CN100391538C - 角膜上皮伸展促进剂 - Google Patents
角膜上皮伸展促进剂 Download PDFInfo
- Publication number
- CN100391538C CN100391538C CNB018102328A CN01810232A CN100391538C CN 100391538 C CN100391538 C CN 100391538C CN B018102328 A CNB018102328 A CN B018102328A CN 01810232 A CN01810232 A CN 01810232A CN 100391538 C CN100391538 C CN 100391538C
- Authority
- CN
- China
- Prior art keywords
- acid
- salt
- uridine
- ectocornea
- receptor stimulating
- 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
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- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- -1 xanthosyl Chemical group 0.000 claims abstract description 9
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 18
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 9
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 9
- 229940045145 uridine Drugs 0.000 claims description 9
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 210000003560 epithelium corneal Anatomy 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 7
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 claims description 6
- PGAVKCOVUIYSFO-XVFCMESISA-N UTP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-N 0.000 claims description 6
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 6
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 claims description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- MWEQTWJABOLLOS-UHFFFAOYSA-L disodium;[[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-oxidophosphoryl] hydrogen phosphate;trihydrate Chemical compound O.O.O.[Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP([O-])(=O)OP(O)([O-])=O)C(O)C1O MWEQTWJABOLLOS-UHFFFAOYSA-L 0.000 claims description 4
- 229940035893 uracil Drugs 0.000 claims description 4
- 206010064996 Ulcerative keratitis Diseases 0.000 claims description 3
- 201000007717 corneal ulcer Diseases 0.000 claims description 3
- 206010023332 keratitis Diseases 0.000 claims description 3
- 229940113082 thymine Drugs 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 102000002298 Purinergic P2Y Receptors Human genes 0.000 abstract description 19
- 108010000818 Purinergic P2Y Receptors Proteins 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 11
- 230000001737 promoting effect Effects 0.000 abstract 2
- 125000002124 5'-adenosyl group Chemical group N1=CN=C2N(C=NC2=C1N)[C@H]1[C@H](O)[C@H](O)[C@H](O1)C* 0.000 abstract 1
- 125000001601 guanosyl group Chemical group 0.000 abstract 1
- 150000003016 phosphoric acids Chemical class 0.000 abstract 1
- 239000000018 receptor agonist Substances 0.000 abstract 1
- 229940044601 receptor agonist Drugs 0.000 abstract 1
- 125000002480 thymidyl group Chemical group 0.000 abstract 1
- 125000002223 uridyl group Chemical group 0.000 abstract 1
- 239000002269 analeptic agent Substances 0.000 description 20
- 210000004087 cornea Anatomy 0.000 description 16
- 239000011734 sodium Substances 0.000 description 13
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- CDVLCTOFEIEUDH-UHFFFAOYSA-K tetrasodium;phosphate Chemical class [Na+].[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O CDVLCTOFEIEUDH-UHFFFAOYSA-K 0.000 description 5
- 208000016134 Conjunctival disease Diseases 0.000 description 4
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- ZQKVPFKBNNAXCE-WFIJOQBCSA-L disodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] phosphate;hydron Chemical compound [Na+].[Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP(O)([O-])=O)O[C@H]1N1C(=O)NC(=O)C=C1 ZQKVPFKBNNAXCE-WFIJOQBCSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
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- 238000012360 testing method Methods 0.000 description 4
- MMJGIWFJVDOPJF-LLWADOMFSA-K trisodium;[[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OP(O)([O-])=O)O[C@H]1N1C(=O)NC(=O)C=C1 MMJGIWFJVDOPJF-LLWADOMFSA-K 0.000 description 4
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 229940057995 liquid paraffin Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
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- 239000011780 sodium chloride Substances 0.000 description 3
- RMJPDRUNCDRUQC-MCDZGGTQSA-M sodium;[[[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound [Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)([O-])=O)[C@@H](O)[C@H]1O RMJPDRUNCDRUQC-MCDZGGTQSA-M 0.000 description 3
- 239000003871 white petrolatum Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000003816 axenic effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
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- 230000028327 secretion Effects 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000005494 xerophthalmia Diseases 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 208000028006 Corneal injury Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
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- 210000000795 conjunctiva Anatomy 0.000 description 1
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- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000012028 nasolacrimal duct disease Diseases 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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Abstract
通过寻找在眼科领域中显示角膜上皮伸展促进效果的化合物，发现以带有腺苷基、尿苷基、黄苷基、鸟苷基或胸苷基的磷酸化合物或其盐为代表的P2Y受体激动剂显示优秀的促进角膜上皮伸展的作用，从而完成了本发明。
Description
技术领域
本发明涉及一种含有P2Y受体激动剂为活性成分的角膜上皮伸展促进剂。
背景技术
角膜是一种直径约1厘米、厚约1毫米的透明、无血管的组织。角膜的透明度极大地影响视觉功能。角膜中的各种生理生化现象的主要功能就是为了维持角膜的透明性。
由于各种疾病如角膜溃疡、角膜上皮剥离、角膜炎或干眼病造成的角膜上皮缺陷能够自然修复，除非角膜并发混合感染。但是，当由于某种原因修复被延迟或者角膜上皮缺陷持续得不到修复时，这种延迟或持续会对上皮的正常生长造成有害的影响，并损害角膜实质和内皮的结构和功能。治疗角膜上皮缺陷的一种传统方法是基于这样一种被动原则：通过保护角膜表面免受外部刺激，让角膜上皮自然伸展并重新覆盖缺陷部分。近年来，随着细胞生物学的发展，一种参与细胞分裂、移动、粘附、伸展等的因子已经得到阐明。据报道，一种促进角膜上皮伸展的化合物在角膜上皮缺陷的修复中发挥着重要的作用(Clin.Opthalm.，46，738-743(1992)，Jpn.J.Ophthalm.Surg.，5，719-727(1992))。
另一方面，也有各种关于P2Y受体激动剂研究的报道，所述激动剂是本发明的活性成分。例如，美国专利5,292,498公开了用尿苷5’-三磷酸(UTP)、腺苷三磷酸(ATP)治疗粘膜分泌之维持特征性相关的肺病。WO 97/29756指出，作为P2Y受体激动剂的UTP以及其他的磷酸核苷作为中耳炎的治疗药物有效。另外，WO 98/34593指出，P2Y受体激动剂如UTP具有泪液分泌作用，可用于治疗干眼病和鼻泪管疾病。但是，对这些P2Y受体激动剂的角膜上皮伸展作用还没有研究。
寻找上述P2Y受体激动剂的新用途是一件意义深远的事情，而在眼科领域中寻找表现角膜上皮伸展促进作用的化合物是非常重要的课题。
发明内容
本发明人研究了各种各样的化合物并测定了它们的药理作用。结果，本发明人发现，P2Y受体激动剂具有角膜伸展促进作用，从而完成了本发明。
本发明提供一种角膜伸展促进剂，它含有P2Y受体激动剂作为活性成分，所述受体激动剂例如是下述通式[I]代表的化合物(除另有说明外，以下称为“本发明化合物”)或其盐。
本发明还提供一种造成角膜上皮伸展的方法，其包括给予患者一种含有有效量P2Y受体激动剂或其药物可接受盐和药物可接受添加剂的组合物。
本发明还提供P2Y受体激动剂在制备角膜上皮伸展促进剂中的用途。
(其中，n是1至4的整数，X是氢或下式[II]代表的基团，
R1和R2相同或不同，为尿嘧啶基、胸腺嘧啶基、腺嘌呤基、黄嘌呤基或鸟嘌呤基)。
本发明化合物中的尿嘧啶基、胸腺嘧啶基、腺嘌呤基、黄嘌呤基和鸟嘌呤基上可以被以下基团取代：卤原子如氟、氯或溴，直链或支链低级烷基如甲基、乙基、丙基或己基，含有1至6个碳原子的直链或支链低级烷氧基如甲氧基、乙氧基、丙氧基或己氧基，芳基如苯基或甲苯基，芳氧基如苯氧基，芳烷基如苄基或苯乙基，羟基等。腺嘌呤基和鸟嘌呤基中的氨基可以由通用的保护基保护。保护基的例子有含有2至6个碳原子的低级烷酰基如乙酰基或新戊酰基，芳酰基如苯甲酰基。R1和R2的优选实例是腺嘌呤基和尿嘧啶基。
本发明化合物的盐没有特别限制，只要这种盐是药物可接受的即可。所述盐的例子有碱金属盐或碱土金属盐如钠盐、钾盐或钙盐，与氨或有机胺的盐如与二乙胺或三乙醇胺的盐，与无机酸如盐酸、硫酸或磷酸的盐，与有机酸如乳酸、马来酸、富马酸、草酸、甲磺酸或对甲苯磺酸的盐。
本发明化合物中存在旋光异构体和非对映异构体，这些异构体也包括在本发明中。本发明化合物还可以是溶剂化物的形式，如水合物。
本发明化合物中具有特别优秀活性作用的化合物的实例是尿苷5’-二磷酸、腺苷5’-二磷酸、尿苷5’-三磷酸、腺苷5’-三磷酸、由下式[III]代表的P1，P4-二(尿苷5’-)四磷酸或它们的盐。
这些化合物中，下式[IV]代表的钠盐具有极佳的角膜上皮伸展作用。
如在背景技术部分所讲到的，角膜上皮伸展紧密地参与修复各种原因引起的角膜损伤。从下述药理试验可以清楚地看出，由于本发明中的P2Y受体激动剂具有优秀的角膜上皮伸展作用，该激动剂可以用于各种角膜疾病的治疗。角膜疾病的例子有角膜溃疡、角膜上皮剥离、角膜炎等。因为角膜和结膜的上皮伸展作用并没有实质性区别，P2Y受体激动剂的修复作用不仅可以作用于角膜疾病，还可以作用于结膜疾病。总体而言，P2Y受体激动剂可以用于治疗角膜结膜疾病。
另外，已知P2Y受体包括一些亚型，其中特别知名的是P2Y2受体。美国专利5,292,498、WO 97/29756等中公开了该P2Y2受体激动剂的典型化合物。
对本发明的P2Y受体激动剂的给药方法没有特别的限制，优选是局部给药，特别是以滴眼剂的形式。
P2Y受体激动剂在滴眼剂中的浓度可以根据症状、年龄等因素调整，没有特别的必要去限制浓度。该浓度为0.0001％至15％，优选0.01％至10％。作为滴眼液，剂量为每次一到几滴，每天一到几次。滴眼剂可以是通常的滴眼液，也可以是用时溶解型的滴眼液形式。还可以是眼膏形式。
可以通过添加可选择的添加剂按常规方法将P2Y受体激动剂配制成制剂，所述添加剂例如为等渗调节剂如氯化钠或氯化钾，缓冲剂如磷酸钠、磷酸氢二钠或磷酸二氢钠，稳定剂如乙二胺四乙酸二钠，保存剂如苯扎氯铵或山梨酸，pH调节剂如氢氧化钠或稀盐酸，眼膏基质如白凡士林或液态石蜡。
以下是本发明的实施例，它们是用于更好地理解本发明，而不是限制本发明的范围。
本发明的最佳实施方式
药理试验
对角膜上皮伸展的作用
利用雄性日本白兔的角膜，按照Nishida等的方法(J.Cell Biol.，97，1653-1657(1983))，以在角膜片组织培养系统中的角膜上皮伸展长度为指标，研究了下列试验化合物对角膜上皮伸展的作用。
试验方法
将分离自兔角膜片的角膜块(每组6块)在含有本发明化合物的培养基(TCM-199)中在37℃-5％CO2的条件下培养24小时。培养后，将角膜块在乙醇-冰醋酸混合液(体积比95∶5)中固定，用石蜡包埋并做切片。从切片上除去石蜡，用苏木精-曙红对切片染色，在显微镜下测定上皮细胞层的伸展长度。在不含本发明化合物的培养基中同样培养的一个角膜块用作对照。
结果
表1显示了以对照为100％时P1，P4-二(尿苷5’-)四磷酸四钠[DUTP-Na]、尿苷5’-二磷酸二钠[UDP-Na]、腺苷5’-二磷酸二钠[ADP-Na]、尿苷5’-三磷酸三钠[UTP-Na]和腺苷5’-三磷酸三钠[ATP-Na]的角膜上皮伸展率(百分比)。
表1
| 药物(浓度) | 角膜上皮伸展率(％) |
| DUTP-Na(100μM) | 118.9 |
| UDP-Na(100μM) | 115.3 |
| ADP-Na(10μM) | 116.1 |
| UTP-Na(100μM) | 123.1 |
| ATP-Na(10μM) | 119.3 |
| 对照 | 100.0 |
制剂
作为本发明化合物的典型实例，以下给出了使用P1，P4-二(尿苷5’-)四磷酸四钠[DUTP-Na]、尿苷5’-三磷酸三钠[UTP-Na]和尿苷5’-二磷酸二钠[UDP-Na]的典型制剂实施例。
实施例1
100毫升中
DUTP-Na 10mg
氯化钠 900mg
无菌纯化水足量
改变P1，P4-二(尿苷5’-)四磷酸四钠[DUTP-Na]的量，还可以制备DUTP-Na的浓度为0.03％(w/v)、0.1％(w/v)、0.3％(w/v)、1.0％(w/v)和3.0％(w/v)的滴眼液。
实施例2
100毫升中
UTP-Na 100mg
氯化钠 800mg
磷酸氢二钠 100mg
磷酸二氢钠 足量
无菌纯化水 足量
改变尿苷5’-三磷酸三钠[UTP-Na]的量，还可以制备UTP-Na的浓度为0.3％(w/v)、0.5％(w/v)、1.5％(w/v)和3.0％(w/v)的滴眼液。
实施例3
100克中
DUTP-Na 0.3g
液态石蜡 10g
白凡士林 足量
改变P1，P4-二(尿苷5’-)四磷酸四钠[DUTP-Na]的量，还可以制备DUTP-Na的浓度为1％(w/w)和3％(w/w)的眼膏。
实施例4
100克中
UDP-Na 0.3g
液态石蜡 10g
白凡士林 足量
改变尿苷5’-二磷酸二钠[UDP-Na]的量，还可以制备UDP-Na的浓度为1％(w/w)和5％(w/w)的眼膏。
表1显示本发明的P1，P4-二(尿苷5’-)四磷酸四钠[DUTP-Na]、尿苷5’-二磷酸二钠[UDP-Na]、腺苷5’-二磷酸二钠[ADP-Na]、尿苷5’-三磷酸三钠[UTP-Na]和腺苷5’-三磷酸三钠[ATP-Na]具有显著的角膜上皮伸展效果。这些药理试验的结果显示，含有本发明P2Y受体激动剂为活性成分的药物显示优秀的促进角膜上皮伸展的效果，并可用于治疗角膜结膜疾病。
工业实用性
P2Y受体激动剂显示优秀的促进角膜上皮伸展的效果并可用于治疗角膜结膜疾病。
Claims (2)
1.由以下通式[I]代表的化合物或其盐在制造角膜溃疡、角膜上皮剥离或角膜炎治疗剂中的用途：
其中n是1至4的整数，X是氢或下式[II]代表的基团，
R1和R2相同或不同，为尿嘧啶基、胸腺嘧啶基、腺嘌呤基、黄嘌呤基或鸟嘌呤基。
2.根据权利要求1所述的用途，其中所述通式[I]代表的化合物是P1，P4-二(尿苷5’-)四磷酸、尿苷5’-二磷酸、腺苷5’-二磷酸、尿苷5’-三磷酸或腺苷5’-三磷酸，或其盐。
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| US6864243B1 (en) * | 2000-05-12 | 2005-03-08 | Inspire Pharmaceuticals, Inc. | Method for treating retinal degeneration with purinergic receptor agonists |
| JP4313033B2 (ja) * | 2002-12-27 | 2009-08-12 | 株式会社日本点眼薬研究所 | 眼科用治療組成物 |
| CN103282039A (zh) * | 2010-12-28 | 2013-09-04 | 参天制药株式会社 | 含有地夸磷索的滴眼液及其制备方法、抑制不溶性析出物产生的方法 |
| SG11201405799TA (en) * | 2012-03-26 | 2014-11-27 | Santen Pharmaceutical Co Ltd | Ophthalmic solution comprising diquafosol |
| SG11202007977RA (en) * | 2018-02-28 | 2020-09-29 | Santen Pharmaceutical Co Ltd | Ophthalmic composition comprising diquafosol and cationic polymer |
| CN117771172A (zh) * | 2019-08-27 | 2024-03-29 | 参天制药株式会社 | 含有地夸磷索或其盐、及聚乙烯吡咯烷酮的水性眼科用组合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5292498A (en) * | 1991-06-19 | 1994-03-08 | The University Of North Carolina At Chapel Hill | Method of treating lung disease with uridine triphosphates |
| WO1998034942A2 (en) * | 1997-02-06 | 1998-08-13 | Inspire Pharmaceuticals, Inc. | Dinucleotides and their use |
| WO1999061012A2 (en) * | 1998-05-22 | 1999-12-02 | Inspire Pharmaceuticals, Inc. | Therapeutic dinucleotide and derivatives |
| WO2000050024A2 (en) * | 1999-02-26 | 2000-08-31 | Inspire Pharmaceuticals, Inc. | Method of promoting mucosal hydration with certain uridine, adenine and cytidine diphosphates and analogs thereof |
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| US5900407A (en) | 1997-02-06 | 1999-05-04 | Inspire Pharmaceuticals, Inc. | Method of treating dry eye disease with uridine triphosphates and related compounds |
| US6696425B2 (en) * | 1997-02-06 | 2004-02-24 | Inspire Pharmaceuticals, Inc. | Method of treating dry eye disease with purinergic receptor agonists |
| US6409175B1 (en) | 1999-07-13 | 2002-06-25 | Grant Prideco, Inc. | Expandable joint connector |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5292498A (en) * | 1991-06-19 | 1994-03-08 | The University Of North Carolina At Chapel Hill | Method of treating lung disease with uridine triphosphates |
| WO1998034942A2 (en) * | 1997-02-06 | 1998-08-13 | Inspire Pharmaceuticals, Inc. | Dinucleotides and their use |
| WO1999061012A2 (en) * | 1998-05-22 | 1999-12-02 | Inspire Pharmaceuticals, Inc. | Therapeutic dinucleotide and derivatives |
| WO2000050024A2 (en) * | 1999-02-26 | 2000-08-31 | Inspire Pharmaceuticals, Inc. | Method of promoting mucosal hydration with certain uridine, adenine and cytidine diphosphates and analogs thereof |
Also Published As
| Publication number | Publication date |
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| AU2001260643B2 (en) | 2006-06-08 |
| KR20030031489A (ko) | 2003-04-21 |
| CA2413928A1 (en) | 2001-12-06 |
| US20060009415A1 (en) | 2006-01-12 |
| US6984629B2 (en) | 2006-01-10 |
| CN1431914A (zh) | 2003-07-23 |
| AU6064301A (en) | 2001-12-11 |
| EP1428538A4 (en) | 2006-04-05 |
| AU2001260643B9 (en) | 2006-10-19 |
| US20030186927A1 (en) | 2003-10-02 |
| KR100832821B1 (ko) | 2008-05-28 |
| EP1428538B1 (en) | 2013-08-14 |
| EP1428538A1 (en) | 2004-06-16 |
| WO2001091795A1 (fr) | 2001-12-06 |
| BR0111297A (pt) | 2004-01-06 |
| CA2413928C (en) | 2011-01-25 |
| MXPA02011710A (es) | 2004-07-30 |
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