DE60224664T2 - Substituierte tetrhydroisochinolin-derivate zur behandlung von entzündlichen erkrankungen - Google Patents

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Publication number

DE60224664T2

DE60224664T2 DE60224664T DE60224664T DE60224664T2 DE 60224664 T2 DE60224664 T2 DE 60224664T2 DE 60224664 T DE60224664 T DE 60224664T DE 60224664 T DE60224664 T DE 60224664T DE 60224664 T2 DE60224664 T2 DE 60224664T2

Authority

DE

Germany

Prior art keywords

group

alkyl

optionally substituted

aryl

compound according

Prior art date

2001-06-06

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 - Lifetime

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• 238000011282 treatment Methods 0.000 title claims description 28
• 208000027866 inflammatory disease Diseases 0.000 title claims description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 228
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 131
• 125000003118 aryl group Chemical group 0.000 claims abstract description 81
• 239000001257 hydrogen Substances 0.000 claims abstract description 74
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 74
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 70
• 150000003839 salts Chemical class 0.000 claims abstract description 62
• 150000002148 esters Chemical class 0.000 claims abstract description 51
• 150000001204 N-oxides Chemical class 0.000 claims abstract description 48
• 229940002612 prodrug Drugs 0.000 claims abstract description 48
• 239000000651 prodrug Substances 0.000 claims abstract description 48
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 39
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 32
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 27
• 239000012453 solvate Substances 0.000 claims abstract description 26
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 22
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 17
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 15
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 14
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 13
• 150000002367 halogens Chemical class 0.000 claims abstract description 13
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 12
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
• 125000004450 alkenylene group Chemical group 0.000 claims abstract description 7
• 125000004419 alkynylene group Chemical group 0.000 claims abstract description 6
• CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims abstract description 6
• 239000001301 oxygen Substances 0.000 claims abstract description 6
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 3
• 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
• -1 cycloalkenylalkyl Chemical group 0.000 claims description 172
• 239000000203 mixture Substances 0.000 claims description 60
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 46
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
• 150000002431 hydrogen Chemical class 0.000 claims description 29
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 230000002378 acidificating effect Effects 0.000 claims description 24
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 21
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
• 125000004432 carbon atom Chemical group C* 0.000 claims description 20
• 125000003342 alkenyl group Chemical group 0.000 claims description 19
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
• 229910052799 carbon Inorganic materials 0.000 claims description 18
• 125000000524 functional group Chemical group 0.000 claims description 17
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 16
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
• 125000004414 alkyl thio group Chemical group 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• YRBBCSUBLBNNKJ-UHFFFAOYSA-N 3-[1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-pyridin-4-ylpropanoic acid Chemical compound CC1=CC=CC=C1NC(OC1=C2)=NC1=CC=C2CC(=O)C1C2=CC(C(CC(O)=O)C=3C=CN=CC=3)=CC=C2CCN1 YRBBCSUBLBNNKJ-UHFFFAOYSA-N 0.000 claims description 13
• 239000005977 Ethylene Substances 0.000 claims description 13
• 230000021164 cell adhesion Effects 0.000 claims description 13
• 125000001424 substituent group Chemical group 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 12
• 238000002360 preparation method Methods 0.000 claims description 12
• 125000000304 alkynyl group Chemical group 0.000 claims description 11
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 10
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 10
• 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 9
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
• 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 9
• 239000003112 inhibitor Substances 0.000 claims description 9
• VYKZWLFZJMDXPY-UHFFFAOYSA-N 3-[2-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-3,4-dihydro-1h-isoquinolin-8-yl]butanoic acid Chemical compound COC1=CC(CC(=O)N2CC3=C(C(C)CC(O)=O)C=CC=C3CC2)=CC=C1NC(=O)NC1=CC=CC=C1C VYKZWLFZJMDXPY-UHFFFAOYSA-N 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 8
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
• 125000003435 aroyl group Chemical group 0.000 claims description 7
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 7
• 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 7
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 7
• 125000002252 acyl group Chemical group 0.000 claims description 6
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 6
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 6
• 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 6
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 6
• 125000004104 aryloxy group Chemical group 0.000 claims description 6
• 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 230000001404 mediated effect Effects 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• 125000004043 oxo group Chemical group O=* 0.000 claims description 6
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 6
• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 5
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
• 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 claims description 5
• BRFHNNYFEPESTQ-UHFFFAOYSA-N 3-[1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-phenylpropanoic acid Chemical compound CC1=CC=CC=C1NC(OC1=C2)=NC1=CC=C2CC(=O)C1C2=CC(C(CC(O)=O)C=3C=CC=CC=3)=CC=C2CCN1 BRFHNNYFEPESTQ-UHFFFAOYSA-N 0.000 claims description 5
• YQMAMHSQQSBGDZ-UHFFFAOYSA-N 3-[1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]butanoic acid Chemical compound C12=CC(C(CC(O)=O)C)=CC=C2CCNC1C(=O)CC(C=C1O2)=CC=C1N=C2NC1=CC=CC=C1C YQMAMHSQQSBGDZ-UHFFFAOYSA-N 0.000 claims description 5
• 125000004442 acylamino group Chemical group 0.000 claims description 5
• 125000005015 aryl alkynyl group Chemical group 0.000 claims description 5
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 5
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
• 125000005110 aryl thio group Chemical group 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 5
• 125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical group NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 4
• OVBZKBCLTOLCGV-UHFFFAOYSA-N 3-[1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]-3-phenylpropanoic acid Chemical compound CC1=CC=CC=C1NC(OC1=C2)=NC1=CC=C2CC(=O)C1C2=CC=C(C(CC(O)=O)C=3C=CC=CC=3)C=C2CCN1 OVBZKBCLTOLCGV-UHFFFAOYSA-N 0.000 claims description 4
• TVZXLIZVCREAPF-UHFFFAOYSA-N 3-[1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]but-2-enoic acid Chemical compound C1=2C(C(=CC(O)=O)C)=CC=CC=2CCNC1C(=O)CC(C=C1O2)=CC=C1N=C2NC1=CC=CC=C1C TVZXLIZVCREAPF-UHFFFAOYSA-N 0.000 claims description 4
• 125000005239 aroylamino group Chemical group 0.000 claims description 4
• 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 4
• 125000005312 heteroarylalkynyl group Chemical group 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000004098 2,6-dichlorobenzoyl group Chemical group O=C([*])C1=C(Cl)C([H])=C([H])C([H])=C1Cl 0.000 claims description 3
• RIDVBCDNWSGWQZ-UHFFFAOYSA-N 3-[1-[2-[4-methyl-2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]butanoic acid Chemical compound N1CCC2=CC(C(CC(O)=O)C)=CC=C2C1C(=O)CC(C=C1O2)=CC(C)=C1N=C2NC1=CC=CC=C1C RIDVBCDNWSGWQZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
• 235000019260 propionic acid Nutrition 0.000 claims description 3
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
• IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
• 150000001555 benzenes Chemical group 0.000 claims 2
• GRYXVSHAAMIBGD-UHFFFAOYSA-N 3-cyclohexyl-3-[1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl]propanoic acid Chemical compound CC1=CC=CC=C1NC(OC1=C2)=NC1=CC=C2CC(=O)C1C2=CC=C(C(CC(O)=O)C3CCCCC3)C=C2CCN1 GRYXVSHAAMIBGD-UHFFFAOYSA-N 0.000 claims 1
• PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims 1
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
• 125000003275 alpha amino acid group Chemical group 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 claims 1
• 235000021286 stilbenes Nutrition 0.000 claims 1
• 239000002253 acid Chemical group 0.000 abstract description 35
• 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 abstract description 19
• 108010067306 Fibronectins Proteins 0.000 abstract description 13
• 102000016359 Fibronectins Human genes 0.000 abstract description 13
• 108010008212 Integrin alpha4beta1 Proteins 0.000 abstract description 11
• 230000003993 interaction Effects 0.000 abstract description 10
• 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 8
• 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 abstract 1
• 238000000034 method Methods 0.000 description 69
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 64
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• 239000000243 solution Substances 0.000 description 53
• 238000006243 chemical reaction Methods 0.000 description 50
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 43
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
• 239000002585 base Substances 0.000 description 20
• 239000007787 solid Substances 0.000 description 20
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 18
• 150000003254 radicals Chemical class 0.000 description 17
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
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• 102000006495 integrins Human genes 0.000 description 16
• 239000003921 oil Substances 0.000 description 15
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• QLHBVRZVXNLWKP-UHFFFAOYSA-N 2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetic acid Chemical compound CC1=CC=CC=C1NC1=NC2=CC=C(CC(O)=O)C=C2O1 QLHBVRZVXNLWKP-UHFFFAOYSA-N 0.000 description 14
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• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 13
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• 238000010992 reflux Methods 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
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• 238000010828 elution Methods 0.000 description 11
• QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 11
• 239000000377 silicon dioxide Substances 0.000 description 11
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• 241000699670 Mus sp. Species 0.000 description 8
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• 239000000725 suspension Substances 0.000 description 6
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 5
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• 229910052786 argon Inorganic materials 0.000 description 5
• 125000001309 chloro group Chemical group Cl* 0.000 description 5
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