ZA200305413B - Acylated indanyl amines and their use as pharmaceuticals. - Google Patents
Acylated indanyl amines and their use as pharmaceuticals. Download PDFInfo
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- ZA200305413B ZA200305413B ZA200305413A ZA200305413A ZA200305413B ZA 200305413 B ZA200305413 B ZA 200305413B ZA 200305413 A ZA200305413 A ZA 200305413A ZA 200305413 A ZA200305413 A ZA 200305413A ZA 200305413 B ZA200305413 B ZA 200305413B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- phenyl
- group
- methyl
- heteroaryl
- Prior art date
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- -1 Acylated indanyl amines Chemical class 0.000 title claims description 459
- 239000003814 drug Substances 0.000 title claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 174
- 229910052736 halogen Inorganic materials 0.000 claims description 118
- 150000002367 halogens Chemical class 0.000 claims description 116
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 113
- 125000001072 heteroaryl group Chemical group 0.000 claims description 103
- 229910052799 carbon Inorganic materials 0.000 claims description 81
- 125000002577 pseudohalo group Chemical group 0.000 claims description 80
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 78
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 35
- 229910052731 fluorine Inorganic materials 0.000 claims description 33
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 21
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 20
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 19
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical class C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 claims description 11
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 8
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 230000003511 endothelial effect Effects 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 4
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 4
- 230000014509 gene expression Effects 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 3
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 3
- XXOKIKKIMRAIDZ-UHFFFAOYSA-N 2-amino-n-(2,3-dihydro-1h-inden-2-yl)benzamide Chemical compound NC1=CC=CC=C1C(=O)NC1CC2=CC=CC=C2C1 XXOKIKKIMRAIDZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
- IGQDZYVWSOKCCO-UHFFFAOYSA-N 2-chloro-n-(2,3-dihydro-1h-inden-2-yl)-6-methylpyridine-3-carboxamide Chemical compound ClC1=NC(C)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 IGQDZYVWSOKCCO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- KLMRGIURJNYXHB-UHFFFAOYSA-N 3-chloro-n-(2,3-dihydro-1h-inden-2-yl)-4-methylthiophene-2-carboxamide Chemical compound CC1=CSC(C(=O)NC2CC3=CC=CC=C3C2)=C1Cl KLMRGIURJNYXHB-UHFFFAOYSA-N 0.000 claims description 3
- WYRYWQXPSLVYJO-UHFFFAOYSA-N 3-chloro-n-(2,3-dihydro-1h-inden-2-yl)-4-propan-2-ylsulfonylthiophene-2-carboxamide Chemical compound CC(C)S(=O)(=O)C1=CSC(C(=O)NC2CC3=CC=CC=C3C2)=C1Cl WYRYWQXPSLVYJO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- QRENWBKXNZJPCB-UHFFFAOYSA-N 5-bromo-n-(2,3-dihydro-1h-inden-2-yl)thiophene-2-carboxamide Chemical compound S1C(Br)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 QRENWBKXNZJPCB-UHFFFAOYSA-N 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- PYXHGQFGOJILPG-UHFFFAOYSA-N [2-(2,3-dihydro-1h-inden-2-ylcarbamoyl)-5-methylphenyl] acetate Chemical compound CC(=O)OC1=CC(C)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 PYXHGQFGOJILPG-UHFFFAOYSA-N 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- QNKGSVMHFYKXMY-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-1h-indole-6-carboxamide Chemical compound C1=C2C=CNC2=CC(C(NC2CC3=CC=CC=C3C2)=O)=C1 QNKGSVMHFYKXMY-UHFFFAOYSA-N 0.000 claims description 3
- OKCJNSDIVCXYAL-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-2,2-difluoro-1,3-benzodioxole-5-carboxamide Chemical compound C1C2=CC=CC=C2CC1NC(=O)C1=CC=C2OC(F)(F)OC2=C1 OKCJNSDIVCXYAL-UHFFFAOYSA-N 0.000 claims description 3
- ILSKEICCKVCVHE-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound C1=C2OCCC2=CC(C(NC2CC3=CC=CC=C3C2)=O)=C1 ILSKEICCKVCVHE-UHFFFAOYSA-N 0.000 claims description 3
- WIMOSWXWAKVJHY-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-2,5-dimethyl-1-(pyridin-4-ylmethyl)pyrrole-3-carboxamide Chemical compound CC1=CC(C(=O)NC2CC3=CC=CC=C3C2)=C(C)N1CC1=CC=NC=C1 WIMOSWXWAKVJHY-UHFFFAOYSA-N 0.000 claims description 3
- KPVOHHOWYRESDB-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-2,5-dimethyl-1h-pyrrole-3-carboxamide Chemical compound N1C(C)=CC(C(=O)NC2CC3=CC=CC=C3C2)=C1C KPVOHHOWYRESDB-UHFFFAOYSA-N 0.000 claims description 3
- YSRBFWINKVMWLT-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-2-hydroxy-4-methylbenzamide Chemical compound OC1=CC(C)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 YSRBFWINKVMWLT-UHFFFAOYSA-N 0.000 claims description 3
- NIHUGSQILVAFLW-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-3-methylthiophene-2-carboxamide Chemical compound C1=CSC(C(=O)NC2CC3=CC=CC=C3C2)=C1C NIHUGSQILVAFLW-UHFFFAOYSA-N 0.000 claims description 3
- LDRDLYITKGCQQZ-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-4-(methylamino)benzamide Chemical compound C1=CC(NC)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 LDRDLYITKGCQQZ-UHFFFAOYSA-N 0.000 claims description 3
- NIXQKUWFMQZTOS-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-4-(trifluoromethyl)benzamide Chemical compound C1=CC(C(F)(F)F)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 NIXQKUWFMQZTOS-UHFFFAOYSA-N 0.000 claims description 3
- MPXUHFXUIZRORK-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-4-ethylsulfanylbenzamide Chemical compound C1=CC(SCC)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 MPXUHFXUIZRORK-UHFFFAOYSA-N 0.000 claims description 3
- KJRZWIKUHMWWFM-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-4-methylsulfanylbenzamide Chemical compound C1=CC(SC)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 KJRZWIKUHMWWFM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical compound C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 238000007306 functionalization reaction Methods 0.000 claims description 2
- SWCDJGBAGZQBMO-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-5-methylthiophene-2-carboxamide Chemical compound S1C(C)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 SWCDJGBAGZQBMO-UHFFFAOYSA-N 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 229920000728 polyester Polymers 0.000 claims 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 2
- NQSTXRNSHFJLMH-UHFFFAOYSA-N 5-acetyl-n-(2,3-dihydro-1h-inden-2-yl)thiophene-2-carboxamide Chemical compound S1C(C(=O)C)=CC=C1C(=O)NC1CC2=CC=CC=C2C1 NQSTXRNSHFJLMH-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
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- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 claims 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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