibitory effect Effects 0.000 claims description 10
229910052721 tungsten Inorganic materials 0.000 claims description 10
229910052727 yttrium Inorganic materials 0.000 claims description 10
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 8
229910052799 carbon Inorganic materials 0.000 claims description 8
206010012601 diabetes mellitus Diseases 0.000 claims description 7
101100451537 Caenorhabditis elegans hsd-1 gene Proteins 0.000 claims description 6
208000032928 Dyslipidaemia Diseases 0.000 claims description 6
208000017170 Lipid metabolism disease Diseases 0.000 claims description 6
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
208000024172 Cardiovascular disease Diseases 0.000 claims description 5
206010012289 Dementia Diseases 0.000 claims description 5
230000006378 damage Effects 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 4
208000010412 Glaucoma Diseases 0.000 claims description 4
208000002705 Glucose Intolerance Diseases 0.000 claims description 4
206010018429 Glucose tolerance impaired Diseases 0.000 claims description 4
206010019280 Heart failures Diseases 0.000 claims description 4
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208000010877 cognitive disease Diseases 0.000 claims description 4
230000002526 effect on cardiovascular system Effects 0.000 claims description 4
206010002383 Angina Pectoris Diseases 0.000 claims description 3
206010003210 Arteriosclerosis Diseases 0.000 claims description 3
201000001320 Atherosclerosis Diseases 0.000 claims description 3
208000028698 Cognitive impairment Diseases 0.000 claims description 3
206010070901 Diabetic dyslipidaemia Diseases 0.000 claims description 3
208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
208000018262 Peripheral vascular disease Diseases 0.000 claims description 3
208000007536 Thrombosis Diseases 0.000 claims description 3
206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
208000029078 coronary artery disease Diseases 0.000 claims description 3
208000006575 hypertriglyceridemia Diseases 0.000 claims description 3
230000002792 vascular Effects 0.000 claims description 3
VLSXXHVAWRTHMV-GJZGRUSLSA-N (3s)-1-[(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidine-3-carbonyl]piperidine-3-carboxylic acid Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2C[C@H](CCC2)C(O)=O)CCC1 VLSXXHVAWRTHMV-GJZGRUSLSA-N 0.000 claims description 2
YVYUWSZAJHKIGM-UHFFFAOYSA-N 1,3,3a,4,5,9b-hexahydrobenzo[e]isoindol-2-yl-[1-(benzenesulfonyl)piperidin-3-yl]methanone Chemical compound C1C2CCC3=CC=CC=C3C2CN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 YVYUWSZAJHKIGM-UHFFFAOYSA-N 0.000 claims description 2
125000004562 2,3-dihydroindol-1-yl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
AHXMVKYKVRBJSO-FDYSRKEFSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidin-3-yl]methanone Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2C3CCCCC3CCC2)CCC1 AHXMVKYKVRBJSO-FDYSRKEFSA-N 0.000 claims description 2
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
208000006011 Stroke Diseases 0.000 claims description 2
JWZFTJNOTOTYCO-QRWMCTBCSA-N [(3r)-1-(2-nitrophenyl)sulfonylpiperidin-3-yl]-(3-pyridin-3-ylpyrrolidin-1-yl)methanone Chemical compound [O-][N+](=O)C1=CC=CC=C1S(=O)(=O)N1C[C@H](C(=O)N2CC(CC2)C=2C=NC=CC=2)CCC1 JWZFTJNOTOTYCO-QRWMCTBCSA-N 0.000 claims description 2
ZKOOSEKUIZQMKP-GOSISDBHSA-N [(3r)-1-(benzenesulfonyl)piperidin-3-yl]-(3,4-dihydro-2h-quinolin-1-yl)methanone Chemical compound C([C@H](C1)C(=O)N2C3=CC=CC=C3CCC2)CCN1S(=O)(=O)C1=CC=CC=C1 ZKOOSEKUIZQMKP-GOSISDBHSA-N 0.000 claims description 2
ZKXHVQWPDAHNCF-MUMRKEEXSA-N [(3r)-1-(benzenesulfonyl)piperidin-3-yl]-(3-pyridin-3-ylpyrrolidin-1-yl)methanone Chemical compound C([C@H](C1)C(=O)N2CC(CC2)C=2C=NC=CC=2)CCN1S(=O)(=O)C1=CC=CC=C1 ZKXHVQWPDAHNCF-MUMRKEEXSA-N 0.000 claims description 2
GTLATAUWZQTMEA-ZVAWYAOSSA-N [(3s)-1-(2-chlorophenyl)sulfonylpiperidin-3-yl]-(3-pyridin-3-ylpyrrolidin-1-yl)methanone Chemical compound ClC1=CC=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2CC(CC2)C=2C=NC=CC=2)CCC1 GTLATAUWZQTMEA-ZVAWYAOSSA-N 0.000 claims description 2
XOZBTMPFBWBSMA-GGYWPGCISA-N [(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidin-3-yl]-(3-pyridin-3-ylpyrrolidin-1-yl)methanone Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2CC(CC2)C=2C=NC=CC=2)CCC1 XOZBTMPFBWBSMA-GGYWPGCISA-N 0.000 claims description 2
JWZFTJNOTOTYCO-UHFFFAOYSA-N [1-(2-nitrophenyl)sulfonylpiperidin-3-yl]-(3-pyridin-3-ylpyrrolidin-1-yl)methanone Chemical compound [O-][N+](=O)C1=CC=CC=C1S(=O)(=O)N1CC(C(=O)N2CC(CC2)C=2C=NC=CC=2)CCC1 JWZFTJNOTOTYCO-UHFFFAOYSA-N 0.000 claims description 2
QGYHFRPWONVZNE-UHFFFAOYSA-N [1-(benzenesulfonyl)piperidin-3-yl]-(4-phenylpiperidin-1-yl)methanone Chemical compound C1CC(C=2C=CC=CC=2)CCN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 QGYHFRPWONVZNE-UHFFFAOYSA-N 0.000 claims description 2
230000008816 organ damage Effects 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 48
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 29
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 19
125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 14
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 8
125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 3
AXFFBWOXZAVNPE-UHFFFAOYSA-N 1'-[1-(benzenesulfonyl)piperidine-3-carbonyl]spiro[2-benzofuran-3,3'-pyrrolidine]-1-one Chemical compound C1CC2(C3=CC=CC=C3C(=O)O2)CN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 AXFFBWOXZAVNPE-UHFFFAOYSA-N 0.000 claims 1
JUPAKBAVGWUQPS-GNZRSQJKSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[(3s)-1-(3-bromophenyl)sulfonylpiperidin-3-yl]methanone Chemical compound BrC1=CC=CC(S(=O)(=O)N2C[C@H](CCC2)C(=O)N2C3CCCCC3CCC2)=C1 JUPAKBAVGWUQPS-GNZRSQJKSA-N 0.000 claims 1
PXUURYWUNSXDKI-QGZVFWFLSA-N 3,4-dihydro-2h-quinolin-1-yl-[(3r)-1-(2-nitrophenyl)sulfonylpiperidin-3-yl]methanone Chemical compound [O-][N+](=O)C1=CC=CC=C1S(=O)(=O)N1C[C@H](C(=O)N2C3=CC=CC=C3CCC2)CCC1 PXUURYWUNSXDKI-QGZVFWFLSA-N 0.000 claims 1
125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
206010049287 Lipodystrophy acquired Diseases 0.000 claims 1
DQICGTZZGCTBOK-KSZLIROESA-N [(3ar,7as)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-[(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidin-3-yl]methanone Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2C[C@@H]3CCCC[C@@H]3C2)CCC1 DQICGTZZGCTBOK-KSZLIROESA-N 0.000 claims 1
XOZBTMPFBWBSMA-OALUTQOASA-N [(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidin-3-yl]-[(3r)-3-pyridin-3-ylpyrrolidin-1-yl]methanone Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2C[C@H](CC2)C=2C=NC=CC=2)CCC1 XOZBTMPFBWBSMA-OALUTQOASA-N 0.000 claims 1
XOZBTMPFBWBSMA-MOPGFXCFSA-N [(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidin-3-yl]-[(3s)-3-pyridin-3-ylpyrrolidin-1-yl]methanone Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2C[C@@H](CC2)C=2C=NC=CC=2)CCC1 XOZBTMPFBWBSMA-MOPGFXCFSA-N 0.000 claims 1
QGYHFRPWONVZNE-NRFANRHFSA-N [(3s)-1-(benzenesulfonyl)piperidin-3-yl]-(4-phenylpiperidin-1-yl)methanone Chemical compound C([C@@H](C1)C(=O)N2CCC(CC2)C=2C=CC=CC=2)CCN1S(=O)(=O)C1=CC=CC=C1 QGYHFRPWONVZNE-NRFANRHFSA-N 0.000 claims 1
VSXDUDCUQBOPRH-ZACQAIPSSA-N [(4ar,8as)-3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl]-[(3s)-1-(2,3-dichlorophenyl)sulfonylpiperidin-3-yl]methanone Chemical compound ClC1=CC=CC(S(=O)(=O)N2C[C@H](CCC2)C(=O)N2C[C@H]3CCCC[C@@H]3CC2)=C1Cl VSXDUDCUQBOPRH-ZACQAIPSSA-N 0.000 claims 1
KCAFDATZQMJKNE-QRVBRYPASA-N [(4ar,8as)-3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl]-[(3s)-1-(3-chloro-2-methylphenyl)sulfonylpiperidin-3-yl]methanone Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)N2C[C@H]3CCCC[C@@H]3CC2)CCC1 KCAFDATZQMJKNE-QRVBRYPASA-N 0.000 claims 1
NKLSJXBJUMLONQ-UHFFFAOYSA-N [1-(benzenesulfonyl)piperidin-3-yl]-(3-methyl-4-phenylpiperazin-1-yl)methanone Chemical compound CC1CN(C(=O)C2CN(CCC2)S(=O)(=O)C=2C=CC=CC=2)CCN1C1=CC=CC=C1 NKLSJXBJUMLONQ-UHFFFAOYSA-N 0.000 claims 1
VKDKBCGFNJUVLV-UHFFFAOYSA-N [1-(benzenesulfonyl)piperidin-3-yl]-(3-phenylpiperidin-1-yl)methanone Chemical compound C1CCC(C=2C=CC=CC=2)CN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 VKDKBCGFNJUVLV-UHFFFAOYSA-N 0.000 claims 1
ZKXHVQWPDAHNCF-UHFFFAOYSA-N [1-(benzenesulfonyl)piperidin-3-yl]-(3-pyridin-3-ylpyrrolidin-1-yl)methanone Chemical compound C1CC(C=2C=NC=CC=2)CN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 ZKXHVQWPDAHNCF-UHFFFAOYSA-N 0.000 claims 1
MWUDAGTUMYLQHD-UHFFFAOYSA-N [1-(benzenesulfonyl)piperidin-3-yl]-spiro[1,3-dihydroindene-2,4'-piperidine]-1'-ylmethanone Chemical compound C1CC2(CC3=CC=CC=C3C2)CCN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 MWUDAGTUMYLQHD-UHFFFAOYSA-N 0.000 claims 1
GPHZODVMJDGJKT-UHFFFAOYSA-N [1-(benzenesulfonyl)piperidin-3-yl]-spiro[1h-2-benzofuran-3,4'-piperidine]-1'-ylmethanone Chemical compound C1CC2(C3=CC=CC=C3CO2)CCN1C(=O)C(C1)CCCN1S(=O)(=O)C1=CC=CC=C1 GPHZODVMJDGJKT-UHFFFAOYSA-N 0.000 claims 1
VACHEPPUZAMMGS-UHFFFAOYSA-N ethyl 1-[1-(benzenesulfonyl)piperidine-3-carbonyl]piperidine-2-carboxylate Chemical compound CCOC(=O)C1CCCCN1C(=O)C1CN(S(=O)(=O)C=2C=CC=CC=2)CCC1 VACHEPPUZAMMGS-UHFFFAOYSA-N 0.000 claims 1
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