AU2004266228A1

AU2004266228A1 - Melanin concentrating hormone receptor antagonists

Melanin concentrating hormone receptor antagonists Download PDF

Info

Publication number: AU2004266228A1
Authority: AU; Australia
Prior art keywords: group; och; hydrogen; alkyl; ethyl
Prior art date: 2003-08-13
Legal status : Abandoned

Application number

AU2004266228A

Other languages

English (en)

Other versions

AU2004266228A2 (en

Inventor

Christopher Hulme

Vu Ma

Paul Tempest

Current Assignee

Amgen Inc

Original Assignee

Amgen Inc

Priority date

2003-08-13

Filing date

2004-08-11

Publication date

2005-03-03

2004-08-11 Application filed by Amgen Inc filed Critical Amgen Inc

2005-03-03 Publication of AU2004266228A2 publication Critical patent/AU2004266228A2/en

2005-03-03 Publication of AU2004266228A1 publication Critical patent/AU2004266228A1/en

Status Abandoned legal-status Critical Current

Links

102000029828 Melanin-concentrating hormone receptor Human genes 0.000 title description 34
108010047068 Melanin-concentrating hormone receptor Proteins 0.000 title description 34
229940123502 Hormone receptor antagonist Drugs 0.000 title description 4
-1 aralkenyl Chemical group 0.000 claims description 1886
125000000217 alkyl group Chemical group 0.000 claims description 240
229910052739 hydrogen Inorganic materials 0.000 claims description 198
239000001257 hydrogen Substances 0.000 claims description 197
150000002431 hydrogen Chemical class 0.000 claims description 183
125000003118 aryl group Chemical group 0.000 claims description 174
125000000753 cycloalkyl group Chemical group 0.000 claims description 163
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 157
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 156
229910052757 nitrogen Inorganic materials 0.000 claims description 156
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 151
125000003710 aryl alkyl group Chemical group 0.000 claims description 136
125000005843 halogen group Chemical group 0.000 claims description 120
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 113
125000003545 alkoxy group Chemical group 0.000 claims description 109
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 105
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 105
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 103
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 101
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 101
125000004104 aryloxy group Chemical group 0.000 claims description 97
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 97
125000004181 carboxyalkyl group Chemical group 0.000 claims description 93
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 92
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 84
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 84
125000004093 cyano group Chemical group *C#N 0.000 claims description 81
125000001624 naphthyl group Chemical group 0.000 claims description 81
235000010290 biphenyl Nutrition 0.000 claims description 80
125000001424 substituent group Chemical group 0.000 claims description 79
239000004305 biphenyl Substances 0.000 claims description 78
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 77
150000001875 compounds Chemical class 0.000 claims description 76
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 73
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 73
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 73
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 71
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 71
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 68
125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 67
125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 66
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 64
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 64
125000000623 heterocyclic group Chemical group 0.000 claims description 61
125000004043 oxo group Chemical group O=* 0.000 claims description 54
125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 50
125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 50
125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 50
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 50
125000005815 pentoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 49
150000003839 salts Chemical class 0.000 claims description 46
GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 40
125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 40
125000001072 heteroaryl group Chemical group 0.000 claims description 40
125000006226 butoxyethyl group Chemical group 0.000 claims description 39
125000006233 propoxy propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 39
125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 39
125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 claims description 39
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 33
238000000034 method Methods 0.000 claims description 31
101800002739 Melanin-concentrating hormone Proteins 0.000 claims description 30
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 30
ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 claims description 30
125000003386 piperidinyl group Chemical group 0.000 claims description 30
125000001309 chloro group Chemical group Cl* 0.000 claims description 29
125000001153 fluoro group Chemical group F* 0.000 claims description 29
125000001246 bromo group Chemical group Br* 0.000 claims description 28
125000002541 furyl group Chemical group 0.000 claims description 22
125000002883 imidazolyl group Chemical group 0.000 claims description 22
125000001041 indolyl group Chemical group 0.000 claims description 22
125000000842 isoxazolyl group Chemical group 0.000 claims description 22
125000001715 oxadiazolyl group Chemical group 0.000 claims description 22
125000002971 oxazolyl group Chemical group 0.000 claims description 22
125000003226 pyrazolyl group Chemical group 0.000 claims description 22
125000000168 pyrrolyl group Chemical group 0.000 claims description 22
125000003831 tetrazolyl group Chemical group 0.000 claims description 22
125000000335 thiazolyl group Chemical group 0.000 claims description 22
125000001544 thienyl group Chemical group 0.000 claims description 22
125000001425 triazolyl group Chemical group 0.000 claims description 22
BWCDLEQTELFBAW-UHFFFAOYSA-N 3h-dioxazole Chemical group N1OOC=C1 BWCDLEQTELFBAW-UHFFFAOYSA-N 0.000 claims description 21
125000003342 alkenyl group Chemical group 0.000 claims description 21
125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 21
125000001786 isothiazolyl group Chemical group 0.000 claims description 21
208000008589 Obesity Diseases 0.000 claims description 18
125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 18
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 18
235000020824 obesity Nutrition 0.000 claims description 18
239000000651 prodrug Substances 0.000 claims description 18
229940002612 prodrug Drugs 0.000 claims description 18
125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 17
125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 17
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 17
125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 16
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 16
125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 14
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
238000011282 treatment Methods 0.000 claims description 13
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 12
125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 11
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 9
208000035475 disorder Diseases 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
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239000002671 adjuvant Substances 0.000 claims description 8
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125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 8
125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 8
125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 8
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125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 8
208000019454 Feeding and Eating disease Diseases 0.000 claims description 7
125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 claims description 7
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125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 7
125000001148 pentyloxycarbonyl group Chemical group 0.000 claims description 7
125000005981 pentynyl group Chemical group 0.000 claims description 7
125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 0.000 claims description 7
125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 7
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
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206010006550 Bulimia nervosa Diseases 0.000 claims description 6
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208000019116 sleep disease Diseases 0.000 claims description 3
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125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 17
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ZTISWCXLXLMLLY-UHFFFAOYSA-N n-(2-pyrrolidin-1-ylethyl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NCCN1CCCC1 ZTISWCXLXLMLLY-UHFFFAOYSA-N 0.000 claims 2
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MMZZPUAORWLZFJ-UHFFFAOYSA-N 1-[2-(3,4-dimethylphenoxy)-5-[2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]phenyl]-3-phenylurea Chemical compound C1=C(C)C(C)=CC=C1OC1=CC=C(C(=O)N2C(CCC2)CN2CCCC2)C=C1NC(=O)NC1=CC=CC=C1 MMZZPUAORWLZFJ-UHFFFAOYSA-N 0.000 claims 1
QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims 1
125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims 1
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125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims 1
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NNYWFUCRJFYYKW-UHFFFAOYSA-N 4-(3,4-dichlorophenoxy)-3-[(3,5-difluorophenyl)carbamoylamino]-n-(2-pyrrolidin-1-ylethyl)benzamide Chemical compound FC1=CC(F)=CC(NC(=O)NC=2C(=CC=C(C=2)C(=O)NCCN2CCCC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 NNYWFUCRJFYYKW-UHFFFAOYSA-N 0.000 claims 1
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 1
125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
ZRWSCHOWCSJWJR-UHFFFAOYSA-N 4-phenoxy-n-(2-pyrrolidin-1-ylethyl)benzamide Chemical compound C=1C=C(OC=2C=CC=CC=2)C=CC=1C(=O)NCCN1CCCC1 ZRWSCHOWCSJWJR-UHFFFAOYSA-N 0.000 claims 1
125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
125000001207 fluorophenyl group Chemical group 0.000 claims 1
125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims 1
102000047659 melanin-concentrating hormone Human genes 0.000 claims 1
NYRXUFQAPFKBTJ-UHFFFAOYSA-N n-[2-(3,4-dimethylphenoxy)-5-(2-pyrrolidin-1-ylethylcarbamoyl)phenyl]naphthalene-2-carboxamide Chemical compound C1=C(C)C(C)=CC=C1OC1=CC=C(C(=O)NCCN2CCCC2)C=C1NC(=O)C1=CC=C(C=CC=C2)C2=C1 NYRXUFQAPFKBTJ-UHFFFAOYSA-N 0.000 claims 1
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