WO1997008150A1 - Urees cycliques substituees et leurs derives utiles en tant qu'inhibiteurs de protease retrovirale - Google Patents
Urees cycliques substituees et leurs derives utiles en tant qu'inhibiteurs de protease retrovirale Download PDFInfo
- Publication number
- WO1997008150A1 WO1997008150A1 PCT/US1996/013765 US9613765W WO9708150A1 WO 1997008150 A1 WO1997008150 A1 WO 1997008150A1 US 9613765 W US9613765 W US 9613765W WO 9708150 A1 WO9708150 A1 WO 9708150A1
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- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- alkyl
- benzyl
- heterocyclic ring
- ring system
- Prior art date
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- -1 cyclic ureas Chemical class 0.000 title claims abstract description 396
- 230000001177 retroviral effect Effects 0.000 title abstract description 15
- 235000013877 carbamide Nutrition 0.000 title abstract description 8
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title abstract description 8
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 166
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 151
- 150000003839 salts Chemical group 0.000 claims abstract description 46
- 239000000651 prodrug Substances 0.000 claims abstract description 45
- 229940002612 prodrug Drugs 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 41
- 230000009385 viral infection Effects 0.000 claims abstract description 6
- 208000036142 Viral infection Diseases 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 336
- 125000000623 heterocyclic group Chemical group 0.000 claims description 257
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 236
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 207
- 229910052739 hydrogen Inorganic materials 0.000 claims description 182
- 239000001257 hydrogen Substances 0.000 claims description 175
- 229910052757 nitrogen Inorganic materials 0.000 claims description 173
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 158
- 229910052736 halogen Inorganic materials 0.000 claims description 154
- 150000002367 halogens Chemical group 0.000 claims description 154
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 150
- 239000011593 sulfur Chemical group 0.000 claims description 149
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 144
- 125000005842 heteroatom Chemical group 0.000 claims description 134
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 133
- 239000001301 oxygen Substances 0.000 claims description 132
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 130
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 116
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 111
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 101
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 89
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 87
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 77
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 229910052799 carbon Inorganic materials 0.000 claims description 70
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 68
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 68
- RBIIKVXVYVANCQ-CUWPLCDZSA-N (2s,4s,5s)-5-amino-n-(3-amino-2,2-dimethyl-3-oxopropyl)-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-propan-2-ylhexanamide Chemical compound C1C(C)(C)N(C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)CC(=O)N1C1=CC=CC=C1Cl RBIIKVXVYVANCQ-CUWPLCDZSA-N 0.000 claims description 65
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 65
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 62
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 61
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 60
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 59
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 57
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 55
- 125000000094 2-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 54
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 52
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 50
- 125000002837 carbocyclic group Chemical group 0.000 claims description 48
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 47
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 46
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 45
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 42
- 150000001413 amino acids Chemical class 0.000 claims description 42
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 40
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 32
- 125000006242 amine protecting group Chemical group 0.000 claims description 31
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 30
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 29
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 28
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 229940124530 sulfonamide Drugs 0.000 claims description 26
- 150000003456 sulfonamides Chemical class 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 125000000468 ketone group Chemical group 0.000 claims description 22
- 229920006395 saturated elastomer Polymers 0.000 claims description 22
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000001931 aliphatic group Chemical group 0.000 claims description 21
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 229930194542 Keto Natural products 0.000 claims description 20
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 20
- 150000007942 carboxylates Chemical class 0.000 claims description 20
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 20
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 19
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 19
- 150000002923 oximes Chemical class 0.000 claims description 18
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 17
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 11
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 11
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 11
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 11
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 10
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 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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- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 6
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 4
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- HZXXSCOUSGLRRX-UHFFFAOYSA-N cyanoboronic acid Chemical compound OB(O)C#N HZXXSCOUSGLRRX-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims description 2
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- 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
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- 229910052740 iodine Inorganic materials 0.000 claims description 2
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims 1
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- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
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- DVVAGRMJGUQHLI-UHFFFAOYSA-N dimethyl cyclohex-4-ene-1,2-dicarboxylate Chemical compound COC(=O)C1CC=CCC1C(=O)OC DVVAGRMJGUQHLI-UHFFFAOYSA-N 0.000 description 1
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- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
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- 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 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
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- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- RBRCCWBAMGPRSN-UHFFFAOYSA-N thieno[2,3-d][1,3]thiazole Chemical compound S1C=NC2=C1C=CS2 RBRCCWBAMGPRSN-UHFFFAOYSA-N 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- YFNGWGVTFYSJHE-UHFFFAOYSA-K trisodium;phosphonoformate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O YFNGWGVTFYSJHE-UHFFFAOYSA-K 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-UHFFFAOYSA-N 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
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- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
Definitions
- This invention relates generally to substituted cyclic ureas and analogs thereof useful as retroviral protease inhibitors, pharmaceutical compositions comprising the same, and methods of using the same for treating viral infection.
- ADT adriamycin that inhibit viral DNA synthesis
- compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell
- Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
- the ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be less prone to drug resistance when compared to current treatments.
- WO93/07128 discloses cyclic carbonyls as inhibitors of HIV protease and synthetic procedures for preparing HIV protease inhibitors.
- WO92/21647 discloses cyclic carbonyls and sulfones as inhibitors of HIV protease.
- the present invention concerns novel substituted cyclic ureas and analogs thereof, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases, such as AIDS. None of the above references teach or suggest the cyclic ureas of the present invention as inhibitors of HIV protease or for treatment of retroviral diseases, i.e., AIDS.
- the substituted cyclic ureas, and analogs thereof, provided by the present invention are
- the compounds of the present invention are of low molecular weight and may, therefore, have good oral absorption properties in mammals.
- one object of the present invention is to provide novel retroviral protease inhibitors.
- compositions with retroviral protease inhibiting activity comprising a
- R 1 is -C(R 4 ) (R 4a )R 5 ;
- R 2 is -C(R 7 ) (R 7a )R 6 ;
- R 1 and R 2 can be taken together with the carbons to which they are attached to form a
- carbocyclic or heterocyclic ring said carbocyclic or heterocyclic ring being optionally substituted with 0-5 R 5 , R 6 , R 4 , R 4a , R 7 or R 7a ;
- R 4 and R 7 are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 4a and R 7a are independently selected from the following:
- R 4 and R 4a can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 ;
- R 7 and R 7a can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 ;
- R 5 and R 6 are independently selected from the following: hydrogen, halogen, -N(R 20 ) 2 , -SR 20 , -OR 20 , or C 1 -C 6 alkyl substituted with 0-3 R 11 ;
- R 5 and R 6 can alternatively join to form -OCH 2 SCH 2 O-
- R 11 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
- R 12 when a substituent on carbon, is selected from the following:
- a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
- R 12 when a substituent on nitrogen, is selected from the following:
- R 12a when a substituent on carbon, is selected from one or more of the following:
- alkylcarbonyl C 1 -C 4 alkylcarbonylamino; -S(O) m Me;
- R 12a when a substituent on nitrogen, is selected from the following:
- R 13 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
- R 14 is selected from the following:
- 0-3 groups selected from OH, C 1 -C 4 alkoxy, halogen, NH 2 ;
- R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
- R 15 is: hydrogen or methyl
- R 20 is selected from the following:
- phenylaminocarbonyl substituted with 0-3 R 12 or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
- n 0, 1 or 2;
- Z is O, S, NR 24 ;
- Z' is O or NR 24 ;
- R 22 and R 23 are independently selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 22a and R 22b are independently selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 24 is independently:
- R 24a is selected from the following:
- R 22 can alternatively join with R 4 or R 4a to form a
- R 23 can alternatively join with R 7 or R 7a to form a
- R 31 is selected from the following:
- amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 32 when a substituent on carbon, is
- heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
- a 3- or 4- carbon chain wherein 0, 1 or 2 of the carbon atoms are replaced with a heteroatom independently selected from oxygen, nitrogen or sulfur, attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being substituted on the aliphatic carbons with 0-3 halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -NR 13 R 14 ;
- R 32 when a substituent on nitrogen, is
- R 40 is hydrogen or C 1 -C 3 alkyl
- R 4 , R 4a , R 7 and R 7a are not all hydrogen and when R 4 , R 4a are hydrogen, then R 22 is not hydrogen;
- T, R 1 , and R 2 are as defined above.
- Z is O, or NR 24 ;
- R 1 is -C(R 4 ) (R 4a )R 5 ;
- R 2 is -C(R 7 ) (R 7a )R 6 ;
- R 1 and R 2 may, together, be
- J may also be S(O) m ; m is 0, 1 or 2;
- R 22 and R 23 may, independently, also be C 1-6 alkyl
- R 31 may also be OR 13 or a C 5-7 carbocyclic residue; and R 32 may also be C 1-4 alkyl substituted with 1-2 -OR 13 ;
- R 4 and R 7 are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 4a and R 7a are independently selected from the following:
- R 5 and R 6 are independently selected from the following:
- R 11 is selected from the following:
- a C 5 -C 14 carbocyclic residue substituted with 0-3 R 12 a 5- to 10-membered heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
- R 11a is selected from the following:
- cycloalkylmethyl phenoxy; benzyloxy; nitro; C 3 -C 6 cycloalkoxy; C 1 -C 4 alkyl substituted with -NH 2 ; C 1 -C 4 hydroxyalkyl; methylenedioxy; ethylenedioxy; C 1 -C 4 haloalkyl; C 1 -C 4 haloalkoxy; C 1 -C 4 alkoxycarbonyl; C 1 -C 4 alkylcarbonyl; C 1 -C 4 alkylcarbonylamino;
- R 12 when a substituent on carbon, is selected from the following:
- phenyl halogen; hydroxy; nitro; cyano; C 1 -C 4 alkyl substituted with 0-2 OR 13 , SR 13 , or NR 11 R 13 ; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkylmethyl; C 7 -C 10 arylalkyl; C 1 -C 4 alkoxy; -CO 2 H; hydroxamic acid; hydrazide; boronic acid; sulfonamide; formyl; C 3 -C 6 cycloalkoxy; -OR 13 ;
- R 12 when a substituent on nitrogen, is selected from the following:
- R 12a when a substituent on carbon, is selected from the following:
- R 12a when a substituent on nitrogen, is selected from the following:
- R 13 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
- R 14 is selected from: hydrogen; hydroxy; C 1 -C 6 alkoxy; NH 2 ; -NH(C 1 -C 4 alkyl); C 2 -C 6 alkenyl; phenyl; benzyl; an amine protecting group when R 14 is bonded to
- R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
- R 20 is selected from:
- R 22 and R 23 are independently selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
- R 22a and R 22b are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 24 is selected from: hydrogen; hydroxy; amino; C 1 - C 4 alkyl; C 1 -C 4 alkoxy; mono-(C 1 -C 6 alkyl) amino; di-(C 1 -C 6 alkyl) amino; cyano; nitro; benzyloxy; or -NHSO 2 aryl, aryl being substituted with 0-1 (C 1 -C 6 ) alkyl;
- R 24a is selected from: hydroxy; amino; C 1 -C 4 alkyl;
- alkyl amino; benzyloxy; or phenoxy;
- -C(R 14 ) N(OR 14 ); 1-3 amino acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; a C 5 -C 14 carbocyclic residue substituted with 1-5 R 32 ; and,
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 32 when a substituent on carbon, is selected from:
- phenyl phenethyl; phenoxy; C 3 -C 10 cycloalkyl; C 3 -C 6 cycloalkylmethyl; C 7 -C 10 arylalkyl; hydrazide; hydroxamic acid; boronic acid; oxime; C 1-6 alkoxy-C 1-6 alkyl;
- heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
- a 3- or 4- carbon chain wherein 0, 1 or 2 of the carbon atoms are replaced with a heteroatom independently selected from oxygen, nitrogen or sulfur, attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with 0-3 halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -NR 13 R 14 ; or,
- alkoxycarbonyl; -CO 2 H; C 1 -C 4 alkylcarbonyloxy; C 1 -C 4 alkylcarbonyl; -C(R 14 ) N(OR 14 );
- R 33 is selected from the following:
- a hydroxy protecting group when R 13 is bonded to O or, a 5- to 10-membered heterocyclic.
- R 40 is hydrogen or C 1 -C 3 alkyl
- R 4 , R 4a , R 7 and R 7a are not all hydrogen
- R 1 does not represent unsubstituted straight or branched alkyl.
- invention provides novel compounds of formula (IIa):
- R 4 and R 7 are independently selected from the following:
- R 5 and R 6 are independently selected from the following:
- R 11 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
- R 11a is selected from the following:
- R 12 when a substituent on carbon, is selected from the following:
- phenyl halogen; hydroxy; nitro; cyano; C 1 -C 4 alkyl substituted with 0-2 OR 13 , SR 13 , or NR 11 R 13 ; C 3 -C 6 cycloalkylmethyl; C 1 -C 4 alkoxy; -CO 2 H; hydroxamic acid; hydrazide; boronic acid; sulfonamide; formyl; C 3 -C 6 cycloalkoxy; -OR 13 ; -NR 13 R 14 ; C 1 -C 4 alkyl substituted with -NR 13 R 14 ; C 1 - 6 alkoxy C 1 _ ⁇ alkyl; C 1 -C 4 hydroxyalkyl;
- alkylcarbonylamino -S(O) m R 13 ; -SO 2 NR 13 R 14 ; -NHSO 2 R 14 ;
- R 14 is selected from the following:
- R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 - or -(CH 2 ) 5 -;
- R 20 is selected from the following:
- R 22 and R 23 are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 32 is selected from the following:
- heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
- R 33 is selected from the following:
- R 4 and R 7 are independently selected from the following:
- R 5 and R 6 are independently selected from the following:
- R 11 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 11 a is selected from the following:
- halogen cyano; -CH 2 NH 2 ; -NH 2 ; -NH(C 1 -C 3 alkyl); -OH;
- R 12 is selected from the following: phenyl; halogen; hydroxy; nitro; cyano; C 1 -C 4 alkyl substituted with 0-2 OR 13 , SR 13 , or NR 11 R 13 ; C 3 -C 6 cycloalkylmethyl; C 1 -C 4 alkoxy; -CO 2 H; C 3 -C 6 cycloalkoxy;
- R 13 is selected from the following:
- R 14 is selected from the following:
- R 20 is selected from the following:
- n 0, 1 or 2;
- R 22 and R 23 are independently selected from the following:
- R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
- R 31 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 32 is selected from the following:
- phenyl phenethyl; phenoxy; benzyloxy; C 3-6 cycloalkyl; halogen; -CO 2 R 13 ; cyano; C 3 -. 6 cycloalkoxy; -NR 13 R 14 ; NO 2 ;
- R 11 NR 14 , or -NR 13 R 14 ;
- R 4 and R 5 together do not represent unsubstituted straight or branched alkyl.
- the present invention provides novel compounds of formula (lib) or pharmaceutically acceptable salt or prodrug forms thereof, wherein;
- R 4 and R 7 are independently C 1-4 alkyl substituted with 0-2 R 11 or -N(CH 3 )(OCH 3 );
- R 11 is selected from the following: hydrogen
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 13 is selected from the following:
- R 20 is hydrogen or any group that, when
- R 22 and R 23 are independently selected from the following:
- R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
- R 31 is selected from the following:
- R 32 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 4 and R 5 together do not represent unsubstituted straight or branched alkyl.
- the present invention provides novel compounds of formula
- R 5 and R 6 are independently selected from the following: hydrogen, hydroxy, F, Cl, Br, I, or CH 2 OH;
- R 22 and R 23 are independently -CH 2 -R 31 ;
- R 22 and R 23 independently nay also be allyl when either R 5 or R 6 or both are halogen;
- R 31 is selected from the following: cyclopropyl, phenyl substituted with 1-2 R 32 , naphthyl, pyridyl; or a 5- to 10-membered heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 12 is selected from the following: methyl, ethyl, propyl, n-butyl, t-butyl, amino, methylamino,
- R 11 is selected from the following: hydrogen
- heterocyclic ring system being substituted with 0-2 R 12 ;
- R 14 is selected from the following: hydrogen, -CH 2 OH, or -CH 2 CH 2 OH.
- the present invention provides novel compounds of formula (IIc) or pharmaceutically acceptable salt or prodrug forms thereof, wherein;
- R 5 and R 6 are independently selected from H, OH, F,
- R 22 and R 23 are as follows :
- R 22 is cyclopropylmethyl and R 23 is 3-hydroxybenzyl ;
- R 22 is cyclopropylmethyl and R 23 is 4-hydroxybenzyl ;
- R 22 is cyclopropylmethyl and R 23 is 3-aminobenzyl
- R 22 is cyclopropylmethyl and R 23 is 4-pyridylmethyl ;
- R 22 is 3-aminobenzyl and R 23 is 2-naphthylmethyl ;
- R 22 is 3-aminobenzyl and R 23 is 4-hydroxymethylbenzyl ;
- R 22 is 3-aminobenzyl and R 23 is 3-hydroxybenzyl ;
- R 22 is 4-hydroxymethylbenzyl and R 23 is 3-hydroxybenzyl
- R 22 is 2-naphthylmethyl and R 23 is 4-hydroxymethylbenzyl ;
- R 22 is allyl and R 23 is benzyl ;
- R 22 is benzyl and R 23 is 3-hydroxybenzyl ;
- R 22 is benzyl and R 23 is 2-naphthylmethyl ;
- R 22 is benzyl and R 23 is 4-pyridylmethyl ;
- R 22 and R 23 are independently the same group and are selected from the following:
- R 22 or R 23 may, independently, both be allyl.
- R 5 and R 6 are as follows:
- R 5 and R 6 are both F
- R 5 and R 6 are both H
- R 5 and R 6 are both CH 2 OH
- R 5 is H and R 6 is CH 2 OH;
- R 5 is H and R 6 is OH;
- R 5 is H and R 6 is Br.
- the present invention provides novel compounds of formula (II) or pharmaceutically acceptable salt or prodrug forms thereof, wherein;
- R 4 and R 7 are independently C 1-2 alkyl substituted with 0-1 R 11 ;
- R 11 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 12 is selected from the following:
- R 13 O-C 1-2 alkyl-
- R 13 is selected from the following:
- R 14 is selected from the following:
- R 22 and R 23 are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 31 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 32 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 .
- X is CR 6 , C-OR 13 , or N;
- Y is CR 7 , C-OR 13, or N;
- each A is a double bond
- R 4 and R 7 are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 5 and R 6 are independently selected from the following:
- R 11 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
- R 11a is selected from the following:
- R 12 when a substituent on carbon, is selected from the following:
- a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
- R 12 when a substituent on nitrogen, is selected from the following:
- R 12a when a substituent on carbon, is selected from one or more of the following:
- alkylcarbonyl C 1 -C 4 alkylcarbonylamino; -S(O) m Me;
- R 12a when a substituent on nitrogen, is selected from the following:
- R 13 is selected from the following:
- R 14 is selected from the following:
- R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
- R 15 is hydrogen or methyl
- R 20 is selected from the following:
- phenylaminocarbonyl substituted with 0-3 R 12 or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
- n 0, 1 or 2;
- T is selected from:
- Z is O, S, or NR 24 ;
- R 22 and R 23 are independently selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 22 and R 23 may both be hydrogen when at least one of X or Y is N;
- R 22 and R 23 may, when at least one of X or Y is C- OR 13 or N, independently be C 2-8 alkenyl substituted with
- R 22a ana R 22b are independently selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 24 is selected from the following:
- R24a is selected from the following:
- R 31 is selected from the following:
- R 32 when a substituent on carbon, is selected from the following:
- phenyl phenethyl; phenoxy; C 3 -C 10 cycloalkyl; C 3 -C 6 cycloalkylmethyl; C 7 -C 10 arylalkyl; hydrazide; hydroxamic acid; boronic acid; oxime; C 1-6 alkoxy-C 1-6 alkyl;
- heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
- R 32 when a substituent on nitrogen, is selected from the following:
- phenyl; benzyl; phenethyl; hydroxy; C 1 -C 4 hydroxyalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkyl; C 3 -C 6 cycloalkyl; C3-C 6 cycloalkylmethyl; -CH 2 NR 13 R 14 ; -NR 13 R 14 ; C 1-6 alkoxy-C 1-6 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkoxycarbonyl; -CO 2 H; C 1 -C 4 alkylcarbonyloxy; and, -C(R 14 ) N(OR 14 ) ;
- R 40 is hydrogen or C 1 -C 3 alkyl
- R 41 is selected from the following:
- the present invention provides novel compounds of formula (lid) or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
- X is CH, C-OR 13 , or N;
- R 4 is hydrogen
- R 22 and R 23 are independently selected from the following: OR 22a and C 1-2 alkyl substituted with R 31 ;
- R 22 and R 23 may both be hydrogen when at least one of X or Y is N;
- R 22 and R 23 may, when at least one of X or Y is C- OR 13 or N, independently be C 2-8 alkenyl substituted with 1-3 C 3 -C 14 carbocyclic ring systems each ring system being substituted with 1-5 R 31 ;
- R 22a is selected from the following:
- R 12 is selected from the following: C 1-4 alkyl substituted with 0-2 OR 13 , amino, methylamino,
- R 13 is selected from the following:
- heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
- R 31 is C 1-3 alkoxy-C 1-3 alkoxy
- R 32 is C 1-2 alkyl substituted with 0-2 OR 13 .
- R is O, S(O) m , NH, or NOR 13 ;
- Y is C(H)(R 7 );
- each A is a single bond
- R 4 and R 7 are independently selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
- R 11 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
- R 11a is selected from the following:
- R 12 when a substituent on carbon, is selected from the following:
- a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
- R 12 when a substituent on nitrogen, is selected from the following:
- R 12a when a substituent on carbon, is selected from one or more of the following:
- alkylcarbonyl C 1 -C 4 alkylcarbonylamino; -S(O) m Me;
- R 12a when a substituent on nitrogen, is selected from the following:
- R 13 is selected from the following:
- heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
- R 14 is selected from the following:
- 0-3 groups selected from OH, C 1 -C 4 alkoxy, halogen, NH 2 ;
- R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
- R 15 is: hydrogen or methyl
- R 20 is selected from the following:
- phenylaminocarbonyl substituted with 0-3 R 12 or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
- n 0, 1 or 2;
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Abstract
L'invention concerne des urées cycliques substituées et leurs analogues représentés par la formule (I) dans laquelle T est sélectionné dans: -N(R22)C(=Z)N(R23)-; -N(R22)C(=Z)C(=Z)N(R23)-; -N(R22)S(=Z')N(R23)-; -N(R22)S(=Z')¿2N(R?23)-; ou -N(R22)P(=O)(R?24a)N(R23¿)-; Z représente O, S, NR24; et, Z' représente O ou NR24 ou leurs sels ou leurs promédicaments, qui sont utiles en tant qu'inhibiteurs de protéase rétrovirale, ainsi que des compositions pharmaceutiques comprenant ces composés et des procédés d'utilisation de ces compositions afin de traiter l'infection virale.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU15926/97A AU1592697A (en) | 1995-08-22 | 1996-08-21 | Substituted cyclic ureas and derivatives thereof useful as retroviral protease inhibitors |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US265395P | 1995-08-22 | 1995-08-22 | |
US60/002,653 | 1995-08-22 | ||
US941795P | 1995-12-29 | 1995-12-29 | |
US60/009,417 | 1995-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997008150A1 true WO1997008150A1 (fr) | 1997-03-06 |
Family
ID=26670689
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/013765 WO1997008150A1 (fr) | 1995-08-22 | 1996-08-21 | Urees cycliques substituees et leurs derives utiles en tant qu'inhibiteurs de protease retrovirale |
Country Status (2)
Country | Link |
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AU (1) | AU1592697A (fr) |
WO (1) | WO1997008150A1 (fr) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5925635A (en) * | 1996-04-17 | 1999-07-20 | Dupont Pharmaceuticals Company | N-(amidinophenyl) cyclourea analogs as factor XA inhibitors |
US6143743A (en) * | 1997-07-03 | 2000-11-07 | Dupont Pharmaceuticals Company | Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders |
EP1640368A2 (fr) | 2000-06-13 | 2006-03-29 | The Centre National de la Recherche Scientifique | Composés urées cycliques et leur procédé de préparation |
US7259174B2 (en) | 2004-05-25 | 2007-08-21 | National Health Research Institutes | Imidazolidinone compounds |
JP2008538366A (ja) * | 2005-04-19 | 2008-10-23 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 置換された環状尿素誘導体及び医薬の製造へのその使用 |
WO2009011910A2 (fr) * | 2007-07-18 | 2009-01-22 | Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Serices | Composés d'imidazolidinone, procédés pour inhiber une désubiquitination et procédés de traitement |
US7501445B2 (en) | 2001-08-21 | 2009-03-10 | National Health Research Institutes | Imidazolidinone compounds |
US8263635B2 (en) | 2009-06-26 | 2012-09-11 | Novartis Ag | Inhibitors of CYP 17 |
US8268868B2 (en) | 2007-01-10 | 2012-09-18 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
US8273770B2 (en) | 2007-07-21 | 2012-09-25 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
WO2013062024A1 (fr) * | 2011-10-28 | 2013-05-02 | 石原産業株式会社 | Agent de lutte contre des maladies de plantes contenant un dérivé arylamidine ou un sel de celui-ci |
US8518968B2 (en) | 2009-12-04 | 2013-08-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hydrazone and diacyl hydrazine compounds and methods of use |
US9029399B2 (en) | 2011-04-28 | 2015-05-12 | Novartis Ag | 17α-hydroxylase/C17,20-lyase inhibitors |
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WO1992007867A1 (fr) * | 1990-11-01 | 1992-05-14 | The Regents Of The University Of Michigan | Benzimidazoles polysubstitues utilises comme agents antiviraux |
WO1993007128A1 (fr) * | 1991-10-11 | 1993-04-15 | The Du Pont Merck Pharmaceutical Company | Urees cycliques et analogues utiles en tant qu'inhibiteurs de la protease retrovirale |
-
1996
- 1996-08-21 AU AU15926/97A patent/AU1592697A/en not_active Abandoned
- 1996-08-21 WO PCT/US1996/013765 patent/WO1997008150A1/fr active Application Filing
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WO1992007867A1 (fr) * | 1990-11-01 | 1992-05-14 | The Regents Of The University Of Michigan | Benzimidazoles polysubstitues utilises comme agents antiviraux |
WO1993007128A1 (fr) * | 1991-10-11 | 1993-04-15 | The Du Pont Merck Pharmaceutical Company | Urees cycliques et analogues utiles en tant qu'inhibiteurs de la protease retrovirale |
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A.B.A. JANSEN ET AL.: "A Search for Biotin Antagonists and the Isolation of gamma-Biotin.", JOURNAL OF THE CHEMICAL SOCIETY, 1962, LETCHWORTH GB, pages 4909 - 4914, XP002021615 * |
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F. OUTURQUIN ET AL.: "N-alkylation de l'amino-3 thiophène et du diamino-3,4 thiophène", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, no. 2, 1986, PARIS FR, pages 259 - 266, XP002021612 * |
S. LAVIELLE ET AL.: "A Total Synthesis of Biotin Based on the Stereoselective Alkylation of Sulfoxides", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 100, no. 5, 1 March 1978 (1978-03-01), DC US, pages 1558 - 1563, XP002021614 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5925635A (en) * | 1996-04-17 | 1999-07-20 | Dupont Pharmaceuticals Company | N-(amidinophenyl) cyclourea analogs as factor XA inhibitors |
US6143743A (en) * | 1997-07-03 | 2000-11-07 | Dupont Pharmaceuticals Company | Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders |
US6362180B1 (en) | 1997-07-03 | 2002-03-26 | Bristol-Myers Squibb Pharma Company | Imidazopyridines for the treatment of neurological disorders |
US6642230B2 (en) | 1997-07-03 | 2003-11-04 | Bristol-Myers Squibb Pharma Company | Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders |
EP1640368A2 (fr) | 2000-06-13 | 2006-03-29 | The Centre National de la Recherche Scientifique | Composés urées cycliques et leur procédé de préparation |
US7501445B2 (en) | 2001-08-21 | 2009-03-10 | National Health Research Institutes | Imidazolidinone compounds |
US7259174B2 (en) | 2004-05-25 | 2007-08-21 | National Health Research Institutes | Imidazolidinone compounds |
US8207182B2 (en) | 2005-04-19 | 2012-06-26 | Gruenenthal Gmbh | Substituted cyclic urea derivatives and the use thereof as vanilloid receptor 1 modulators |
JP2008538366A (ja) * | 2005-04-19 | 2008-10-23 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 置換された環状尿素誘導体及び医薬の製造へのその使用 |
US8268868B2 (en) | 2007-01-10 | 2012-09-18 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
WO2009011910A2 (fr) * | 2007-07-18 | 2009-01-22 | Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Serices | Composés d'imidazolidinone, procédés pour inhiber une désubiquitination et procédés de traitement |
WO2009011910A3 (fr) * | 2007-07-18 | 2009-04-30 | Us Gov Health & Human Serv | Composés d'imidazolidinone, procédés pour inhiber une désubiquitination et procédés de traitement |
US8637560B2 (en) | 2007-07-18 | 2014-01-28 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Imidazolidinone compounds, methods to inhibit deubiquitination and methods of treatment |
US8273770B2 (en) | 2007-07-21 | 2012-09-25 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
US8263635B2 (en) | 2009-06-26 | 2012-09-11 | Novartis Ag | Inhibitors of CYP 17 |
USRE45173E1 (en) | 2009-06-26 | 2014-09-30 | Novartis Ag | Inhibitors of CYP 17 |
US8518968B2 (en) | 2009-12-04 | 2013-08-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hydrazone and diacyl hydrazine compounds and methods of use |
US9029399B2 (en) | 2011-04-28 | 2015-05-12 | Novartis Ag | 17α-hydroxylase/C17,20-lyase inhibitors |
US9339501B2 (en) | 2011-04-28 | 2016-05-17 | Novartis Ag | 17a-hydroxylase/C17,20-lyase inhibitors |
WO2013062024A1 (fr) * | 2011-10-28 | 2013-05-02 | 石原産業株式会社 | Agent de lutte contre des maladies de plantes contenant un dérivé arylamidine ou un sel de celui-ci |
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