WO2023198192A1 - 甾体化合物在制备预防和/或治疗老花眼的药物中的应用 - Google Patents
甾体化合物在制备预防和/或治疗老花眼的药物中的应用 Download PDFInfo
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- WO2023198192A1 WO2023198192A1 PCT/CN2023/088387 CN2023088387W WO2023198192A1 WO 2023198192 A1 WO2023198192 A1 WO 2023198192A1 CN 2023088387 W CN2023088387 W CN 2023088387W WO 2023198192 A1 WO2023198192 A1 WO 2023198192A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- aryl
- heterocyclyl
- heteroaryl
- Prior art date
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- -1 steroid compound Chemical class 0.000 title claims abstract description 157
- 201000010041 presbyopia Diseases 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- 229940002612 prodrug Drugs 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 7
- 229910052805 deuterium Inorganic materials 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 5
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 5
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 5
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 claims description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 5
- 125000000532 dioxanyl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 5
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 5
- 125000005503 thioxanyl group Chemical group 0.000 claims description 5
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims description 4
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 claims description 4
- 125000005883 dithianyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 229920001993 poloxamer 188 Polymers 0.000 claims description 4
- 229940044519 poloxamer 188 Drugs 0.000 claims description 4
- 229920001992 poloxamer 407 Polymers 0.000 claims description 4
- 229940044476 poloxamer 407 Drugs 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 230000003637 steroidlike Effects 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000003943 azolyl group Chemical group 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 230000004438 eyesight Effects 0.000 abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 239000003889 eye drop Substances 0.000 description 15
- 125000002619 bicyclic group Chemical group 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
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- 241000699670 Mus sp. Species 0.000 description 9
- 229940012356 eye drops Drugs 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
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- 239000000126 substance Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 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 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
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- 239000000243 solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
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- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
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- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 4
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- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
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- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
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- 238000011161 development Methods 0.000 description 3
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 3
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 2
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- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
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- 229910002651 NO3 Inorganic materials 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
Definitions
- the invention belongs to the technical field of chemical medicine and relates to the application of a steroid compound in preparing drugs for preventing and/or treating presbyopia.
- Presbyopia also known as presbyopia
- presbyopia is a physiological state that causes the lens to harden and the vision adjustment function of the eyes to decrease with age.
- the initial symptoms are that the target needs to be kept at a certain distance to see clearly. If the light is insufficient, it will be more difficult to read at close range, and these conditions will continue to worsen with age.
- the development of presbyopia is also related to refractive errors, physical fitness, drugs and other factors.
- the main methods for treating presbyopia include wearing frame reading glasses, wearing contact lenses, corneal refraction, scleral refraction and lens refractive surgery.
- FDA U.S. Food and Drug Administration
- the ophthalmic drug Vuity potentiol
- Allergan a subsidiary of AbbVie
- Vuity is instilled into both eyes once a day. It takes effect 15 minutes after instillation, and the effect is long-lasting. Patients can read without wearing glasses. It is the first eye drop specially used to treat presbyopia. However, it can only relieve its symptoms but cannot completely cure presbyopia. Therefore, there is an urgent clinical need for other drugs that can prevent, alleviate or treat presbyopia.
- the purpose of the present invention is to provide an application of a steroid compound in the preparation of medicines for preventing and/or treating presbyopia.
- the steroid compound provided by the present invention can effectively treat and slow down presbyopia. and preventive effects, which can greatly reduce and/or cure presbyopia and improve vision clarity.
- the present invention adopts the following technical solutions:
- the present invention provides the use of a steroid compound in the preparation of medicines for preventing and/or treating presbyopia.
- the steroid compound is a compound with a structure shown in Formula I, or a compound with a structure shown in Formula I.
- R is H, D (deuterium), alkyl, sulfate, phosphate, alkylsilyl, benzyl or -C(O)-X;
- X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl;
- aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl, alkylsilyl and alkyl groups mentioned in R and X are optionally substituted by 1, 2, 3 or 4 identical or different substituents replaced;
- R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
- the steroid compound is a compound with a structure as shown in Formula II, or a stereoisomer, tautomer, nitrogen oxide, solvate, or a compound with a structure as shown in Formula II.
- R is the same as formula (I).
- R is H, D, C 1-6 alkyl, sulfate, phosphate, C 1-6 alkylsilyl, benzyl, or -C(O)-X.
- X is selected from C 6-10 aryl, C 2-9 heteroaryl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 1-6 heteroalkyl, or C 1 -6 alkyl.
- R and , C 1-6 alkylsilyl or C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 identical or different substituents.
- R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
- X is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, mercaptoethyl , aminomethyl, aminoethyl, aminopropyl, phenylmethyl, phenylethyl, imidazolylmethyl, carboxymethyl, carboxyethyl, methylthiomethyl, methylthioethyl, phenyl , naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, disulfide ring Pentyl, tetrahydropyranyl, dihydr
- the substituents described in R and C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 2-9 heteroaryl.
- X is selected from any of the following groups:
- the compound of the structure shown in formula I or II is selected from any one of the following compounds:
- the steroidal compounds provided by the present invention can be used for treatment as raw chemicals or can be provided as active ingredients of pharmaceutical compositions.
- the present invention provides the use of a composition in the preparation of medicines for preventing and/or treating presbyopia.
- the composition includes the steroid compound described in the first aspect, and a pharmaceutically acceptable carrier and excipient. , diluents, auxiliaries or vehicles.
- Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; sorbate potash; saturated plant Mixtures of partial glycerides of fatty acids; water; salts; electrolytes such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates ; Waxes; Polyethylene-polyoxypropylene-blocking polymers; Lanolin; Sugars, such as lactose, glucose and sucrose; Starches, such as corn starch and potato starch; Cellulose and its derivatives, such as sodium carboxymethylcellulose, Ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa
- the composition includes: a steroid compound of the invention, hypromellose, poloxamer 407, poloxamer 188, and water.
- the composition includes: 10 to 40 parts by mass of the steroid compound of the present invention, 110 to 120 parts by mass of hypromellose, 2050 to 2060 parts by mass of poloxamer 407, 160 to 160 parts by mass 170 parts by mass of poloxamer 188 and 10000 parts by mass of water.
- the composition can be eye drops.
- the eye drops may be suspension eye drops.
- the size of the eye drops may be 10 mL.
- the present invention provides a method for preventing and/or treating presbyopia, comprising administering the steroid compound described in the first aspect or the composition described in the second aspect to a subject in need.
- the present invention has the following beneficial effects:
- the present invention finds that the steroid compound provided by the present invention can improve the elasticity of the lens, improve the patient's near vision, and can be used to prevent, treat, treat or alleviate the patient's presbyopia with minimal or almost no side effects.
- Stereoisomers refer to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
- the compounds of the invention can be expressed as one of the possible isomers or as a mixture thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ) exists in the form.
- Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. if The compound contains a double bond, and the substituent may be in E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have cis or trans configuration.
- Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.
- the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Therefore, the individual stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.
- prodrug used in the present invention represents a compound that is converted into a compound of Formula I in the body. Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue.
- the prodrug compound of the present invention can be an ester.
- esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonate esters. , carbamates and amino acid esters.
- a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound.
- prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent.
- phosphate esters which are obtained by phosphorylation of the hydroxyl group of the parent.
- Any resulting racemate of the final product or intermediate may be resolved into its optical antipodes by known methods familiar to those skilled in the art, e.g., by subjecting the diastereomeric salts thereof obtained separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using chiral adsorbents.
- enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E .Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E.L.
- tautomer or "tautomeric form” refers to structural isomers with different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
- protontautomers also known as prototropic tautomers
- Valence tautomers involve interconversions through the reorganization of some of the bonding electrons.
- Keto-enol tautomers A specific example of isomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
- tautomerism is phenol-ketone tautomerism.
- a specific example of phenol-keto tautomerism is the tautomerization of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- salts mentioned in the present invention are pharmaceutically acceptable salts, and "pharmaceutically acceptable salts" are well known in the art.
- pharmaceutically acceptable salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, and nitrates.
- organic acid salts such as carboxylates, sulfonates, sulfinates, sulfur carboxylates, etc., specifically such as, but not limited to, methanesulfonate, ethanesulfonate, methanesulfonate, etc.
- Acid acetate, succinate, benzoate, succinate, pamoate, salicylate, galactoate, glucoheptanoate, mandelate, 1,2 -Ethanyl disulfonate, 2-naphthalene sulfonate, carbonate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, Citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate or oxalic acid, or as described in books and literature Other methods such as ion exchange are used to obtain these salts.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonic acid Salt, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, enanthate, caproic acid Salt, hydroiodide, 2-hydroxy-ethanesulfonate, lactouronate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamate, fruit Collate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc.
- pharmaceutically acceptable salts also include salts derived from appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- bases such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- the present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
- Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and others.
- Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates compounds and aromatic sulfonates.
- salts can be formed with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/carbonates , bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline salt, citrate, ethylene disulfonate, fumarate, glucoheptonate, gluconate, Glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactosuronate, lauryl sulfate, malate, maleate, propylene glycol acid salt, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate , Pamate, phosphate
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, Succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
- Solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association of solvent molecules with water.
- “Pharmaceutical composition” means a mixture of one or more compounds, salts or physiologically/pharmaceutically acceptable salts or prodrugs thereof as described herein with other chemical components, e.g. physiologically/pharmaceutically acceptable Acceptable carrier or excipient.
- the purpose of pharmaceutical compositions is to facilitate the administration of compounds to an organism.
- any disease or condition as used herein means ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof).
- “treating” or “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient.
- “treating” or “treating” refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both.
- “treating” or “treating” refers to preventing or delaying the onset, development, or progression of a disease or disorder.
- alkyl as used herein means 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or A saturated linear or branched chain monovalent hydrocarbon group of 1 to 3 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention.
- alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2 -Butyl (-C(CH 3 ), 2-
- alkyl and its prefix “alkyl” as used herein include both straight and branched saturated carbon chains.
- alkylene refers to a saturated divalent hydrocarbon radical obtained by eliminating two hydrogen atoms from a linear or branched saturated hydrocarbon. Examples of such include, but are not limited to, methylene, ethylene , sub-isopropyl and so on.
- cycloalkyl refers to a monovalent or polyvalent, nonaromatic, saturated or partially unsaturated ring and containing no heteroatoms, including a monocyclic ring of 3 to 12 carbon atoms or a monocyclic ring of 7 to 12 carbon atoms.
- the second ring Bicyclic carbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocycles with 9 or 10 atoms It can be two rings [5,6] or [6,6] system.
- Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
- cyclic aliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl base, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
- heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms are independently and optionally substituted by heteroatoms having the meaning as described herein, the ring may be fully saturated or contain one or more degrees of unsaturation, but is never aromatic, There is only one connection point to other molecules. Hydrogen atoms on one or more rings are independently and optionally substituted with one or more substituents described herein.
- the "heterocycle", “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , when said When the ring is a three-membered ring with only one heteroatom), or a 7-10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P optionally substituted by one or more oxygen atoms to give groups such as SO, SO 2 , PO, PO 2 ).
- Heterocyclyl groups may be carbon or heteroatom groups.
- Heterocyclyl also includes groups formed by combining a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl , piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-meth
- heterocyclic groups also include, 1,1-dioxothiomorpholinyl, and pyrimidinedione groups in which two carbon atoms on the ring are replaced by oxygen atoms.
- aryl may be used alone or as a large part of "aralkyl", “aralkoxy” or “aryloxyalkyl” to mean monocyclic, bicyclic, and bicyclic rings containing a total of 6 to 14 members.
- a tricyclic carbocyclic ring system in which at least one ring system is aromatic and in which each ring system contains a 3- to 7-membered ring and has only one point of attachment to the rest of the molecule.
- aryl may be used interchangeably with the term "aromatic ring”.
- aromatic rings may include phenyl, naphthyl and anthracenyl.
- heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems containing a total of 5 to 14 membered rings, in which at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroaryl Atoms have the meaning given herein, wherein each ring system contains a 3-7 membered ring and has only one point of attachment to the rest of the molecule.
- heteroaryl may be used interchangeably with the term “aromatic heterocycle” or "heteroaromatic compound.”
- the heteroaryl group includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazole- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazoly
- heteroatom means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in heterocycles
- N e.g. N in 3,4-dihydro-2H-pyrrolyl
- NH e.g. NH in pyrrolidinyl
- NR e.g. N-substituted pyrrole in alkyl NR
- heteroalkyl means that one or more heteroatoms may be inserted into the middle of the alkyl chain, wherein the alkyl group and the heteroatoms have the meanings described herein. Unless otherwise specified, heteroalkyl groups contain 1 to 10 carbon atoms. In other embodiments, heteroalkyl groups contain 1 to 8 carbon atoms. In other embodiments, heteroalkyl groups contain 1. -6 carbon atoms, in other embodiments the heteroalkyl group contains 1-4 carbon atoms, in other embodiments the heteroalkyl group contains 1-3 carbon atoms.
- Such examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, CH 3 SCH 2 CH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, etc.
- halogen refers to F, Cl, Br or I.
- Halo as used in the present invention means substituting a subsequent group with a halogen, and the number of substitutions may be one or more.
- Hydro-substituted in the present invention means that the following groups are replaced with hydroxyl groups, and the number of substitutions can be one or more.
- substituted in the present invention is used between two groups, it is preceded by a substituent.
- aryl-substituted alkyl means that the alkyl group has an aryl substituent
- alkoxycarbonyl "Substituted alkyl” means an alkyl group having an alkoxycarbonyl substituent.
- substitution relationship is from left to right, such as "arylalkyl”, which represents an aryl-substituted alkyl group, and "alkoxyalkoxy”, which represents an alkoxy group. Substituted alkoxy.
- the present invention provides an eye drop, the composition of which is shown in Table 1.
- the preparation method is as follows:
- the vision examination uses the ETDR near visual acuity chart to test the patient's improvement in uncorrected near visual acuity (UCNVA).
- UNVA uncorrected near visual acuity
- mice C57BL/6J male mice were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., 40 mice were 8 months old and 10 mice were 8 weeks old.
- the administration method is eye drop administration with a pipette.
- the eye drop volume is 5 ⁇ L. Only the left eye is dropped.
- the administration frequency is once a day (QD) or three times a day (TID) according to the group. ), and the mouse lens elasticity was tested 28 days after administration.
- mice were killed by excessive carbon dioxide, and the eyeballs on the eye drop side were removed using ophthalmic tweezers. They were quickly placed in HBSS solution containing 95% O 2 and 5% CO 2. After three rinses, Venus scissors were used to remove the lens. Microforceps are used to remove the optic nerve, sclera, cornea, and retina in sequence under a stereoscope to obtain the lens, which is then soaked in HBSS;
- Preparation for shooting Prepare the slide and cover slip (weigh the weight, both are about 0.24g), place the slide under the stereoscope, and select a fixed position to place the lens and subsequent cover slip.
- Image acquisition Use a disposable pipette to suck out the lens from the HBSS solution and place it on a glass slide. After quickly absorbing the excess liquid, use the camera attached to the stereoscope to obtain the lens image (uncompressed lens image 1), and quickly transfer the lens to the glass slide. Place the lens on the lens from a fixed position, and acquire the lens image again (use the image after leaving it for 2 minutes as lens image 2).
- Lens elasticity value Lens perimeter in image 2 - Lens perimeter in image 1.
- lens elasticity values after 28 days of administration are shown in Table 4. From the statistical data, the lens elasticity of 8-month-old mice was significantly smaller than that of 8-week-old mice. In addition, compared with vehicle control group 3, prescription 2 was administered once a day or three times a day. Square 2 shows a strong lens elasticity improvement effect.
- the lens elasticity of 8-month-old mice is significantly weaker than that of 8-week-old mice, which can be used as a model of reduced lens elasticity.
- Prescription 2 eye drops administered once a day and three times a day can significantly improve the lens elasticity of 8-month-old mice, so it can be used for the prevention or treatment of presbyopia and ophthalmic diseases caused by reduced lens elasticity.
Abstract
本发明提供了一种甾体化合物在制备预防和/或治疗老花眼的药物中的应用。本发明提供的甾体化合物如式(I)所示,对老花眼具有治疗、减缓和预防效果,能够极大程度地减轻和/或治愈老花眼,提高视力清晰度。
Description
本发明属于化学医药技术领域,涉及一种甾体化合物在制备预防和/或治疗老花眼的药物中的应用。
老花眼又称老视眼(presbyopia),是一种随着年龄增长而引起晶状体硬化、眼部视力调节功能下降的生理状态。初期的表现症状为需要目标保持一定距离才能看得清,如果光线不足,近距离阅读会更加困难,并且这些状态会随着年龄的增大而持续加重。除了年龄因素以外,老花眼的发展还与屈光不正、身体素质、药物等因素相关。
目前治疗老花眼的主要手段有佩戴框架老花镜、佩戴角膜接触镜、角膜屈光术、巩膜屈光术以及和晶状体屈光手术等。2021年10月,美国食品和药物管理局(FDA)批准艾伯维(AbbVie)旗下公司艾尔建(Allergan)眼科药物Vuity(pilocarpine,毛果芸香碱,1.25%滴眼液)治疗老花眼。Vuity作为一种外用药物,每天滴入双眼1次,滴入眼睛后,15min能起效,且疗效持久,患者无需戴眼镜就能阅读,是第一种专门用于治疗老花眼的滴眼液,但其只能缓解其症状而不能彻底根治老花眼。因此,临床上亟需其他可以预防、缓解或治疗老花眼的药物。
发明内容
针对现有技术存在的不足,本发明的目的在于提供一种甾体化合物在制备预防和/或治疗老花眼的药物中的应用,本发明提供的甾体化合物能够对老花眼有很好的治疗、减缓和预防效果,能够极大程度的减轻和/或治愈老花眼,提高视力清晰度。
为达此目的,本发明采用以下技术方案:
第一方面,本发明提供了一种甾体化合物在制备预防和/或治疗老花眼的药物中的应用,所述甾体化合物为如式I所示结构的化合物,或为如式I所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药;
其中,R为H、D(氘)、烷基、硫酸基、磷酸基、烷基硅基、苄基或-C(O)-X;
X选自芳基、杂芳基、环烷基、杂环基、杂烷基或烷基;
R和X中所述芳基、杂芳基、环烷基、杂环基、杂烷基、烷基硅基和烷基任选地被1、2、3或4个相同或不同的取代基所取代;
所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、烷基羰基、烷基、卤代烷基、环烷基、杂环基、芳基、芳基烷基、杂芳基、羧基、R1R2NC(=O)-或R1R2NC(=NH)-NR3-;
R1、R2和R3各自独立地选自-H、-D或烷基。
在一些实施方案中,所述甾体化合物为如式II所示结构的化合物,或为如式II所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药;
其中R的定义同式(I)。
在一些实施方案中,R为H、D、C1-6烷基、硫酸基、磷酸基、C1-6烷基硅基、苄基或-C(O)-X。
在一些实施方案中,X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基或C1-6烷基。
在一些实施方案中,R和X中所述C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基、C1-6烷基硅基或C1-6烷基任选地被1、2、3或4个相同或不同的取代基所取代。
在一些实施方案中,所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、卤代C1-6烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C6-10芳基C1-6烷基、C2-9杂芳基、羧基(例如-COOH)、R1R2NC(=O)-或R1R2NC(=NH)-NR3-。
在一些实施方案中,R1、R2和R3各自独立地选自-H、-D或C1-6烷基。
在一些实施方案中,X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、
哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、带有H2NC(=O)-取代基的C1-3烷基或带有H2NC(=NH)-NH-取代基的C1-3烷基。
在一些实施方案中,R和X中所述取代基选自-H、-D、卤素、羟基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-9杂环基、C6-10芳基或C2-9杂芳基。
在另外一些实施方案中,R和X中所述取代基选自-H、-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。
作为本发明的一种具体实施方式,X选自如下任一基团:
作为本发明的一种具体实施方式,所述式I或II所示结构的化合物选自如下化合物中的任意一种:
本发明提供的甾体化合物可以作为未加工的化学药品用于治疗,也可以作为药物组合物的活性成分提供。
第二方面,本发明提供了组合物在制备预防和/或治疗老花眼的药物中的应用,所述组合物包括第一方面所述的甾体化合物,及药学上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。
可作为药学上可接受载体的物质包括,但并不限于,离子交换剂;铝;硬脂酸铝;卵磷脂;血清蛋白,如人血清蛋白;缓冲物质如磷酸盐;甘氨酸;山梨酸;山梨酸钾;饱和植物
脂肪酸的部分甘油酯混合物;水;盐;电解质,如硫酸鱼精蛋白;磷酸氢二钠;磷酸氢钾;氯化钠;锌盐;胶体硅;三硅酸镁;聚乙烯吡咯烷酮;聚丙烯酸脂;蜡;聚乙烯-聚氧丙烯-阻断聚合体;羊毛脂;糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
在一些实施方案中,所述组合物包括:本发明所述的甾体化合物、羟丙甲纤维素、泊洛沙姆407、泊洛沙姆188和水。
在一些实施方案中,所述组合物包括:10~40质量份本发明所述的甾体化合物、110~120质量份羟丙甲纤维素、2050~2060质量份泊洛沙姆407、160~170质量份泊洛沙姆188和10000质量份水。
在一些实施方案中,所述组合物可以是滴眼液。所述滴眼液可为混悬型滴眼液。本发明的一些方案中,所述滴眼液的规格可为10mL。
第三方面,本发明提供了一种预防和/或治疗老花眼的方法,包括向有需要的受试者施用第一方面所述的甾体化合物或者第二方面所述的组合物。
与现有技术相比,本发明具有以下有益效果:
本发明发现,本发明提供的甾体化合物可以改善晶状体的弹性,提高患者的近视力,可以用于预防、处理、治疗或减轻患者的老花眼,并且副作用极小,基本没有。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述具体实施方式仅仅是帮助理解本发明,不应视为对本发明的具体限制。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。
本发明所述的“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。如果
化合物含有一个双键,取代基可能为E或Z构型;如果化合物中含有二取代的环烷基,环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式I所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates andPhosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体,如,通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离,如,使用手性吸附剂的高效液相色谱(HPLC)。特别地,对映异构体可以通过不对称合成制备,例如,可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer)包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变
异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
本发明所提到的盐为药学上可接受的盐,其中“药学上可接受的盐”在所属领域是为我们所熟知的,如文献:Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。药学上可接受的非限定性的盐例子包括与氨基基团反应形成的无机酸盐,如有盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、硝酸盐、高氯酸盐,和有机酸盐,如羧酸盐、磺酸盐、亚磺酸盐、硫羧酸盐等,具体的如,但不限于,甲磺酸盐、乙磺酸盐、甲酸盐、乙酸盐、丁二酸盐、苯甲酸盐、琥珀酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、碳酸盐、三氟乙酸盐、羟基乙酸盐、羟乙基磺酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、富马酸盐、乳酸盐、乳糖酸盐或草酸,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、月桂酸盐、月桂基硫酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、十一酸盐、戊酸盐,等等。此外,药学上可接受的盐还包括通过适当的碱得到的盐,如碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。
可药用的盐可与无机酸和有机酸形成,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、
琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
“药物组合物”表示一种或多种本文所述化合物、盐或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物,其他组分例如生理学上/药学上可以接受的载体或赋形剂。药物组合物的目的是促进化合物对生物体的给药。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明使用的术语“烷基”表示1-20个碳原子,或1-10个碳原子,或1-8个碳原子,或1-6个碳原子,或1-4个碳原子,或1-3个碳原子的饱和直链或支链的单价烃基,其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代。烷基的实例包括,但并不限于,甲基(Me,-CH3),乙基(Et,-CH2CH3),正丙基(n-Pr,-CH2CH2CH3),异丙基(i-Pr,-CH(CH3)2),正丁基(n-Bu,-CH2CH2CH2CH3),异丁基(i-Bu,-CH2CH(CH3)2),仲丁基(s-Bu,-CH(CH3)CH2CH3),叔丁基(t-Bu,-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),正己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3),正庚基,正辛基,等等。术语“烷基”和其前缀“烷”在此处使用,都包含直链和支链的饱和碳链。术语“烷撑”在此处使用,表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基,这样的实例包括,但并不限于,亚甲基,次乙基,次异丙基等等。
术语“环烷基”是指一价或多价,非芳香族,饱和或部分不饱和的环,且不包含杂原子,其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5],[5,5],[5,6]或[6,6]体系,同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]
体系。合适的环状脂肪族基包括,但并不限于,环烷基,环烯基和环炔基。环状脂肪族基的实例包括,但绝不限于,环丙基,环丁基,环戊基,1-环戊基-1-烯基,1-环戊基-2-烯基,1-环戊基-3-烯基,环己基,1-环己基-1-烯基,1-环己基-2-烯基,1-环己基-3-烯基,环己二烯基,环庚基,环辛基,环壬基,环癸基,环十一烷基,环十二烷基等等。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,环烷基、杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O),烷基-C(=O),烷基-S(=O),烷基-S(=O)2-,羟基取代的烷基-S(=O),羟基取代的烷基-S(=O)2,羧基烷氧基等等。
术语“杂环”,“杂环基”,“杂脂环族”或“杂环的”在此处可交换使用,都是指单环,双环,或三环体系,其中环上一个或多个碳原子独立且任选地被杂原子所取代,所述杂原子具有如本发明所述的含义,环可以是完全饱和的或包含一个或多个不饱和度,但绝不是芳香族类,只有一个连接点连接到其他分子上去。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是,“杂环”,“杂环基”,“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO2,PO,PO2的基团,当所述的环为三元环时,其中只有一个杂原子),或7-10元的双环(4-9个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO2,PO,PO2的基团)。
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括,但并不限于,吡咯烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,四氢吡喃基,二氢吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,噻噁烷基,噻唑烷基,噁唑烷基,哌嗪基,高哌嗪基,氮杂环丁基,氧杂环丁基,硫杂环丁基,哌啶基,高哌啶基,环氧丙基,氮杂环庚基,氧杂环庚基,硫杂环庚基,4-甲氧基-哌啶-1-基,1,2,3,6-四氢吡啶-1-基,氧氮杂基,二氮杂基,硫氮杂基,吡咯啉-1-基,2-吡咯啉基,3-吡咯啉基,二氢吲哚基,2H-吡喃基,4H-吡喃基,二氧杂环己基,1,3-二氧戊基,吡唑啉基,二噻烷基,二噻茂烷基,二氢噻吩基,吡唑烷基咪唑啉基,咪唑烷基,1,2,3,4-四氢异喹啉基,1,2,6-噻二嗪烷1,1-二氧代-2-基,4-羟基-1,4-氮杂磷烷4-氧化物-1-基,2-羟基-1-(哌嗪-1-基)乙酮-4-基,2-羟基-1-(5,6-二氢-1,2,4-三嗪-1(4H)-基)乙酮-4-基,5,6-二氢-4H-1,2,4-噁二嗪-4-基,2-羟基-1-(5,6-二氢吡啶-1(2H)-基)乙酮-4-基,3-氮杂双环[3.1.0]己基,3-氮杂双环[4.1.0]庚基,氮杂双环[2.2.2]己基,2-甲基-5,6,7,8-四氢-[1,2,4]三唑[1,5-c]嘧啶-6-基,4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基,3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基,2-氧-5-氮杂双环[2.2.2]辛烷-5-基,喹嗪基和N-吡啶基尿素。杂环基团的实例还包括,1,1-二氧代硫代吗啉基,和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是
取代或未取代的,其中取代基可以是,但并不限于,氧代(=O),羟基,氨基,卤素,氰基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O),烷基-C(=O),烷基-S(=O),烷基-S(=O)2-,羟基取代的烷基-S(=O),羟基取代的烷基-S(=O)2,羧基烷氧基等等。
术语“芳基”可以单独使用或作为“芳烷基”,“芳烷氧基”或“芳氧基烷基”的一大部分,表示共含有6-14元环的单环,双环,和三环的碳环体系,其中,至少一个环体系是芳香族的,其中每一个环体系包含3-7元环,且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用,如芳香环可以包括苯基,萘基和蒽基。并且所述芳基可以是取代或未取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O),烷基-C(=O),烷基-S(=O),烷基-S(=O)2-,羟基取代的烷基-S(=O),羟基取代的烷基-S(=O)2,羧基烷氧基,等等。
术语“杂芳基”表示共含有5-14元环的单环,双环,和三环体系,其中至少一个环体系是芳香族的,且至少一个环体系包含一个或多个杂原子,其中杂原子具有本发明所述的含义,其中每一个环体系包含3-7元环,且只有一个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷氨基,烷基,烯基,炔基,环烷基,杂环基,巯基,硝基,芳氧基,羟基取代的烷氧基,羟基取代的烷基-C(=O)-,烷基-C(=O)-,烷基-S(=O)-,烷基-S(=O)2-,羟基取代的烷基-S(=O)-,羟基取代的烷基-S(=O)2-,羧基烷氧基等等。
另外一些实施方案是,杂芳基包括以下的单环,但并不限于这些单环:2-呋喃基,3-呋喃基,N-咪唑基,2-咪唑基,4-咪唑基,5-咪唑基,3-异噁唑基,4-异噁唑基,5-异噁唑基,2-噁唑基,4-噁唑基,5-噁唑基,4-甲基异噁唑-5-基,N-吡咯基,2-吡咯基,3-吡咯基,2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,4-嘧啶基,嘧啶-5-基,哒嗪基(如3-哒嗪基),2-噻唑基,4-噻唑基,5-噻唑基,四唑基(如5-四唑基),三唑基(如2-三唑基和5-三唑基),2-噻吩基,3-噻吩基,吡唑基(如2-吡唑基),异噻唑基,1,2,3-噁二唑基,1,2,5-噁二唑基,1,2,4-噁二唑基,1,2,3-三唑基,1,2,3-硫代二唑基,1,3,4-硫代二唑基,1,2,5-硫代二唑基,1,3,4-噻二唑-2-基,吡嗪基,吡嗪-2-基,1,3,5-三嗪基;也包括以下的双环,但绝不限于这些双环:苯并咪唑基,苯并呋喃基,苯并噻吩基,吲哚基(如2-吲哚基),嘌呤基,喹啉基(如2-喹啉基,3-喹啉基,4-喹啉基),和异喹啉基(如1-异喹啉基,3-异喹啉基或4-异喹啉基),苯并[d]噻唑-2-基,咪唑并[1,5-a]吡啶-6-基。
术语“杂原子”表示一个或多个O,S,N,P和Si原子,包括N,S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(例如3,4-二氢-2H-吡咯基中的N),NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中
的NR)。
术语“杂烷基”表示烷基链中间可以插入一个或多个杂原子,其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明,杂烷基基团含有1-10个碳原子,另外一些实施方案是,杂烷基基团含有1-8个碳原子,另外一些实施方案是,杂烷基基团含有1-6个碳原子,另外一些实施方案是,杂烷基基团含有1-4个碳原子,另外一些实施方案是,杂烷基基团含有1-3个碳原子。这样的实例包括,但并不限于,CH3OCH2-,CH3CH2OCH2-,CH3SCH2-,CH3SCH2CH2-,(CH3)2NCH2-,(CH3)2CH2OCH2-,CH3OCH2CH2-,CH3CH2OCH2CH2-等。
术语“卤素”是指F,Cl,Br或I。
本发明所述的“卤代”表示用卤素取代其后接的基团,取代的个数可以是一个或多个。
本发明所述的“羟基取代的”表示用羟基取代其后接的基团,取代的个数可以是一个或多个。
本发明所述的“取代的”用于两个基团之间时,则其前面为取代基,如“芳基取代的烷基”表示烷基上具有芳基取代基,“烷氧基羰基取代的烷基”表示烷基上具有烷氧基羰基取代基。
当本发明多个基团联合使用时,从左到右,依次为取代关系,如“芳基烷基”,表示芳基取代的烷基,“烷氧基烷氧基”,表示烷氧基取代的烷氧基。
实施例1
本发明提供了一种滴眼液,组成如表1所示。
表1
制备方法如下:
在无菌操作下,将上述成分混合,于2-8℃搅拌过夜,得到均一混合液后,在眼药瓶中保存。
实施例2老花效果测试方法
招募患有老花的患者,在签署了知情同意书之后,每日施用按照实施例1制备的滴眼液,一日四次,每次每只眼睛滴入1滴,连续给药8周。在给药前(V1,基线),给药后的2周(V2)、4周(V3)和8周(V4),进行视力检查,监测患者的老花改善/治疗情况。
视力检查采用ETDR近视力表,测试患者的裸眼近视力(UCNVA)改善情况。
测试结果列于下表2中。
表2
从表2的结果可以看出,不同程度的老花眼患者在连续使用滴眼液8周后,老花症状有了很大的改善,裸眼近视力平均提高了13个左右字母数。这些结果表明本发明的滴眼液对老花眼患者有良好的治疗效果,且安全方便。
实施例3小鼠晶状体弹性测试试验
1,动物和仪器
1)实验动物
C57BL/6J雄性小鼠,购买自浙江维通利华实验动物技术有限公司,40只8月龄和10只8周龄。
2)实验器械和仪器
表3.实验主要仪器
2,实验方法过程
1),给药:给药方式为移液枪滴眼给药,滴眼体积均为5μL,仅滴左眼,根据组别给药频次为每日一次(QD),或者每日三次(TID),给药28天后测试小鼠晶状体弹性。
2),晶状体弹性测试
晶状体取材:通过过量二氧化碳处死小鼠,使用眼科镊摘取滴眼侧眼球,快速置于通有95%O2,5%CO2的HBSS溶液中,三次冲洗后,使用维纳斯剪和显微镊在体式镜下依次去除视神经、巩膜、角膜、视网膜,得到晶状体,并浸泡在HBSS中;
拍摄准备:准备载玻片和盖玻片(称取重量,均约为0.24g),将载玻片置于体视镜下,选取固定位置放置晶状体和随后的盖玻片。
图像采集:使用一次性吸管将晶状体从HBSS溶液中吸出,放置于载玻片上,快速吸取多余液体后,使用体式镜配套的相机获取晶状体图像(未经压缩的晶状体图像1),快速将载玻片从固定位置置在晶状体上,再次获取晶状体图像(使用放置2分钟后的图像作为晶状体图像2)。
数据分析:使用Excel软件收集数据。使用Prism(Graph pad software,Inc.)软件进行数据分析,各组之间晶状体弹性值比较使用单因素方差分析附加Sidak比较检验数据,p<0.05认为是有显著性差异。
计算公式:晶状体弹性值=图像2的晶状体周长-图像1的晶状体周长。
3,实验结果
在本实验中,我们评价了实施例1中的处方2在老年C57BL/6小鼠自发晶状体弹性降低模型中的药效。
给药28天后的晶状体弹性值统计如表4所示。从统计数据值来看,8月龄小鼠的晶状体弹性均显著小于8周龄小鼠,此外,相较于溶媒对照组3,处方2每天一次或每天三次处
方2显示出很强的晶状体弹性改善效果。
表4:给药四周后晶状体弹性变化值
4,结论
总体而言,8月龄小鼠的晶状体弹性显著弱于8周龄小鼠,可作为晶状体弹性降低模型。每日1次和每日三次给予处方2滴眼液能明显提高8月龄小鼠的晶状体弹性,因此可用于老花以及晶状体弹性降低引起的眼科疾病预防或治疗。
虽然,上文中已经用一般性说明、具体实施方式及试验,对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (11)
- 甾体化合物在制备预防和/或治疗老花眼的药物中的应用,其特征在于,所述甾体化合物为如式(I)所示结构的化合物,或为式(I)所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药;
其中,R为H、D、烷基、硫酸基、磷酸基、烷基硅基、苄基或-C(O)-X;X选自芳基、杂芳基、环烷基、杂环基、杂烷基或烷基;R和X中所述芳基、杂芳基、环烷基、杂环基、杂烷基、烷基硅基和烷基任选地被1、2、3或4个相同或不同的取代基所取代;所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、烷基羰基、烷基、卤代烷基、环烷基、杂环基、芳基、芳基烷基、杂芳基、羧基、R1R2NC(=O)-或R1R2NC(=NH)-NR3-;R1、R2和R3各自独立地选自H、D或烷基。 - 根据权利要求1所述的应用,其中,所述甾体化合物为如式(II)所示结构的化合物或为式(II)所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药,
其中R的定义同式(I)。 - 根据权利要求1所述的应用,其中,R为H、D、C1-6烷基、硫酸基、磷酸基、C1-6 烷基硅基、苄基或-C(O)-X;X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基或C1-6烷基;R和X中所述C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基、C1-6烷基硅基或C1-6烷基任选地被1、2、3或4个相同或不同的取代基所取代;所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、卤代C1-6烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C6-10芳基C1-6烷基、C2-9杂芳基、羧基、R1R2NC(=O)-或R1R2NC(=NH)-NR3-;R1、R2和R3各自独立地选自H、D或C1-6烷基。
- 根据权利要求1-3任一项所述的应用,其特征在于,X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、 带有H2NC(=O)-取代基的C1-3烷基或带有H2NC(=NH)-NH-取代基的C1-3烷基。
- 根据权利要求1-4任一项所述的应用,其特征在于,所述取代基选自-D、卤素、羟基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-9杂环基、C6-10芳基或C2-9杂芳基。
- 根据权利要求1-5任一项所述的应用,其特征在于,所述取代基选自-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢 吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。
- 根据权利要求1-6任一项所述的应用,其特征在于,X选自如下任一基团:
- 根据权利要求1所述的应用,其特征在于,所述式I所示结构的化合物选自如下化合物中的任意一种:
- 组合物在制备预防和/或治疗老花眼的药物中的应用,其特征在于,所述组合物包括权利要求1-8中的任一项所述的甾体化合物,及药学上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。
- 根据权利要求9所述的应用,其特征在于,所述组合物包括:甾体化合物、羟丙甲纤维素、泊洛沙姆407、泊洛沙姆188和水;可选地,所述组合物包括:10~40质量份甾体化合物、110~120质量份羟丙甲纤维素、2050~2060质量份泊洛沙姆407、160~170质量份泊洛沙姆188和10000质量份水。
- 一种预防和/或治疗老花眼的方法,包括向有需要的受试者施用权利要求1-10中任一项所述应用中限定的甾体化合物或者组合物。
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