AU2003259891A1 - Piperidinyl compounds that selectively bind integrins - Google Patents

Info

Publication number

AU2003259891A1

AU2003259891A1 AU2003259891A AU2003259891A AU2003259891A1 AU 2003259891 A1 AU2003259891 A1 AU 2003259891A1 AU 2003259891 A AU2003259891 A AU 2003259891A AU 2003259891 A AU2003259891 A AU 2003259891A AU 2003259891 A1 AU2003259891 A1 AU 2003259891A1

Authority

AU

Australia

Prior art keywords

tetrahydro

compound

alkyl

salkyl

naphthyridin

Prior art date

2002-08-16

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.)

Abandoned

Links

• Espacenet
• Global Dossier
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• 108010044426 integrins Proteins 0.000 title claims description 101
• 102000006495 integrins Human genes 0.000 title claims description 101
• 125000003386 piperidinyl group Chemical group 0.000 title description 9
• 150000001875 compounds Chemical class 0.000 claims description 613
• 125000000217 alkyl group Chemical group 0.000 claims description 249
• 239000000203 mixture Substances 0.000 claims description 207
• 238000000034 method Methods 0.000 claims description 180
• -1 -N(C 1 4alkyl) 2 Chemical group 0.000 claims description 134
• 229910052739 hydrogen Inorganic materials 0.000 claims description 108
• 239000001257 hydrogen Substances 0.000 claims description 106
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 79
• 206010028980 Neoplasm Diseases 0.000 claims description 77
• 125000001424 substituent group Chemical group 0.000 claims description 63
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 60
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
• 125000003545 alkoxy group Chemical group 0.000 claims description 51
• 208000035475 disorder Diseases 0.000 claims description 38
• 125000005843 halogen group Chemical group 0.000 claims description 37
• 230000001404 mediated effect Effects 0.000 claims description 36
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 35
• 229910052799 carbon Inorganic materials 0.000 claims description 34
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
• 125000004043 oxo group Chemical group O=* 0.000 claims description 29
• 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 29
• 125000004432 carbon atom Chemical group C* 0.000 claims description 26
• 229910052757 nitrogen Inorganic materials 0.000 claims description 26
• 150000003839 salts Chemical class 0.000 claims description 26
• 208000035269 cancer or benign tumor Diseases 0.000 claims description 24
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
• 201000010099 disease Diseases 0.000 claims description 22
• 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 21
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 16
• 208000037803 restenosis Diseases 0.000 claims description 16
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 13
• 208000006386 Bone Resorption Diseases 0.000 claims description 11
• 230000024279 bone resorption Effects 0.000 claims description 11
• 208000001132 Osteoporosis Diseases 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 10
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 10
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 9
• 238000001415 gene therapy Methods 0.000 claims description 9
• 239000012216 imaging agent Substances 0.000 claims description 9
• 238000002560 therapeutic procedure Methods 0.000 claims description 9
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
• 108010011222 cyclo(Arg-Pro) Proteins 0.000 claims description 8
• 230000001225 therapeutic effect Effects 0.000 claims description 8
• OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
• 238000001356 surgical procedure Methods 0.000 claims description 7
• 125000003342 alkenyl group Chemical group 0.000 claims description 6
• 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
• 238000001959 radiotherapy Methods 0.000 claims description 6
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 230000007170 pathology Effects 0.000 claims description 5
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
• HBEDSQVIWPRPAY-UHFFFAOYSA-N dihydro-benzofuran Natural products C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 4
• 238000009169 immunotherapy Methods 0.000 claims description 4
• 230000005764 inhibitory process Effects 0.000 claims description 4
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
• 206010010356 Congenital anomaly Diseases 0.000 claims description 2
• 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
• 206010023421 Kidney fibrosis 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
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
• 230000001028 anti-proliverative effect Effects 0.000 claims description 2
• 238000002512 chemotherapy Methods 0.000 claims description 2
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 206010061989 glomerulosclerosis Diseases 0.000 claims description 2
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
• 230000008692 neointimal formation Effects 0.000 claims description 2
• 208000003154 papilloma Diseases 0.000 claims description 2
• 230000000069 prophylactic effect Effects 0.000 claims description 2
• 238000002054 transplantation Methods 0.000 claims description 2
• 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 4
• 108010059278 Pyrin Proteins 0.000 claims 1
• 102000005583 Pyrin Human genes 0.000 claims 1
• 230000003187 abdominal effect Effects 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
• 239000000243 solution Substances 0.000 description 100
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 99
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 47
• 229910001868 water Inorganic materials 0.000 description 46
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 44
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 43
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
• 229920006395 saturated elastomer Polymers 0.000 description 34
• 239000011734 sodium Substances 0.000 description 34
• 239000007787 solid Substances 0.000 description 34
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
• 239000003795 chemical substances by application Substances 0.000 description 33
• 235000019439 ethyl acetate Nutrition 0.000 description 32
• 230000015572 biosynthetic process Effects 0.000 description 31
• 238000005481 NMR spectroscopy Methods 0.000 description 30
• 238000004007 reversed phase HPLC Methods 0.000 description 29
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 27
• 238000006243 chemical reaction Methods 0.000 description 25
• 239000003814 drug Substances 0.000 description 25
• 238000003818 flash chromatography Methods 0.000 description 24
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 239000011541 reaction mixture Substances 0.000 description 23
• 235000002639 sodium chloride Nutrition 0.000 description 23
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 22
• 239000003153 chemical reaction reagent Substances 0.000 description 21
• 238000001819 mass spectrum Methods 0.000 description 21
• 230000002829 reductive effect Effects 0.000 description 21
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• 239000002253 acid Substances 0.000 description 19
• 150000001721 carbon Chemical group 0.000 description 19
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 19
• 239000002904 solvent Substances 0.000 description 19
• 230000008685 targeting Effects 0.000 description 19
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
• 238000011282 treatment Methods 0.000 description 18
• 239000003054 catalyst Substances 0.000 description 17
• 239000003480 eluent Substances 0.000 description 17
• 239000007788 liquid Substances 0.000 description 17
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 17
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
• 239000002246 antineoplastic agent Substances 0.000 description 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 239000003921 oil Substances 0.000 description 15
• 235000019198 oils Nutrition 0.000 description 15
• 239000007858 starting material Substances 0.000 description 15
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
• 239000000741 silica gel Substances 0.000 description 14
• 229910002027 silica gel Inorganic materials 0.000 description 14
• 229960001866 silicon dioxide Drugs 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• 238000003786 synthesis reaction Methods 0.000 description 14
• 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 13
• 230000002378 acidificating effect Effects 0.000 description 13
• 125000003118 aryl group Chemical group 0.000 description 13
• 239000012267 brine Substances 0.000 description 13
• 229940127089 cytotoxic agent Drugs 0.000 description 13
• 235000019441 ethanol Nutrition 0.000 description 13
• 238000002360 preparation method Methods 0.000 description 13
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
• 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
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• 230000033115 angiogenesis Effects 0.000 description 12
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• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
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• 125000001072 heteroaryl group Chemical group 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
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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
• 229910052786 argon Inorganic materials 0.000 description 10
• 125000004434 sulfur atom Chemical group 0.000 description 10
• YLSSVFGTKZXLPA-UHFFFAOYSA-N 2-(1-benzyl-2-ethyl-3-oxamoylbenzo[g]indol-4-yl)oxyacetic acid Chemical compound CCC1=C(C(=O)C(N)=O)C2=C(OCC(O)=O)C=C3C=CC=CC3=C2N1CC1=CC=CC=C1 YLSSVFGTKZXLPA-UHFFFAOYSA-N 0.000 description 9
• CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 9
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• 210000001519 tissue Anatomy 0.000 description 9
• 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
• AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
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• 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 6
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