CA2677441C - Nitric oxide releasing steroids - Google Patents
Nitric oxide releasing steroids Download PDFInfo
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- CA2677441C CA2677441C CA2677441A CA2677441A CA2677441C CA 2677441 C CA2677441 C CA 2677441C CA 2677441 A CA2677441 A CA 2677441A CA 2677441 A CA2677441 A CA 2677441A CA 2677441 C CA2677441 C CA 2677441C
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title description 5
- 150000003431 steroids Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 638
- 239000003246 corticosteroid Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 208000022873 Ocular disease Diseases 0.000 claims abstract description 6
- 229910004679 ONO2 Inorganic materials 0.000 claims description 34
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 206010030043 Ocular hypertension Diseases 0.000 claims description 4
- 206010038926 Retinopathy hypertensive Diseases 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 201000001948 hypertensive retinopathy Diseases 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 230000002207 retinal effect Effects 0.000 claims description 4
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 3
- 201000011190 diabetic macular edema Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 85
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 11
- 230000003637 steroidlike Effects 0.000 abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 208000023504 respiratory system disease Diseases 0.000 abstract description 2
- 229960001334 corticosteroids Drugs 0.000 abstract 1
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 189
- 229910052727 yttrium Inorganic materials 0.000 description 160
- 150000003254 radicals Chemical class 0.000 description 145
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 80
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 72
- 229910002651 NO3 Inorganic materials 0.000 description 71
- 150000002828 nitro derivatives Chemical class 0.000 description 66
- 125000002947 alkylene group Chemical group 0.000 description 61
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
- -1 methylthio- (CH2) 2- Chemical group 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 150000007513 acids Chemical class 0.000 description 31
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 30
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 description 26
- 239000000047 product Substances 0.000 description 24
- 125000001309 chloro group Chemical group Cl* 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- 239000003480 eluent Substances 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- 125000000217 alkyl group Chemical group 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 16
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 15
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 9
- 229960002117 triamcinolone acetonide Drugs 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 8
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 7
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 229910001961 silver nitrate Inorganic materials 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 6
- 229960001347 fluocinolone acetonide Drugs 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 4
- 229960002537 betamethasone Drugs 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WCFJUSRQHZPVKY-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NCCC(O)=O WCFJUSRQHZPVKY-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- HXHGULXINZUGJX-UHFFFAOYSA-N 4-chlorobutanol Chemical compound OCCCCCl HXHGULXINZUGJX-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Chemical group 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- 125000002993 cycloalkylene group Chemical group 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 2
- IIPYXGDZVMZOAP-UHFFFAOYSA-N lithium nitrate Chemical compound [Li+].[O-][N+]([O-])=O IIPYXGDZVMZOAP-UHFFFAOYSA-N 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 1
- UHZCUZQKFIELAH-UHFFFAOYSA-N 1-o-(2,3-dinitrooxypropyl) 4-o-(4-nitrophenyl) 2-[(2-methylpropan-2-yl)oxycarbonylamino]butanedioate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)COC(=O)C(NC(=O)OC(C)(C)C)CC(=O)OC1=CC=C([N+]([O-])=O)C=C1 UHZCUZQKFIELAH-UHFFFAOYSA-N 0.000 description 1
- DWHMPBALQYTJFJ-UHFFFAOYSA-N 2-aminobutanedioic acid;hydrochloride Chemical compound Cl.OC(=O)C(N)CC(O)=O DWHMPBALQYTJFJ-UHFFFAOYSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 description 1
- 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 description 1
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Vascular Medicine (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89937607P | 2007-02-05 | 2007-02-05 | |
| US60/899,376 | 2007-02-05 | ||
| US92945607P | 2007-06-28 | 2007-06-28 | |
| US60/929,456 | 2007-06-28 | ||
| PCT/EP2008/050938 WO2008095806A1 (en) | 2007-02-05 | 2008-01-28 | Nitric oxide releasing steroids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2677441A1 CA2677441A1 (en) | 2008-08-14 |
| CA2677441C true CA2677441C (en) | 2016-04-12 |
Family
ID=39232800
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2677441A Expired - Fee Related CA2677441C (en) | 2007-02-05 | 2008-01-28 | Nitric oxide releasing steroids |
| CA002677442A Abandoned CA2677442A1 (en) | 2007-02-05 | 2008-01-28 | Nitric oxide releasing steroids |
| CA002677290A Abandoned CA2677290A1 (en) | 2007-02-05 | 2008-01-28 | Nitric oxide releasing steroids |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002677442A Abandoned CA2677442A1 (en) | 2007-02-05 | 2008-01-28 | Nitric oxide releasing steroids |
| CA002677290A Abandoned CA2677290A1 (en) | 2007-02-05 | 2008-01-28 | Nitric oxide releasing steroids |
Country Status (15)
| Country | Link |
|---|---|
| US (4) | US8933062B2 (enExample) |
| EP (3) | EP2109617A1 (enExample) |
| JP (1) | JP5216782B2 (enExample) |
| KR (1) | KR20090107525A (enExample) |
| CN (1) | CN101652380A (enExample) |
| AU (1) | AU2008213046B2 (enExample) |
| BR (1) | BRPI0807078A2 (enExample) |
| CA (3) | CA2677441C (enExample) |
| ES (1) | ES2601102T3 (enExample) |
| IL (1) | IL199815A (enExample) |
| MX (1) | MX2009008334A (enExample) |
| NZ (1) | NZ579067A (enExample) |
| RU (1) | RU2442790C2 (enExample) |
| WO (3) | WO2008095809A1 (enExample) |
| ZA (1) | ZA200905067B (enExample) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2011243947A1 (en) | 2010-04-23 | 2012-12-06 | Piramal Enterprises Limited | Nitric oxide releasing prodrugs of therapeutic agents |
| US8846723B2 (en) | 2010-07-29 | 2014-09-30 | Eastman Chemical Company | Esters of O-substituted hydroxy carboxylic acids and preparations thereof |
| KR20140103099A (ko) | 2011-10-12 | 2014-08-25 | 아센디스 파마 옵탈몰로지 디비젼 에이/에스 | 안구 병태의 예방 및 치료 |
| EP2729220B1 (en) * | 2011-12-20 | 2015-11-04 | Oriflame Research and Development Ltd. | Compounds with anti-aging activities |
| WO2014056915A1 (en) | 2012-10-11 | 2014-04-17 | Ascendis Pharma A/S | Diagnosis, prevention and treatment of diseases of the joint |
| CA2897571C (en) | 2013-01-21 | 2018-12-18 | Apparao Satyam | Nitric oxide releasing prodrugs of therapeutic agents containing at least one carboxylic acid group |
| RU2545416C1 (ru) * | 2014-02-18 | 2015-03-27 | Ксения Юрьевна Еременко | Способ лечения возрастной макулярной дистрофии |
| CN103880907A (zh) * | 2014-03-11 | 2014-06-25 | 天津金耀集团有限公司 | 丁酸氢化可的松半水合物 |
| AU2017359043B2 (en) | 2016-11-08 | 2022-06-16 | Regeneron Pharmaceuticals, Inc. | Steroids and protein-conjugates thereof |
| KR20200007905A (ko) | 2017-05-18 | 2020-01-22 | 리제너론 파마슈티칼스 인코포레이티드 | 사이클로덱스트린 단백질 약물 접합체 |
| CA3080857A1 (en) | 2017-11-07 | 2019-05-16 | Regeneron Pharmaceuticals, Inc. | Hydrophilic linkers for antibody drug conjugates |
| EA202091672A1 (ru) | 2018-01-08 | 2021-02-01 | Регенерон Фармасьютикалз, Инк. | Стероиды и их антитело-конъюгаты |
| WO2019217591A1 (en) | 2018-05-09 | 2019-11-14 | Regeneron Pharmaceuticals, Inc. | Anti-msr1 antibodies and methods of use thereof |
| WO2020047496A1 (en) * | 2018-08-31 | 2020-03-05 | Aerie Pharmaceuticals, Inc. | Isoquinoline-steroid conjugates and uses thereof |
| WO2022135332A1 (zh) * | 2020-12-21 | 2022-06-30 | 映恩生物制药（苏州）有限公司 | 一种甾体偶联物 |
| JP7687973B2 (ja) * | 2022-01-24 | 2025-06-03 | 芳弘 二村 | フィブロネクチン活性化作用を介した表皮細胞増殖作用を呈するジテルペン誘導体 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3183252A (en) | 1963-09-05 | 1965-05-11 | Syntex Corp | 16-nitratoalkyl-pregnanes |
| US3494941A (en) * | 1967-12-04 | 1970-02-10 | American Home Prod | Nitrate esters of 17beta-(hydroxyalkoxy)steroid 3-ols,3-ones and 3-amidinohydrazones |
| HU164115B (enExample) | 1971-05-07 | 1973-12-28 | ||
| IT1285770B1 (it) * | 1996-10-04 | 1998-06-18 | Nicox Sa | Composti corticoidei |
| IT1311922B1 (it) * | 1999-04-13 | 2002-03-20 | Nicox Sa | Composti farmaceutici. |
| ITMI20020148A1 (it) * | 2002-01-29 | 2003-07-29 | Nicox Sa | Nuovi corticosteroidi |
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| AU2006286838C1 (en) * | 2005-09-02 | 2013-05-02 | Ferrer Internacional S.A. | Nitrooxy derivatives of glucocorticoids |
-
2008
- 2008-01-28 CN CN200880004081A patent/CN101652380A/zh active Pending
- 2008-01-28 WO PCT/EP2008/050948 patent/WO2008095809A1/en not_active Ceased
- 2008-01-28 JP JP2009547651A patent/JP5216782B2/ja not_active Expired - Fee Related
- 2008-01-28 US US12/525,970 patent/US8933062B2/en not_active Expired - Fee Related
- 2008-01-28 CA CA2677441A patent/CA2677441C/en not_active Expired - Fee Related
- 2008-01-28 EP EP08708270A patent/EP2109617A1/en not_active Withdrawn
- 2008-01-28 CA CA002677442A patent/CA2677442A1/en not_active Abandoned
- 2008-01-28 WO PCT/EP2008/050947 patent/WO2008095808A1/en not_active Ceased
- 2008-01-28 ES ES08708261.6T patent/ES2601102T3/es active Active
- 2008-01-28 BR BRPI0807078-4A2A patent/BRPI0807078A2/pt not_active IP Right Cessation
- 2008-01-28 MX MX2009008334A patent/MX2009008334A/es active IP Right Grant
- 2008-01-28 AU AU2008213046A patent/AU2008213046B2/en not_active Ceased
- 2008-01-28 US US12/526,005 patent/US20100041633A1/en not_active Abandoned
- 2008-01-28 EP EP08708261.6A patent/EP2118120B1/en active Active
- 2008-01-28 CA CA002677290A patent/CA2677290A1/en not_active Abandoned
- 2008-01-28 NZ NZ579067A patent/NZ579067A/en not_active IP Right Cessation
- 2008-01-28 RU RU2009132993/04A patent/RU2442790C2/ru not_active IP Right Cessation
- 2008-01-28 US US12/525,822 patent/US20100234334A1/en not_active Abandoned
- 2008-01-28 KR KR1020097016395A patent/KR20090107525A/ko not_active Abandoned
- 2008-01-28 WO PCT/EP2008/050938 patent/WO2008095806A1/en not_active Ceased
- 2008-01-28 EP EP08708271A patent/EP2109618A1/en not_active Withdrawn
-
2009
- 2009-07-12 IL IL199815A patent/IL199815A/en not_active IP Right Cessation
- 2009-07-20 ZA ZA200905067A patent/ZA200905067B/xx unknown
-
2014
- 2014-11-26 US US14/554,830 patent/US20150105547A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP2109617A1 (en) | 2009-10-21 |
| IL199815A (en) | 2015-03-31 |
| EP2118120B1 (en) | 2016-10-05 |
| AU2008213046A1 (en) | 2008-08-14 |
| ZA200905067B (en) | 2010-04-28 |
| US8933062B2 (en) | 2015-01-13 |
| ES2601102T3 (es) | 2017-02-14 |
| US20100234334A1 (en) | 2010-09-16 |
| RU2009132993A (ru) | 2011-03-20 |
| WO2008095809A1 (en) | 2008-08-14 |
| CN101652380A (zh) | 2010-02-17 |
| IL199815A0 (en) | 2010-04-15 |
| RU2442790C2 (ru) | 2012-02-20 |
| JP2010517955A (ja) | 2010-05-27 |
| CA2677290A1 (en) | 2008-08-14 |
| WO2008095808A1 (en) | 2008-08-14 |
| BRPI0807078A2 (pt) | 2014-04-08 |
| JP5216782B2 (ja) | 2013-06-19 |
| US20100041633A1 (en) | 2010-02-18 |
| EP2109618A1 (en) | 2009-10-21 |
| US20150105547A1 (en) | 2015-04-16 |
| CA2677441A1 (en) | 2008-08-14 |
| CA2677442A1 (en) | 2008-08-14 |
| KR20090107525A (ko) | 2009-10-13 |
| NZ579067A (en) | 2012-02-24 |
| EP2118120A1 (en) | 2009-11-18 |
| US20100093685A1 (en) | 2010-04-15 |
| AU2008213046B2 (en) | 2013-02-14 |
| WO2008095806A1 (en) | 2008-08-14 |
| MX2009008334A (es) | 2009-08-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20130121 |
|
| MKLA | Lapsed |
Effective date: 20190128 |