ES2355139T3 - Compuestos de piperidinilo que unen selectivamente a receptores de integrinas. - Google Patents
Compuestos de piperidinilo que unen selectivamente a receptores de integrinas. Download PDFInfo
- Publication number
- ES2355139T3 ES2355139T3 ES03791686T ES03791686T ES2355139T3 ES 2355139 T3 ES2355139 T3 ES 2355139T3 ES 03791686 T ES03791686 T ES 03791686T ES 03791686 T ES03791686 T ES 03791686T ES 2355139 T3 ES2355139 T3 ES 2355139T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- compound
- tetrahydro
- formula
- naphthyridin
- Prior art date
- 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
Links
- -1 PIPERIDINYL COMPOUNDS Chemical class 0.000 title claims description 118
- 150000001875 compounds Chemical class 0.000 claims abstract description 616
- 239000000203 mixture Substances 0.000 claims abstract description 212
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 132
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 90
- 239000001257 hydrogen Substances 0.000 claims abstract description 88
- 125000001424 substituent group Chemical group 0.000 claims abstract description 57
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 51
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 36
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 23
- 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 abstract description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 17
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 75
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 71
- 102000006495 integrins Human genes 0.000 claims description 67
- 108010044426 integrins Proteins 0.000 claims description 67
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 54
- 238000011282 treatment Methods 0.000 claims description 35
- 230000015572 biosynthetic process Effects 0.000 claims description 34
- 208000035475 disorder Diseases 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 31
- 125000004429 atom Chemical group 0.000 claims description 30
- 230000001404 mediated effect Effects 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 208000037803 restenosis Diseases 0.000 claims description 17
- 150000001721 carbon Chemical group 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 12
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 12
- 208000006386 Bone Resorption Diseases 0.000 claims description 11
- 210000000988 bone and bone Anatomy 0.000 claims description 11
- 230000024279 bone resorption Effects 0.000 claims description 11
- 230000006872 improvement Effects 0.000 claims description 11
- 208000001132 Osteoporosis Diseases 0.000 claims description 10
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 10
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 206010003246 arthritis Diseases 0.000 claims description 6
- 208000002780 macular degeneration Diseases 0.000 claims description 6
- 230000007170 pathology Effects 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 206010010356 Congenital anomaly Diseases 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 2
- 208000003154 papilloma Diseases 0.000 claims description 2
- 206010038433 renal dysplasia Diseases 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 208000034827 Neointima Diseases 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 9
- 125000001475 halogen functional group Chemical group 0.000 abstract 4
- 238000000034 method Methods 0.000 description 167
- 238000001819 mass spectrum Methods 0.000 description 101
- 239000000243 solution Substances 0.000 description 97
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- 229910001868 water Inorganic materials 0.000 description 57
- 238000005481 NMR spectroscopy Methods 0.000 description 49
- 239000003795 chemical substances by application Substances 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 239000002253 acid Substances 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 238000004007 reversed phase HPLC Methods 0.000 description 23
- 235000002639 sodium chloride Nutrition 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 22
- 208000035269 cancer or benign tumor Diseases 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000003153 chemical reaction reagent Substances 0.000 description 21
- 239000000126 substance Substances 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 239000007832 Na2SO4 Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 239000002246 antineoplastic agent Substances 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 17
- 239000003480 eluent Substances 0.000 description 17
- 239000007788 liquid Substances 0.000 description 17
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 15
- 229940127089 cytotoxic agent Drugs 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000005557 antagonist Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 238000002360 preparation method Methods 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
- 230000033115 angiogenesis Effects 0.000 description 13
- 125000003118 aryl group Chemical group 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- 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
- 229940079593 drug Drugs 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 210000002997 osteoclast Anatomy 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 238000000576 coating method Methods 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- CTCHDPAJHVDPRN-UHFFFAOYSA-N integrin Chemical compound C=1C(OC)=CC(O)=C(C(C=2CC=C(C)C)=O)C=1OC=2C1=CC=C(O)C=C1O CTCHDPAJHVDPRN-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 150000003254 radicals Chemical class 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 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
- 239000004480 active ingredient Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 239000011248 coating agent Substances 0.000 description 10
- 230000002074 deregulated effect Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 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 9
- 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
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-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
- 241000282414 Homo sapiens Species 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000002378 acidificating effect Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 230000002792 vascular Effects 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
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 229940125796 compound 3d Drugs 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 238000001415 gene therapy Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
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- 102100025306 Integrin alpha-IIb Human genes 0.000 description 7
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 108010031318 Vitronectin Proteins 0.000 description 7
- 102100035140 Vitronectin Human genes 0.000 description 7
- 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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- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
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- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 6
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 125000003386 piperidinyl group Chemical group 0.000 description 6
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 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 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
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Classifications
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
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- Medicinal Chemistry (AREA)
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- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Immunology (AREA)
- Surgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20040224986A1 (en) | 2002-08-16 | 2004-11-11 | Bart De Corte | Piperidinyl targeting compounds that selectively bind integrins |
| US7351711B2 (en) * | 2003-07-31 | 2008-04-01 | Janssen Pharmaceutical, N.V. | Tricyclic indanyls as integrin inhibitors |
| EP2394662B1 (en) * | 2004-04-02 | 2018-03-21 | The Regents of The University of California | Methods and compositions for treating and preventing disease associated with alpha v beta 5 integrin |
| AU2005321543A1 (en) * | 2004-12-30 | 2006-07-06 | Cinvention Ag | Combination comprising an agent providing a signal, an implant material and a drug |
| CN101272808B (zh) * | 2005-01-06 | 2012-03-21 | 通用电气医疗集团股份有限公司 | 光学成像 |
| US8636995B2 (en) * | 2006-08-31 | 2014-01-28 | Cardiac Pacemakers, Inc. | Methods and devices to regulate stem cell homing |
| US20080058922A1 (en) * | 2006-08-31 | 2008-03-06 | Cardiac Pacemakers, Inc. | Methods and devices employing vap-1 inhibitors |
| US8372399B2 (en) * | 2006-08-31 | 2013-02-12 | Cardiac Pacemakers, Inc. | Bispecific antibodies and agents to enhance stem cell homing |
| ATE539075T1 (de) * | 2007-08-02 | 2012-01-15 | Recordati Ireland Ltd | Neue heterocyclische verbindungen als mglu5- antagonisten |
| JP2011519340A (ja) * | 2007-10-30 | 2011-07-07 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 置換アルカン酸調製のためのエナンチオ選択的プロセスこの米国特許正規出願は、２００７年１０月３０日に提出された米国特許仮出願第６１／００１，００４号、及び２００８年２月２９日に提出された米国特許仮出願第６１／０６７，８４２号の権利を主張する。 |
| WO2009061448A2 (en) * | 2007-11-08 | 2009-05-14 | The General Hospital Corporation | Methods and compositions for the treatment of proteinuric diseases |
| US10087252B2 (en) | 2009-07-24 | 2018-10-02 | The Regents Of The University Of California | Methods and compositions for treating and preventing disease associated with αvβ5 integrin |
| HUE063437T2 (hu) | 2013-09-24 | 2024-01-28 | Fujifilm Corp | Nitrogént tartalmazó vegyületet vagy sóját vagy fémkomplexét tartalmazó gyógyászati készítmény |
| US10906874B2 (en) | 2016-09-18 | 2021-02-02 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | YAP1 inhibitors that target the interaction of YAP1 with OCT4 |
| EP3538527B1 (en) * | 2016-11-08 | 2021-10-13 | Bristol-Myers Squibb Company | Azole amides and amines as alpha v integrin inhibitors |
| WO2018089360A1 (en) * | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Pyrrole amides as alpha v integrin inhibitors |
| MA52117A (fr) | 2017-02-28 | 2022-04-06 | Morphic Therapeutic Inc | Inhibiteurs de l'intégrine (alpha-v) (bêta-6) |
| TW201835078A (zh) | 2017-02-28 | 2018-10-01 | 美商萊築理公司 | αvβ6整合蛋白之抑制劑 |
| MX2020009519A (es) | 2018-03-14 | 2020-10-22 | H Lee Moffitt Cancer Ct & Res | Inhibidores de yap1 que dirigen la interaccion de yap1 con oct4. |
| MX2021002181A (es) | 2018-08-29 | 2021-07-15 | Morphic Therapeutic Inc | Inhibicion de la integrina alfa v beta 6. |
| WO2025067433A1 (zh) * | 2023-09-28 | 2025-04-03 | 云合智药（苏州）生物科技有限公司 | 靶向整合素的化合物及其在RNAi剂中的应用 |
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| IN148482B (enExample) * | 1977-06-03 | 1981-03-07 | Pfizer | |
| AU3737893A (en) * | 1992-03-05 | 1993-10-05 | Board Of Regents, The University Of Texas System | Diagnostic and/or therapeutic agents, targeted to neovascular endothelial cells |
| US5474765A (en) * | 1992-03-23 | 1995-12-12 | Ut Sw Medical Ctr At Dallas | Preparation and use of steroid-polyanionic polymer-based conjugates targeted to vascular endothelial cells |
| US5902795A (en) * | 1992-06-16 | 1999-05-11 | Trustees Of Tufts College | Oligosaccharides reactive with hyaluronan-binding protein and their methods of use |
| US5340798A (en) * | 1992-10-14 | 1994-08-23 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| US5753659A (en) * | 1993-03-29 | 1998-05-19 | Zeneca Limited | Heterocyclic compouds |
| US5700801A (en) * | 1994-12-23 | 1997-12-23 | Karl Thomae, Gmbh | Piperazine derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
| DE19516483A1 (de) * | 1995-05-05 | 1996-11-07 | Merck Patent Gmbh | Adhäsionsrezeptor-Antagonisten |
| DE19613933A1 (de) * | 1996-04-06 | 1997-10-09 | Merck Patent Gmbh | Cyclische Adhäsionsinhibitoren |
| US5919792A (en) * | 1996-10-30 | 1999-07-06 | Merck & Co., Inc. | Integrin antagonists |
| AU738452B2 (en) * | 1997-12-17 | 2001-09-20 | Merck & Co., Inc. | Integrin receptor antagonists |
| US6211191B1 (en) * | 1997-12-17 | 2001-04-03 | Merck & Co., Inc. | Integrin receptor antagonists |
| EP1091945A1 (en) * | 1998-06-29 | 2001-04-18 | Du Pont Pharmaceuticals Company | Cyclic carbamates and isoxazolidines as iib/iiia antagonists |
| MXPA01010891A (es) * | 1999-04-28 | 2002-11-07 | Univ Texas | Composiciones y metodos para el tratamiento contra el cancer mediante la inhibicion selectiva del factor de crecimiento endotelial vascular (vegf). |
| US6776796B2 (en) * | 2000-05-12 | 2004-08-17 | Cordis Corportation | Antiinflammatory drug and delivery device |
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- 2003-08-15 ES ES03791686T patent/ES2355139T3/es not_active Expired - Lifetime
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- 2003-08-15 AT AT03791686T patent/ATE489378T1/de active
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- 2003-08-15 BR BR0313534-9A patent/BR0313534A/pt not_active IP Right Cessation
- 2003-08-15 AU AU2003259891A patent/AU2003259891A1/en not_active Abandoned
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2010
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Also Published As
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| EP1539739B1 (en) | 2010-11-24 |
| KR20050031464A (ko) | 2005-04-06 |
| CR7692A (es) | 2009-01-14 |
| RU2333210C2 (ru) | 2008-09-10 |
| CY1111194T1 (el) | 2015-06-11 |
| UA83467C2 (uk) | 2008-07-25 |
| NO20051273L (no) | 2005-05-10 |
| CA2496127A1 (en) | 2005-02-16 |
| DK1539739T3 (da) | 2011-03-07 |
| CA2496127C (en) | 2012-05-29 |
| EP1539739A1 (en) | 2005-06-15 |
| JP4554364B2 (ja) | 2010-09-29 |
| CN100506815C (zh) | 2009-07-01 |
| CN1688572A (zh) | 2005-10-26 |
| IL166534A (en) | 2012-05-31 |
| IL166534A0 (en) | 2006-01-15 |
| JP2005539049A (ja) | 2005-12-22 |
| US20040077684A1 (en) | 2004-04-22 |
| AR041010A1 (es) | 2005-04-27 |
| SI1539739T1 (sl) | 2011-04-29 |
| PL375562A1 (en) | 2005-11-28 |
| MXPA05001859A (es) | 2005-06-03 |
| RU2005104115A (ru) | 2005-08-27 |
| ATE489378T1 (de) | 2010-12-15 |
| DE60335118D1 (de) | 2011-01-05 |
| BR0313534A (pt) | 2005-07-12 |
| AU2010236002B2 (en) | 2012-05-03 |
| PT1539739E (pt) | 2011-01-05 |
| WO2004020435A1 (en) | 2004-03-11 |
| AU2010236002A1 (en) | 2010-11-11 |
| PL219749B1 (pl) | 2015-07-31 |
| AU2003259891A1 (en) | 2004-03-19 |
| NO332036B1 (no) | 2012-06-04 |
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