NO332036B1 - Piperidinylforbindelser som selektivt binder integriner og sammensetninger derav - Google Patents

Info

Publication number

NO332036B1

NO332036B1 NO20051273A NO20051273A NO332036B1 NO 332036 B1 NO332036 B1 NO 332036B1 NO 20051273 A NO20051273 A NO 20051273A NO 20051273 A NO20051273 A NO 20051273A NO 332036 B1 NO332036 B1 NO 332036B1

Authority

NO

Norway

Prior art keywords

compound

tetrahydro

formula

naphthyridin

dihydro

Prior art date

2002-08-16

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• 108010044426 integrins Proteins 0.000 title claims abstract description 55
• 102000006495 integrins Human genes 0.000 title claims abstract description 55
• 239000000203 mixture Substances 0.000 title claims description 146
• 125000003386 piperidinyl group Chemical group 0.000 title abstract description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 577
• 230000001404 mediated effect Effects 0.000 claims abstract description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 109
• -1 tetrahydropyrimidinyl Chemical group 0.000 claims description 94
• 229910052739 hydrogen Inorganic materials 0.000 claims description 79
• 239000001257 hydrogen Substances 0.000 claims description 78
• 206010028980 Neoplasm Diseases 0.000 claims description 72
• 125000001424 substituent group Chemical group 0.000 claims description 56
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 54
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 45
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
• 125000003545 alkoxy group Chemical group 0.000 claims description 33
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
• 229910052799 carbon Inorganic materials 0.000 claims description 30
• 125000005843 halogen group Chemical group 0.000 claims description 30
• 239000003814 drug Substances 0.000 claims description 25
• 150000003839 salts Chemical class 0.000 claims description 25
• 201000010099 disease Diseases 0.000 claims description 24
• 125000004043 oxo group Chemical group O=* 0.000 claims description 23
• 125000004432 carbon atom Chemical group C* 0.000 claims description 21
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 20
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 201000011510 cancer Diseases 0.000 claims description 18
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 208000037803 restenosis Diseases 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 208000006386 Bone Resorption Diseases 0.000 claims description 12
• 230000024279 bone resorption Effects 0.000 claims description 12
• 208000001132 Osteoporosis Diseases 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 10
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 claims description 9
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 230000007170 pathology Effects 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
• 206010003246 arthritis Diseases 0.000 claims description 6
• 230000002757 inflammatory effect Effects 0.000 claims description 6
• 208000002780 macular degeneration Diseases 0.000 claims description 6
• 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 claims description 5
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 206010010356 Congenital anomaly Diseases 0.000 claims description 2
• 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
• 208000007696 Multicystic Dysplastic Kidney Diseases 0.000 claims description 2
• 208000034827 Neointima Diseases 0.000 claims description 2
• 201000004681 Psoriasis Diseases 0.000 claims description 2
• KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
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• 230000008692 neointimal formation Effects 0.000 claims description 2
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• 201000002793 renal fibrosis Diseases 0.000 claims description 2
• 238000011282 treatment Methods 0.000 abstract description 28
• 238000000034 method Methods 0.000 description 145
• 239000000243 solution Substances 0.000 description 98
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 96
• 238000006243 chemical reaction Methods 0.000 description 90
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
• 238000002360 preparation method Methods 0.000 description 69
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
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• 229920006395 saturated elastomer Polymers 0.000 description 36
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• 235000019439 ethyl acetate Nutrition 0.000 description 29
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• 239000012044 organic layer Substances 0.000 description 27
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 26
• 238000003818 flash chromatography Methods 0.000 description 25
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
• 238000004007 reversed phase HPLC Methods 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
• 239000011541 reaction mixture Substances 0.000 description 23
• 230000002829 reductive effect Effects 0.000 description 22
• 235000002639 sodium chloride Nutrition 0.000 description 22
• 208000035269 cancer or benign tumor Diseases 0.000 description 21
• 150000001721 carbon Chemical group 0.000 description 21
• 239000003153 chemical reaction reagent Substances 0.000 description 21
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• 239000002246 antineoplastic agent Substances 0.000 description 19
• 239000002904 solvent Substances 0.000 description 19
• 210000004027 cell Anatomy 0.000 description 18
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• 239000003054 catalyst Substances 0.000 description 16
• 229940127089 cytotoxic agent Drugs 0.000 description 16
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 16
• 239000003921 oil Substances 0.000 description 16
• 235000019198 oils Nutrition 0.000 description 16
• 239000007858 starting material Substances 0.000 description 15
• 125000003118 aryl group Chemical group 0.000 description 14
• 239000000741 silica gel Substances 0.000 description 14
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• 230000033115 angiogenesis Effects 0.000 description 13
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• KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 12
• SRSGVKWWVXWSJT-ATVHPVEESA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-n-(2-pyrrolidin-1-ylethyl)-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C(C)C=1C(=O)NCCN1CCCC1 SRSGVKWWVXWSJT-ATVHPVEESA-N 0.000 description 12
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 239000005557 antagonist Substances 0.000 description 12
• 235000019441 ethanol Nutrition 0.000 description 12
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• 229910052760 oxygen Inorganic materials 0.000 description 12
• 229920000642 polymer Polymers 0.000 description 12
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
• 238000002560 therapeutic procedure Methods 0.000 description 12
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
• 230000002378 acidificating effect Effects 0.000 description 11
• 239000004480 active ingredient Substances 0.000 description 11
• 239000012267 brine Substances 0.000 description 11
• 238000001816 cooling Methods 0.000 description 11
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• 108090000623 proteins and genes Proteins 0.000 description 11
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• LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
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• KSQVGVMZECCPAT-AEFFLSMTSA-N [(1R)-4-phenyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]butyl]boronic acid Chemical compound B([C@H](CCCC1=CC=CC=C1)NC(=O)[C@@H](CCC)NC(=O)C2=NC=CN=C2)(O)O KSQVGVMZECCPAT-AEFFLSMTSA-N 0.000 description 10
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• QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 9
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• QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 8
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• OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 7
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