CA2629311C - Glucagon receptor antagonists, preparation and therapeutic uses - Google Patents

Info

Publication number

CA2629311C

CA2629311C CA2629311A CA2629311A CA2629311C CA 2629311 C CA2629311 C CA 2629311C CA 2629311 A CA2629311 A CA 2629311A CA 2629311 A CA2629311 A CA 2629311A CA 2629311 C CA2629311 C CA 2629311C

Authority

CA

Canada

Prior art keywords

dimethyl

thiophene

biphenyl

carboxylic acid

amide

Prior art date

2005-11-23

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.)

Expired - Fee Related

Links

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• 229940122904 Glucagon receptor antagonist Drugs 0.000 title abstract description 9
• 238000002360 preparation method Methods 0.000 title description 38
• 230000001225 therapeutic effect Effects 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 153
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 30
• 150000003839 salts Chemical class 0.000 claims abstract description 27
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 95
• 150000002367 halogens Chemical class 0.000 claims description 66
• -1 3,3-dimethylbutyl Chemical group 0.000 claims description 51
• ZHCLIFKUVIFYBY-UHFFFAOYSA-N 2h-tetrazol-5-ylmethanamine Chemical compound NCC1=NN=NN1 ZHCLIFKUVIFYBY-UHFFFAOYSA-N 0.000 claims description 31
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
• 238000011282 treatment Methods 0.000 claims description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 11
• 125000001153 fluoro group Chemical group F* 0.000 claims description 11
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 239000001257 hydrogen Substances 0.000 claims description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 10
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 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 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 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 6
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 5
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000000439 4-methylpentoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
• 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
• 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• HRNLJUXKOVDOON-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanyl-3,3-dimethylbutyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C(C)=C(C=2C=CC(=CC=2)C(F)(F)F)C(C)=CC=1SC(CC(C)(C)C)C(S1)=CC=C1C(=O)NCC1=NN=NN1 HRNLJUXKOVDOON-UHFFFAOYSA-N 0.000 claims 2
• ULVIXJPSVNNLQE-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanyl-3-methylbutyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C=C(C(=O)NCC=2NN=NN=2)SC=1C(CC(C)C)SC(C=C1C)=CC(C)=C1C1=CC=C(C(F)(F)F)C=C1 ULVIXJPSVNNLQE-UHFFFAOYSA-N 0.000 claims 2
• VQAZHBAPCPZVGY-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanylpentyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C=C(C(=O)NCC=2NN=NN=2)SC=1C(CCCC)SC(C=C1C)=CC(C)=C1C1=CC=C(C(F)(F)F)C=C1 VQAZHBAPCPZVGY-UHFFFAOYSA-N 0.000 claims 2
• FHSPIZOLUZGKDA-UHFFFAOYSA-N 5-[1-[4-(4-tert-butylphenyl)-3,5-dimethylphenyl]sulfanyl-2,2-dimethylpropyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C(C)=C(C=2C=CC(=CC=2)C(C)(C)C)C(C)=CC=1SC(C(C)(C)C)C(S1)=CC=C1C(=O)NCC=1N=NNN=1 FHSPIZOLUZGKDA-UHFFFAOYSA-N 0.000 claims 2
• OHJQJUXJVGUOEP-UHFFFAOYSA-N 5-[1-[4-(4-tert-butylphenyl)-3,5-dimethylphenyl]sulfanylpropyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C=C(C(=O)NCC2=NNN=N2)SC=1C(CC)SC(C=C1C)=CC(C)=C1C1=CC=C(C(C)(C)C)C=C1 OHJQJUXJVGUOEP-UHFFFAOYSA-N 0.000 claims 2
• NYYGWCMQGHADAH-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanyl-2,2-dimethylpropyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C(C)=C(C=2C=CC(=CC=2)C(F)(F)F)C(C)=CC=1SC(C(C)(C)C)C(S1)=CC=C1C(=O)NCC1=NN=NN1 NYYGWCMQGHADAH-UHFFFAOYSA-N 0.000 claims 1
• BZZPIRSETRDIPE-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanyl-2,2-dimethylpropyl]thiophene-2-carboxylic acid Chemical compound C=1C(C)=C(C=2C=CC(=CC=2)C(F)(F)F)C(C)=CC=1SC(C(C)(C)C)C1=CC=C(C(O)=O)S1 BZZPIRSETRDIPE-UHFFFAOYSA-N 0.000 claims 1
• CUGPERPOARNZLC-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanyl-2-methylpropyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C=C(C(=O)NCC=2NN=NN=2)SC=1C(C(C)C)SC(C=C1C)=CC(C)=C1C1=CC=C(C(F)(F)F)C=C1 CUGPERPOARNZLC-UHFFFAOYSA-N 0.000 claims 1
• JCEKALXHEUXGLX-UHFFFAOYSA-N 5-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)phenyl]phenyl]sulfanylbutyl]-n-(2h-tetrazol-5-ylmethyl)thiophene-2-carboxamide Chemical compound C=1C=C(C(=O)NCC=2NN=NN=2)SC=1C(CCC)SC(C=C1C)=CC(C)=C1C1=CC=C(C(F)(F)F)C=C1 JCEKALXHEUXGLX-UHFFFAOYSA-N 0.000 claims 1
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
• 229960004666 glucagon Drugs 0.000 abstract description 63
• 102000051325 Glucagon Human genes 0.000 abstract description 61
• 108060003199 Glucagon Proteins 0.000 abstract description 61
• MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 abstract description 61
• 238000000034 method Methods 0.000 abstract description 37
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• 125000000217 alkyl group Chemical group 0.000 description 37
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