ES2897954T3 - Derivados de indol n-sustituidos como moduladores de los receptores de PGE2 - Google Patents

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Publication number

ES2897954T3

ES2897954T3 ES16797577T ES16797577T ES2897954T3 ES 2897954 T3 ES2897954 T3 ES 2897954T3 ES 16797577 T ES16797577 T ES 16797577T ES 16797577 T ES16797577 T ES 16797577T ES 2897954 T3 ES2897954 T3 ES 2897954T3

Authority

ES

Spain

Prior art keywords

carbon atoms

alkyl

methyl

alkoxy

oxo

Prior art date

2015-11-20

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.)

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• -1 N-substituted indole Chemical class 0.000 title claims abstract description 1330
• 229940054051 antipsychotic indole derivative Drugs 0.000 title description 5
• 102000008866 Prostaglandin E receptors Human genes 0.000 title description 4
• 108010088540 Prostaglandin E receptors Proteins 0.000 title description 4
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 872
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 295
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 294
• 239000001257 hydrogen Substances 0.000 claims abstract description 292
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 190
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 166
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 164
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 153
• 150000001875 compounds Chemical class 0.000 claims abstract description 147
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 136
• 125000001424 substituent group Chemical group 0.000 claims abstract description 131
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 124
• 239000011737 fluorine Substances 0.000 claims abstract description 122
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 116
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 111
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 96
• 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 95
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 76
• 150000002367 halogens Chemical class 0.000 claims abstract description 75
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 66
• 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 63
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 60
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 58
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 41
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 41
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 40
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 37
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 36
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 36
• 125000004428 fluoroalkoxy group Chemical group 0.000 claims abstract description 34
• 125000003118 aryl group Chemical group 0.000 claims abstract description 30
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 30
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 27
• 125000004434 sulfur atom Chemical group 0.000 claims abstract description 26
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 24
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 24
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 22
• 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims abstract description 20
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims abstract description 19
• 125000001041 indolyl group Chemical group 0.000 claims abstract description 19
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 19
• 150000003839 salts Chemical class 0.000 claims abstract description 19
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 18
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 17
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 17
• 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims abstract description 16
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 16
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 14
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 14
• 239000001301 oxygen Chemical group 0.000 claims abstract description 14
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 13
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 12
• 125000002993 cycloalkylene group Chemical group 0.000 claims abstract description 11
• 239000011593 sulfur Chemical group 0.000 claims abstract description 11
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 10
• 125000004429 atom Chemical group 0.000 claims abstract description 7
• 125000004990 dihydroxyalkyl group Chemical group 0.000 claims abstract description 7
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 78
• 229910052801 chlorine Inorganic materials 0.000 claims description 78
• 239000000460 chlorine Substances 0.000 claims description 78
• 206010028980 Neoplasm Diseases 0.000 claims description 66
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 51
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 27
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
• 125000000335 thiazolyl group Chemical group 0.000 claims description 23
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 21
• 150000001721 carbon Chemical group 0.000 claims description 16
• 125000001544 thienyl group Chemical group 0.000 claims description 16
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
• 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 15
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 15
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
• 125000002971 oxazolyl group Chemical group 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 12
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 12
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 12
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 11
• 125000002883 imidazolyl group Chemical group 0.000 claims description 11
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
• 238000000034 method Methods 0.000 claims description 9
• 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 9
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
• 125000001425 triazolyl group Chemical group 0.000 claims description 8
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
• 125000006574 non-aromatic ring group Chemical group 0.000 claims description 7
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
• 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 6
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 6
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
• 206010005003 Bladder cancer Diseases 0.000 claims description 5
• 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
• JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 5
• 206010033128 Ovarian cancer Diseases 0.000 claims description 5
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
• 208000002193 Pain Diseases 0.000 claims description 5
• 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
• 125000001246 bromo group Chemical group Br* 0.000 claims description 5
• 201000010881 cervical cancer Diseases 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 206010035664 Pneumonia Diseases 0.000 claims description 4
• 230000001154 acute effect Effects 0.000 claims description 4
• 229910052740 iodine Inorganic materials 0.000 claims description 4
• 230000003143 atherosclerotic effect Effects 0.000 claims description 3
• ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 3
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
• 125000006413 ring segment Chemical group 0.000 claims description 3
• BORYWUCSBBFDPD-UHFFFAOYSA-N 3-chloro-5-[6-[2-(6-fluoro-4-methoxy-2-methylindol-1-yl)ethylamino]pyrimidin-4-yl]thiophene-2-carboxylic acid Chemical compound ClC1=C(SC(=C1)C1=NC=NC(=C1)NCCN1C(=CC2=C(C=C(C=C12)F)OC)C)C(=O)O BORYWUCSBBFDPD-UHFFFAOYSA-N 0.000 claims description 2
• ZVPVHJUGAJRSKA-UHFFFAOYSA-N 5-[6-[2-(2-cyanoindol-1-yl)ethylamino]pyrimidin-4-yl]-3-ethoxythiophene-2-carboxylic acid Chemical compound C(#N)C=1N(C2=CC=CC=C2C=1)CCNC1=CC(=NC=N1)C1=CC(=C(S1)C(=O)O)OCC ZVPVHJUGAJRSKA-UHFFFAOYSA-N 0.000 claims description 2
• QJAKVRUQSYMCTE-UHFFFAOYSA-N 6-(2,3-dihydro-1H-indol-5-yl)-N-[2-(6-fluoro-4-methoxy-2-methylindol-1-yl)ethyl]pyrimidin-4-amine Chemical compound N1CCC2=CC(=CC=C12)C1=CC(=NC=N1)NCCN1C(=CC2=C(C=C(C=C12)F)OC)C QJAKVRUQSYMCTE-UHFFFAOYSA-N 0.000 claims description 2
• 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
• 229910052796 boron Inorganic materials 0.000 claims description 2
• 230000028993 immune response Effects 0.000 claims description 2
• 210000000987 immune system Anatomy 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 239000000126 substance Substances 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 3
• OMRRUNXAWXNVFW-UHFFFAOYSA-N fluoridochlorine Chemical compound ClF OMRRUNXAWXNVFW-UHFFFAOYSA-N 0.000 claims 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 10
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract description 4
• FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 abstract description 4
• 125000005843 halogen group Chemical group 0.000 abstract 1
• 101001117519 Homo sapiens Prostaglandin E2 receptor EP2 subtype Proteins 0.000 description 62
• 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 61
• 101000836978 Homo sapiens Sperm-associated antigen 11B Proteins 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• 102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 description 40
• 101001117509 Homo sapiens Prostaglandin E2 receptor EP4 subtype Proteins 0.000 description 39
• 201000011510 cancer Diseases 0.000 description 39
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 38
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 33
• 239000005557 antagonist Substances 0.000 description 32
• 239000002253 acid Substances 0.000 description 30
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 30
• 238000011282 treatment Methods 0.000 description 28
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
• 239000002904 solvent Substances 0.000 description 25
• XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 24
• 229960002986 dinoprostone Drugs 0.000 description 23
• XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 23
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• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
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