CN111757750A - 用于预防和治疗眼病的中性内肽酶(nep)及人类可溶性内肽酶(hsep)的抑制剂 - Google Patents
用于预防和治疗眼病的中性内肽酶(nep)及人类可溶性内肽酶(hsep)的抑制剂 Download PDFInfo
- Publication number
- CN111757750A CN111757750A CN201980011177.2A CN201980011177A CN111757750A CN 111757750 A CN111757750 A CN 111757750A CN 201980011177 A CN201980011177 A CN 201980011177A CN 111757750 A CN111757750 A CN 111757750A
- Authority
- CN
- China
- Prior art keywords
- glaucoma
- treatment
- prevention
- macular
- dystrophy
- 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.)
- Pending
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 33
- 230000002265 prevention Effects 0.000 title claims abstract description 30
- 102000003729 Neprilysin Human genes 0.000 title abstract description 16
- 108090000028 Neprilysin Proteins 0.000 title abstract description 16
- 102000005593 Endopeptidases Human genes 0.000 title abstract description 7
- 108010059378 Endopeptidases Proteins 0.000 title abstract description 7
- 208000022873 Ocular disease Diseases 0.000 title abstract description 7
- 239000003112 inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- -1 phosphono-substituted benzazepines Chemical class 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 208000010412 Glaucoma Diseases 0.000 claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 201000010099 disease Diseases 0.000 claims description 21
- 208000030533 eye disease Diseases 0.000 claims description 21
- 208000014674 injury Diseases 0.000 claims description 17
- 230000008733 trauma Effects 0.000 claims description 17
- 230000004438 eyesight Effects 0.000 claims description 15
- 208000029257 vision disease Diseases 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 208000001344 Macular Edema Diseases 0.000 claims description 10
- 206010025415 Macular oedema Diseases 0.000 claims description 10
- 206010046851 Uveitis Diseases 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 10
- 201000004949 exfoliation syndrome Diseases 0.000 claims description 10
- 201000010230 macular retinal edema Diseases 0.000 claims description 10
- 230000002207 retinal effect Effects 0.000 claims description 10
- 230000002269 spontaneous effect Effects 0.000 claims description 10
- 201000007790 vitelliform macular dystrophy Diseases 0.000 claims description 10
- 201000006321 fundus dystrophy Diseases 0.000 claims description 9
- 210000001525 retina Anatomy 0.000 claims description 9
- 208000010038 Ischemic Optic Neuropathy Diseases 0.000 claims description 8
- 208000021921 corneal disease Diseases 0.000 claims description 8
- 230000002980 postoperative effect Effects 0.000 claims description 8
- 210000001927 retinal artery Anatomy 0.000 claims description 8
- 239000002464 receptor antagonist Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 208000002780 macular degeneration Diseases 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 claims description 5
- 208000003569 Central serous chorioretinopathy Diseases 0.000 claims description 5
- 208000005590 Choroidal Neovascularization Diseases 0.000 claims description 5
- 206010060823 Choroidal neovascularisation Diseases 0.000 claims description 5
- 208000002691 Choroiditis Diseases 0.000 claims description 5
- 206010018325 Congenital glaucomas Diseases 0.000 claims description 5
- 201000001353 Doyne honeycomb retinal dystrophy Diseases 0.000 claims description 5
- 206010074026 Exfoliation glaucoma Diseases 0.000 claims description 5
- 208000037312 Familial drusen Diseases 0.000 claims description 5
- 206010022557 Intermediate uveitis Diseases 0.000 claims description 5
- 206010022941 Iridocyclitis Diseases 0.000 claims description 5
- 206010025412 Macular dystrophy congenital Diseases 0.000 claims description 5
- 206010067013 Normal tension glaucoma Diseases 0.000 claims description 5
- 208000016113 North Carolina macular dystrophy Diseases 0.000 claims description 5
- 206010069385 Ocular ischaemic syndrome Diseases 0.000 claims description 5
- 206010030348 Open-Angle Glaucoma Diseases 0.000 claims description 5
- 208000003435 Optic Neuritis Diseases 0.000 claims description 5
- 206010061323 Optic neuropathy Diseases 0.000 claims description 5
- 208000003971 Posterior uveitis Diseases 0.000 claims description 5
- 206010064714 Radiation retinopathy Diseases 0.000 claims description 5
- 206010038848 Retinal detachment Diseases 0.000 claims description 5
- 208000017442 Retinal disease Diseases 0.000 claims description 5
- 208000014139 Retinal vascular disease Diseases 0.000 claims description 5
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims description 5
- 206010038923 Retinopathy Diseases 0.000 claims description 5
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 5
- 206010038935 Retinopathy sickle cell Diseases 0.000 claims description 5
- 206010039705 Scleritis Diseases 0.000 claims description 5
- 206010043189 Telangiectasia Diseases 0.000 claims description 5
- 208000002903 Thalassemia Diseases 0.000 claims description 5
- 208000025531 adult-onset foveomacular vitelliform dystrophy Diseases 0.000 claims description 5
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 5
- 201000004612 anterior uveitis Diseases 0.000 claims description 5
- 208000007474 aortic aneurysm Diseases 0.000 claims description 5
- 230000010339 dilation Effects 0.000 claims description 5
- 230000001631 hypertensive effect Effects 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 201000002978 low tension glaucoma Diseases 0.000 claims description 5
- 230000003211 malignant effect Effects 0.000 claims description 5
- 201000003142 neovascular glaucoma Diseases 0.000 claims description 5
- 208000020911 optic nerve disease Diseases 0.000 claims description 5
- 201000007407 panuveitis Diseases 0.000 claims description 5
- 201000004616 primary angle-closure glaucoma Diseases 0.000 claims description 5
- 201000006672 primary congenital glaucoma Diseases 0.000 claims description 5
- 201000006366 primary open angle glaucoma Diseases 0.000 claims description 5
- 230000004264 retinal detachment Effects 0.000 claims description 5
- 210000001957 retinal vein Anatomy 0.000 claims description 5
- 208000009056 telangiectasis Diseases 0.000 claims description 5
- 201000006397 traumatic glaucoma Diseases 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 208000020941 Benign concentric annular macular dystrophy Diseases 0.000 claims description 4
- 206010010996 Corneal degeneration Diseases 0.000 claims description 4
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 4
- 206010018341 Gliosis Diseases 0.000 claims description 4
- 208000032578 Inherited retinal disease Diseases 0.000 claims description 4
- 201000002287 Keratoconus Diseases 0.000 claims description 4
- 208000002720 Malnutrition Diseases 0.000 claims description 4
- 206010030113 Oedema Diseases 0.000 claims description 4
- 206010030924 Optic ischaemic neuropathy Diseases 0.000 claims description 4
- 206010073286 Pathologic myopia Diseases 0.000 claims description 4
- 208000032430 Retinal dystrophy Diseases 0.000 claims description 4
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 claims description 4
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 208000034698 Vitreous haemorrhage Diseases 0.000 claims description 4
- 208000034700 Vitreous opacities Diseases 0.000 claims description 4
- 238000005299 abrasion Methods 0.000 claims description 4
- 201000007058 anterior ischemic optic neuropathy Diseases 0.000 claims description 4
- 208000037875 astrocytosis Diseases 0.000 claims description 4
- 230000007341 astrogliosis Effects 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 201000004573 corneal ectasia Diseases 0.000 claims description 4
- 208000001309 degenerative myopia Diseases 0.000 claims description 4
- 230000004340 degenerative myopia Effects 0.000 claims description 4
- 230000009977 dual effect Effects 0.000 claims description 4
- 230000003511 endothelial effect Effects 0.000 claims description 4
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 208000017532 inherited retinal dystrophy Diseases 0.000 claims description 4
- 238000002430 laser surgery Methods 0.000 claims description 4
- 230000001071 malnutrition Effects 0.000 claims description 4
- 235000000824 malnutrition Nutrition 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 208000001491 myopia Diseases 0.000 claims description 4
- 230000004379 myopia Effects 0.000 claims description 4
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 201000000041 pigment dispersion syndrome Diseases 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 238000001356 surgical procedure Methods 0.000 claims description 4
- 231100000397 ulcer Toxicity 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 238000002681 cryosurgery Methods 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims description 2
- 229930182837 (R)-adrenaline Natural products 0.000 claims description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 2
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 claims description 2
- 229930003347 Atropine Natural products 0.000 claims description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 2
- 108010036949 Cyclosporine Proteins 0.000 claims description 2
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 2
- 206010013774 Dry eye Diseases 0.000 claims description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical class O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 2
- 102000035195 Peptidases Human genes 0.000 claims description 2
- 108091005804 Peptidases Proteins 0.000 claims description 2
- 239000004365 Protease Substances 0.000 claims description 2
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 108010059993 Vancomycin Proteins 0.000 claims description 2
- AQLVRTWKJDTWQQ-SDBHATRESA-N [(2r,3s,4r,5r)-5-[6-(cyclopentylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl nitrate Chemical compound O[C@@H]1[C@H](O)[C@@H](CO[N+]([O-])=O)O[C@H]1N1C2=NC=NC(NC3CCCC3)=C2N=C1 AQLVRTWKJDTWQQ-SDBHATRESA-N 0.000 claims description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 2
- 229960004373 acetylcholine Drugs 0.000 claims description 2
- 229960002964 adalimumab Drugs 0.000 claims description 2
- 239000002582 adenosine A1 receptor agonist Substances 0.000 claims description 2
- 239000000048 adrenergic agonist Substances 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 claims description 2
- 229960000396 atropine Drugs 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 229940097320 beta blocking agent Drugs 0.000 claims description 2
- 229960002470 bimatoprost Drugs 0.000 claims description 2
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 2
- 229960003065 bosentan Drugs 0.000 claims description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 claims description 2
- 229960003679 brimonidine Drugs 0.000 claims description 2
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 229960004342 cetirizine hydrochloride Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229960001265 ciclosporin Drugs 0.000 claims description 2
- 239000003246 corticosteroid Substances 0.000 claims description 2
- 229960001334 corticosteroids Drugs 0.000 claims description 2
- 229930182912 cyclosporin Natural products 0.000 claims description 2
- 229940127089 cytotoxic agent Drugs 0.000 claims description 2
- 229960003957 dexamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone 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-CXSFZGCWSA-N 0.000 claims description 2
- 229960005139 epinephrine Drugs 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 2
- 229960004752 ketorolac Drugs 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 239000002840 nitric oxide donor Substances 0.000 claims description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 2
- 229940101267 panthenol Drugs 0.000 claims description 2
- 239000011619 pantothenol Substances 0.000 claims description 2
- 235000020957 pantothenol Nutrition 0.000 claims description 2
- 239000000734 parasympathomimetic agent Substances 0.000 claims description 2
- 230000001499 parasympathomimetic effect Effects 0.000 claims description 2
- 229940005542 parasympathomimetics Drugs 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229950009215 phenylbutanoic acid Drugs 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- 229960001416 pilocarpine Drugs 0.000 claims description 2
- 229960003876 ranibizumab Drugs 0.000 claims description 2
- 230000001172 regenerating effect Effects 0.000 claims description 2
- 229940108325 retinyl palmitate Drugs 0.000 claims description 2
- 239000011769 retinyl palmitate Substances 0.000 claims description 2
- 235000019172 retinyl palmitate Nutrition 0.000 claims description 2
- 239000003590 rho kinase inhibitor Substances 0.000 claims description 2
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 claims description 2
- 229960002578 sitaxentan Drugs 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229960004605 timolol Drugs 0.000 claims description 2
- 229950000854 trabodenoson Drugs 0.000 claims description 2
- 229960003165 vancomycin Drugs 0.000 claims description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 2
- 239000002525 vasculotropin inhibitor Substances 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 150000003751 zinc Chemical class 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims 2
- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 claims 1
- 208000036443 AIPL1-related retinopathy Diseases 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 208000035719 Maculopathy Diseases 0.000 claims 1
- 208000027073 Stargardt disease Diseases 0.000 claims 1
- 201000006754 cone-rod dystrophy Diseases 0.000 claims 1
- 239000006185 dispersion Substances 0.000 claims 1
- 230000004761 fibrosis Effects 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 230000000642 iatrogenic effect Effects 0.000 claims 1
- 208000023343 iris disease Diseases 0.000 claims 1
- 230000000302 ischemic effect Effects 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 1
- 210000004127 vitreous body Anatomy 0.000 claims 1
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 abstract description 10
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical class S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 abstract description 3
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical class O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 3
- 150000008038 benzoazepines Chemical class 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 22
- 230000006907 apoptotic process Effects 0.000 description 19
- 229960004679 doxorubicin Drugs 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 108050009340 Endothelin Proteins 0.000 description 8
- 102000002045 Endothelin Human genes 0.000 description 8
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 210000003994 retinal ganglion cell Anatomy 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 210000001508 eye Anatomy 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 241000282412 Homo Species 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 5
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940044551 receptor antagonist Drugs 0.000 description 5
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 4
- 102400001282 Atrial natriuretic peptide Human genes 0.000 description 4
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 4
- 206010052428 Wound Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 210000003733 optic disk Anatomy 0.000 description 4
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 3
- 102400000686 Endothelin-1 Human genes 0.000 description 3
- 101800004490 Endothelin-1 Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000004410 intraocular pressure Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004386 ocular blood flow Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HZZGDPLAJHVHSP-GKHTVLBPSA-N big endothelin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]2CSSC[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CSSC1)C1=CN=CN1 HZZGDPLAJHVHSP-GKHTVLBPSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 230000004406 elevated intraocular pressure Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000002227 vasoactive effect Effects 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- CNJLMVZFWLNOEP-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[4.1.0]heptan-5-one Chemical compound O=C1C(C)CCC2C(C)(C)C12 CNJLMVZFWLNOEP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102100034283 Annexin A5 Human genes 0.000 description 1
- 108010006835 Atrial Natriuretic Factor Receptors Proteins 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 1
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 description 1
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 1
- 241000131458 Elsholtzia Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000006219 Matteson homologation reaction Methods 0.000 description 1
- 206010027202 Meningitis bacterial Diseases 0.000 description 1
- 206010027260 Meningitis viral Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000014171 Milk Proteins Human genes 0.000 description 1
- 108010011756 Milk Proteins Proteins 0.000 description 1
- 101100379123 Mus musculus Npr1 gene Proteins 0.000 description 1
- 241000450412 Nierembergia repens Species 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 208000034777 Vitreous degeneration Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 201000009904 bacterial meningitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 229940066758 endopeptidases Drugs 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000002592 gangliocyte Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 201000011475 meningoencephalitis Diseases 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 235000021239 milk protein Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 201000010044 viral meningitis Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 201000011288 vitreous syneresis Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- 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
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及同时具有中性内肽酶(NEP)和/或人类可溶性内肽酶(hSEP)及内皮素转化酶(ECE)抑制活性的苯并氮杂
苯并氧氮杂
苯并硫氮杂
‑N‑乙酸以及膦酰基取代的苯并氮杂
Description
发明领域
本说明书描述的是内皮素转化酶-1(ECE-1)及中性内肽酶(NEP)和/或人类可溶性内肽酶(hSEP)单独的双重抑制剂，以及其组合物，条件是所述的药物组合物可以任选包含如下一种或多种或不包含其中任一成分：碳酸酐酶抑制剂，例如布林唑胺，α2-肾上腺素激动剂，例如溴莫尼定，β-阻断剂，例如噻吗洛尔，前列腺素类似物，例如比马前列素，rho激酶抑制剂，例如奈妥舒迪(netarsudil)，腺苷A1受体激动剂，例如trabodenoson，ETA内皮素受体拮抗剂，例如西他生坦，双重内皮素受体拮抗剂，例如波生坦，一氧化氮供体，例如丁二醇，拟副交感神经药，例如毛果芸香碱、乙酰胆碱，儿茶酚胺类，例如肾上腺素，毒蕈碱型受体拮抗剂，例如阿托平，血管内皮生长因子抑制剂，例如雷珠单抗，皮质类固醇，例如地塞米松，抗生素，例如万古霉素，组织再生剂，例如聚羧甲基葡萄糖，维生素及维生素原，例如泛醇及棕榈酸视黄酯，化学治疗剂，例如丝裂霉素，非甾类抗炎药，例如酮咯酸，H1受体拮抗剂，例如盐酸西替利嗪，单克隆抗体，例如阿达木单抗，蛋白酶，例如奥克纤溶酶，免疫抑制剂，例如环孢素，用于预防和/或治疗眼病。
发明科学背景
眼内压升高及眼部血流量减少是人类青光眼的主要危险因子。青光眼是最常见的视神经头神经病变，并且在形态学上于失去视网膜神经节细胞相关且在临床上与视野恶化相关。青光眼的治疗以降低眼内压并防止视神经病变的发生或进展为基础。目前尚无治疗方法可用于青光眼期间缓和眼部血流量变化，或限制在青光眼的过程中细胞凋亡方式的视网膜神经节细胞的死亡(B.C.Chauhan(2008)Can.J.Ophthalmol.43，356–360)。
内皮素是目前为止已知人体中最有效的血管活性肽。如同“血管活性肽”一词所意味，此肽通过血管收缩剂活性参与眼内血压的调控。内皮素一经释放会造成眼部血流量减少，接着引起视网膜及视神经头的病变。
内皮素除了其血管收缩剂活性外，还通过影响小梁外流来参与眼内压力的调控。小梁外流是流体流出眼睛的主要途径。内皮素增加小梁网的收缩性，因此减少眼睛的流体流出，使眼压提升，接着出现视网膜及视神经头的病变。
内皮素除了影响眼内血压及调控眼内流体压力外，还通过ETB受体起作用影响视网膜神经节细胞的细胞凋亡，以及通过ETA受体与ETB受体起作用诱导人类视神经头星形胶质细胞的增殖(G.Prasanna，R.Krishnamoorthy，A.F.Clark，R.J.Wordinger&T.Yorio(2002)Invest.Ophthalmol.Vis.Sci.43，2704-2713)。
内皮素为一种由21种氨基酸组成的肽，此种肽由内皮细胞合成并释放。内皮素由断裂前体肽大内皮素(Big ET-1)中的Trp-Val键而产生。内皮素转化酶-1(ECE-1)为一种膜结合的金属蛋白酶，催化大内皮素-1(Big ET-1)的蛋白水解活化成为ET-1，并构成控制活性肽产生的调控点。
中性内肽酶(NEP)为一种含锌的金属肽酶，降解心钠肽(ANP)并构成控制活性肽浓度的调控点。在血清剥除性嗜铬细胞瘤细胞中，ANP通过使cGMP提升来抑制细胞凋亡。皮质中传播性抑制后，接着是ANP表达与细胞内cGMP浓度的长时间持续升高。利钠肽受体NPrA通过刺激活化cGMP依赖性蛋白激酶G路径的颗粒鸟苷酸环化酶(pGC)来调控细胞内cGMP浓度。
由于已报导ET-1受体的上调与ANP受体的下调发生于受到代谢或氧化损伤的细胞中，这促使我们探讨双重ECE/NEP抑制对于经历细胞凋亡的啮齿动物细胞的影响，该细胞凋亡类似于在患眼科疾病期间例如在患青光眼期间人类中所报导的细胞凋亡。
发明内容
本发明涉及具有中性内肽酶(NEP)和/或人类可溶性内肽酶(hSEP)的抑制活性的苯并氮杂
苯并氧氮杂
苯并硫氮杂
-N-乙酸以及膦酰基取代的苯并氮杂
酮衍生物的新用途。本发明的化合物可用于制备用于预防及治疗眼病的药物组合物。
本发明涉及专利EP1706121B1中所揭露的化合物用于制造产生有益效果的药物的用途。有益效果公开在本说明书中或根据本说明书及本领域的公常知识对本领域技术人员而言是明显的。本发明还涉及本发明的化合物用于制造用于治疗或预防疾病或状况的药物的用途。更特别而言，本发明涉及一种治疗疾病或状况的新用途，该疾病或状况公开在本说明书中或根据本说明书及本领域的公常知识对本领域技术人员而言是明显的。本发明的实施方案中将本说明书中所公开的特定化合物用于制造药物。
EP1706121B1涉及对中性内肽酶和/或人类可溶性内肽酶(hSEP)及内皮素转化酶(ECE)具有抑制活性的某些化合物的用途，用于治疗和/或预防神经变性疾病，例如外伤性脑损伤、急性弥漫性脑脊髓炎、癫痫相关脑部损伤、脊髓损伤、细菌性或病毒性脑膜炎和脑膜脑炎、普里昂病、神经毒性化合物中毒以及辐射诱发脑部损伤，以及用于预防缺血性中风，条件是所述药物组合物不包含醛固酮受体拮抗剂。
2004年3月18日提交且于2004年9月30日公开的WO2004/082637揭露了一种用于预防或治疗数量巨大的病理状况的方法，它包含给予醛固酮受体拮抗剂以及ECE抑制剂。所列的病理状况中有青光眼、高血压或糖尿病视网膜病变及眼内压升高。然而，没有公开关于优选化合物在这些适应症中的益处。
本发明的目标为鉴别特定的金属蛋白酶抑制剂，当在不含醛固酮受体拮抗剂的药物组合物中被施用时，它们具有治疗价值。
令人惊讶的是，现在发现具有中性内肽酶(NEP)及人类可溶性内肽酶(hSEP)的抑制活性的苯并氮杂
苯并氧氮杂
苯并硫氮杂
-N-乙酸以及膦酰基取代的苯并氮杂
酮衍生物阻止了啮齿动物模型中的细胞凋亡，该细胞凋亡类似于在人类中眼病过程中的细胞凋亡。此性质使该些化合物可用于治疗和/或预防视力和/或眼睛疾病和/或制备用于治疗和/或预防视力和/或眼睛疾病的药物组合物，所述的视力和/或眼睛疾病选自由下述疾病组成的组：例如(i)所有形式的原发性青光眼与继发性青光眼，优选例如原发性开角型青光眼、正常张力青光眼、原发性闭角型青光眼、假表皮脱落综合征与青光眼、色素分散综合征与青光眼、新生血管性青光眼、炎性青光眼晶状体相关青光眼、创伤性青光眼、原发性先天青光眼、医源性诱发青光眼以及恶性青光眼；(ii)获得性黄斑障碍，优选例如年龄相关性黄斑变性、自发性脉络膜新血管发生、中心浆液性脉络膜视网膜病变、玻璃体界面障碍、自发性黄斑毛细血管扩张、囊状黄斑水肿以及微囊状黄斑水肿；(iii)视神经病变，优选例如前部或后部缺血性视神经病变；(iv)视神经炎；(v)葡萄膜炎，优选例如前葡萄膜炎、中葡萄膜炎、后葡萄膜炎以及全葡萄膜炎；(vi)遗传性眼底营养不良，优选例如色素性视网膜炎、视网膜色素变性、锥体营养不良、锥体-视网膜杆营养不良、视网膜杆营养不良、施塔加特病、Bietti晶状体角膜视网膜营养不良、家族性良性斑点视网膜、贝斯特氏卵黄样黄斑营养不良、成年发病卵黄样黄斑营养不良、北卡罗来纳黄斑营养不良、家族性显性脉络膜小疣以及同心环形黄斑营养不良；(vii)视网膜血管疾病，优选例如糖尿病视网膜病变、非糖尿病视网膜病变、视网膜静脉闭塞性疾病、视网膜动脉闭塞性疾病、眼缺血综合征、高血压眼病、镰状细胞视网膜病变、地中海贫血视网膜病变、早产儿视网膜病变、视网膜动脉大动脉瘤、原发性视网膜毛细血管扩张、伊尔斯病以及辐射性视网膜病变；(viii)巩膜炎以及巩膜外层炎；(ix)视网膜脱离；(x)眼球创伤；(xi)玻璃体混浊，优选例如玻璃体出血以及星状玻璃体变性；(xii)近视以及变性近视；(xiii)手术后创伤，优选例如由常规手术造成的机械创伤、由激光手术造成的热创伤以及冷冻手术诱导的创伤；(xiv)干眼病；(xv)角膜疾病，优选例如擦伤、撕裂、溃疡、营养不良、混浊、内皮与上皮代偿失调、手术后水肿、角膜退化、角膜血管形成；以及角膜扩张，优选例如圆锥角膜。
从欧洲专利EP0733642、EP0916679及EP1468010中已知本发明的化合物，包含详细的合成，可以用通式(1)表示本发明的化合物：
其中：
R1代表式(2)或式(3)的基团：
A表示CH2、O或S，
R2与R3独立地表示氢或卤素，
R4与R6独立地表示氢或形成生物不稳定羧酸酯的基团，
R5选自由可以被(C1-C6)-烷氧基取代的(C1-C6)-烷氧基-(C1-C6)-烷基，苯基-(C1-C6)-烷基及苯氧基-(C1-C6)-烷基，其中苯基可以被(C1-C6)-烷基、(C1-C6)-烷氧基或卤素取代，以及萘基-(C1-C6)-烷基组成的组，
R7与R8独立地表示氢或形成生物不稳定膦酸酯的取代基。
所有具有通式(1)的化合物、外消旋体、非对映异构体的混合物以及单独的立体异构体，也包含其药学上可接受的盐，皆属于本发明。因此，在潜在不对称碳原子上的取代基为R-构型或S-构型的化合物皆属于本发明。
药学上可接受的盐可以使用本技术领域中已知的标准程序来获得，例如通过使本发明的化合物与适当的金属阳离子或是有机碱(例如胺类)混合。
可以通过制备如上所述具有通式(1)的化合物的金属盐类达到此目标，其中金属离子为锂离子或二价金属离子。优选的二价金属盐类为钙盐、镁盐及锌盐。最优选的为钙盐。
本发明涉及如上述所定义具有通式(1)的化合物的用途，用于治疗和/或预防视力和/或眼睛疾病和/或制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物，所述的视力和/或眼睛疾病选自由下述疾病组成的组：例如(i)所有形式的原发性青光眼与继发性青光眼，优选例如原发性开角型青光眼、正常张力青光眼、原发性闭角型青光眼、假表皮脱落综合征与青光眼、色素分散综合征与青光眼、新生血管性青光眼、炎性青光眼晶状体相关青光眼、创伤性青光眼、原发性先天青光眼、医源性诱发青光眼以及恶性青光眼；(ii)获得性黄斑障碍，优选例如年龄相关性黄斑变性、自发性脉络膜新血管发生、中心浆液性脉络膜视网膜病变、玻璃体界面障碍、自发性黄斑毛细血管扩张、囊状黄斑水肿以及微囊状黄斑水肿；(iii)视神经病变，优选例如前部或后部缺血性视神经病变；(iv)视神经炎；(v)葡萄膜炎，优选例如前葡萄膜炎、中葡萄膜炎、后葡萄膜炎以及全葡萄膜炎；(vi)遗传性眼底营养不良，优选例如色素性视网膜炎、视网膜色素变性、锥体营养不良、锥体-视网膜杆营养不良、视网膜杆营养不良、施塔加特病、Bietti晶状体角膜视网膜营养不良、家族性良性斑点视网膜、贝斯特氏卵黄样黄斑营养不良、成年发病卵黄样黄斑营养不良、北卡罗来纳黄斑营养不良、家族性显性脉络膜小疣以及同心环形黄斑营养不良；(vii)视网膜血管疾病，优选例如糖尿病视网膜病变、非糖尿病视网膜病变、视网膜静脉闭塞性疾病、视网膜动脉闭塞性疾病、眼缺血综合征、高血压眼病、镰状细胞视网膜病变、地中海贫血视网膜病变、早产儿视网膜病变、视网膜动脉大动脉瘤、原发性视网膜毛细血管扩张、伊尔斯病以及辐射性视网膜病变；(viii)巩膜炎以及巩膜外层炎；(ix)视网膜脱离；(x)眼球创伤；(xi)玻璃体混浊，优选例如玻璃体出血以及星状玻璃体变性；(xii)近视以及变性近视；(xiii)手术后创伤，优选例如由常规手术造成的机械创伤、由激光手术造成的热创伤以及冷冻手术诱导的创伤；(xiv)干眼病；(xv)角膜疾病，优选例如擦伤、撕裂、溃疡、营养不良、混浊、内皮与上皮代偿失调、手术后水肿、角膜退化、角膜血管形成；以及角膜扩张，优选例如圆锥角膜，附带条件为该药物组合物不包含醛固酮受体拮抗剂。
后面的权利要求书中定义了本发明的另外实施方案。
本发明特别涉及具有通式(4)的化合物的用途：
其中符号具有如上所给出的含义。
更特别，本发明涉及具有通式(5)的化合物的用途：
其中符号具有如上所给出的含义。
根据本发明使用的最优选的活性物质是：
(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-氧代-2,3,4,5-四氢-1H-1-苯并氮杂
-3-基]氨基}羰基)环戊基]甲基}-4-苯基丁酸(6)：
(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-氧代-2,3,4,5-四氢-1H-1-苯并氮杂
-3-基]氨基}羰基)环戊基]甲基}-4-(1-萘基)丁酸(7)：
叔丁基-((3S)-3-{[1-{[(苄氧基)(乙氧基)磷酰基]甲基}环戊基]-羰基]氨基)-2-氧代-2,3,4,5-四氢-1H-1-苯并氮杂
-1-基)乙酸酯(8)：
药物组合物
本发明的化合物可以通过使用辅助物质例如液体或载体材料的常见方法来制成适合给药的形式。本发明的药物组合物可以局部和/或系统性施药，特别例如局部施药至眼睛，以结膜下、眼球筋膜下、眼球后或眼球周围方式在眼睛周围给药，眼内施药到眼睛中，但也可以经肠、经口、肠胃外(肌内或静脉内)、皮下或直肠的方式施药。这些药物组合物可以以溶液、混悬液、软膏(乳膏、凝胶、形成凝胶的溶液、喷雾、眼插入物/沉淀剂、接触棱镜)、眼植入物的形式给药，也可以以片剂、胶囊、软凝胶、粉末、栓剂、纳米制剂或通过离子电渗法的形式给药，或通过基于纳米粒子载体系统的药物组合物的形式给药。用于此类制剂的适当赋形剂为药学上常用的液体或固体填充剂、增量剂、溶剂、乳化剂、润滑剂、矫味剂、着色剂和/或缓冲物质。可以提及的常用辅助物质为碳酸镁、二氧化钛、乳糖、甘露糖醇及其他醣类，滑石、乳蛋白、明胶、淀粉、纤维素及其衍生物、动物与植物油，例如鱼肝油、葵花油、花生油或芝麻油、聚乙二醇以及溶剂，例如无菌水及单元醇或多元醇，例如甘油。
本发明的化合物通常作为药物组合物给药。可以使用的药物组合物的类型包含但不限于溶液、混悬液、软膏(乳膏、凝胶或喷雾)，也包含但不限于片剂、咀嚼片、胶囊、软凝胶、肠胃外用溶液、栓剂，以及本说明书中公开的或根据本说明书及本领域公常知识对本领域技术人员而言明显的其他类型。本发明的药物组合物不包含醛固酮受体拮抗剂。
本发明的实施方案中，提供了一种药物包装或套装产品，其包含一个或多个容器，其中填充了一种或多种本发明的药物组合物的成分。与这些容器相关的可以是不同的书面材料，例如使用说明，或以由监管药物产品制造、使用或销售的政府机构所规定的形式的通知，该通知反映了政府机构批准用于人类或兽医施药的制造、使用或销售。
适合本发明化合物的非常特定制剂描述于专利申请WO 03/068266与WO 04/062692中。
上述特定化合物旨在更详细说明本发明，因此不认为它们以任何方式限制本发明的范围。
眼病：延迟人类以及实验模型中视网膜细胞死亡
细胞凋亡为视力和/或眼睛疾病中细胞死亡的重要组分，所述的视力和/或眼睛疾病包含：(i)所有形式的原发性青光眼与继发性青光眼，优选例如原发性开角型青光眼、正常张力青光眼、原发性闭角型青光眼、假表皮脱落综合征与青光眼、色素分散综合征与青光眼、新生血管性青光眼、炎性青光眼晶状体相关青光眼、创伤性青光眼、原发性先天青光眼、医源性诱发青光眼以及恶性青光眼(R.Agarwal，S.K.Gupta，P.Agarwal，R.Saxena&S.S.Agrawal(2009)Indian J.Ophthalmol.57，257-266)；(ii)获得性黄斑障碍，优选例如年龄相关性黄斑变性、自发性脉络膜新血管发生、中心浆液性脉络膜视网膜病变、玻璃体界面障碍、自发性黄斑毛细血管扩张、囊状黄斑水肿以及微囊状黄斑水肿(J.L.Dunaief，T.Dentchev，G.-S.Ying&A.H.Milam(2002)Arch.Ophthalmol.120，1435-1442)；(iii)视神经病变，优选例如前部或后部缺血性视神经病变(B.J.Slater，Z.Mehrabian，Y.Guo，A.Hunter&S.L.Bernstein(2008)Invest.Ophthalmol.Vis.Sci.49，3671-3676)；(iv)视神经炎(K.S.Shindler，E.Ventura，M.Dutt&A.Rostami(2008)Exp.Eye Res.87，208-213)；(v)葡萄膜炎，优选例如前葡萄膜炎、中葡萄膜炎、后葡萄膜炎以及全葡萄膜炎(C.-C.Chan，D.M.Matteson，Q.Li，S.M.Whitcup&R.B.Nussenblatt(1997)Arch.Ophthalmol.115，1559-1567)；(vi)遗传性眼底营养不良，优选例如色素性视网膜炎、视网膜色素变性、锥体营养不良、锥体-视网膜杆营养不良、视网膜杆营养不良、施塔加特病、Bietti晶状体角膜视网膜营养不良、家族性良性斑点视网膜、贝斯特氏卵黄样黄斑营养不良、成年发病卵黄样黄斑营养不良、北卡罗来纳黄斑营养不良、家族性显性脉络膜小疣以及同心环形黄斑营养不良(H.Zhang，X.Li，X.Dai，J.Han，Y.Zhang，Y.Qi，Y.He，Y.Liu，B.Chang&J.J.Pang(2017)J.Ophthalmol.2017，1-13 9721362)；(vii)视网膜血管疾病，优选例如糖尿病视网膜病变、非糖尿病视网膜病变、视网膜静脉闭塞性疾病、视网膜动脉闭塞性疾病、眼缺血综合征、高血压眼病、镰状细胞视网膜病变、地中海贫血视网膜病变、早产儿视网膜病变、视网膜动脉大动脉瘤、原发性视网膜毛细血管扩张、伊尔斯病以及辐射性视网膜病变(G.Donati，A.Kapetanios，M.Dubois-Dauphin&C.J.Pournaras(2008)Acta Ophthalmol.86，302-306)；(viii)巩膜炎以及巩膜外层炎(C.Heinz，N.Bograd，J.Koch&A.Heiligenhaus(2013)Graefes Arch.Clin.Exp.Ophthalmol.251，139-142)；(ix)视网膜脱离(J.G.Arroyo，L.Yang，D.Bula&D.F.Chen(2005)Am.J.Ophthalmol.139，605-610)；(x)眼球创伤(H.-C.H.Wang，J.-H.Choi，W.A.Greene，M.L.Plamper，H.E.Cortez，M.Chavko，Y.Li，J.J.DalleLucca&A.J.Johnson(2014)Military Med.179，S34-S40)；(xi)玻璃体混浊，优选例如玻璃体出血以及星状玻璃体变性(A.Alamri，H.Alkatan&I.Aljadaan(2016)Middle EastAfrican J.Ophthalmol.23，271-273)；(xii)近视以及变性近视(G.Z.Xu，W.W.Li&M.O.Tso(1996)Trans.Am.Ophthalmol.Soc.94，411-431)；(xiii)手术后创伤，优选例如由常规手术造成的机械创伤、由激光手术造成的热创伤以及冷冻手术诱导的创伤(A.Barak，T.Goldkorn&L.S.Morse(2005)Invest.Ophthalmol.Vis.Sci.46，2587-2591；X.Liu，S.Ling，X.Gao，C.Xu&F.Wang(2013)JAMA Ophthalmol.131，1070-1072；D.Reichstein(2015)Curr.Opin.Ophthalmol.26，157-166)；(xiv)干眼病(S.Yeh，X.J.Song，D.Q.Li，W.Farley，M.E.Stern&S.C.Pflugfelder(2003)Invest.Ophthalmol.Vis.Sci.43，124-129)；(xv)角膜疾病，优选例如擦伤、撕裂、溃疡、营养不良、混浊、内皮与上皮代偿失调、手术后水肿、角膜退化、角膜血管形成；以及角膜扩张，优选例如圆锥角膜(R.M.Kaldawy，J.Wagner，S.Ching&G.M.Seigel(2002)Cornea 21，206-209；N.Szentmary，B.Szende&I.Suveges(2005)Eur.J.Ophthalmol.15，17-22)。在人类中，使用荧光染剂DY-776标记的膜联蛋白5通过实时成像，已证实细胞凋亡发生于视网膜神经节细胞中青光眼过程中(M.F.Cordeiro，E.M.Normando，M.J.Cardoso，S.Miodragovic，S.Jeylani，B.M.Davis，L.Guo，S.Ourselin，R.A'Hern&P.A.Bloom(2017)Brain 140，1757-1767)。为了在非人类实验中建模这种细胞凋亡，对大鼠系统性施予多柔比星，并评估在大器官如肝脏或心脏中的细胞凋亡(R.Gillet，G.Grimber，M.Bennoun，C.Caron de Fromentel，P.Briand&V.Joulin(2000)Oncogene 19，3498-3507；L.L.Fan，G.P.Sun，W.Wei，Z.G.Wang，L.Ge，W.Z.Fu&H.Wang(2010)World J.Gastroenterol.16，1473-1481)，或使大鼠眼睛中经受多柔比星的作用，并评估视网膜神经节细胞中的细胞凋亡(I.M.Parhad，J.W.Griffin，A.W.Clark&J.F.Koves(1984)J.Neuropathol.Exp.Neurol.43，188-200)。我们利用大鼠中多柔比星诱发的细胞凋亡以评估系统性给予化合物实例是否阻止该细胞凋亡。
实施例
方法：200-250g的韦斯(Wistar)大鼠以400mg/kg的水合氯醛麻醉，植入前灌注的渗透微型泵装填载体或剂量为60mg/kg/d的代表本发明化合物的实例(6)，并皮下注入。其后，大鼠(n＝7)在第1、2、3天一天三次腹膜内接受剂量为5mg/kg的多柔比星，或者大鼠(n＝8)在第1天由Hamilton微量注射器在五分钟内在眼睛玻璃体中接受剂量为5μg的多柔比星或体积为5μL的载体。大鼠在第一次腹膜内注射多柔比星的后五天或是在玻璃体中给予多柔比星后的五天被安乐死，并且经心脏灌流包含4％低聚甲醛的磷酸盐缓冲溶液。随后取出肝脏及眼睛并将其包埋在石蜡中。为了可视化细胞凋亡，于10μm石蜡切片上进行基于末端脱氧核苷酸转移酶介导的dUTP切口末端标记(TUNEL)染色。使用立体解剖器方法(L.M.Cruz-Orive&E.R.Weibel(1990)Am.J.Physiol.258，L148-L156)量化细胞凋亡。对于肝脏使用无偏差的计数框(0.05x0.05mm,解剖器高0.01mm)，以及(0.10x 0.025mm，解剖器高0.01mm)用于视网膜神经节细胞取样。用8-10个解剖器确定TUNEL阳性细胞的Nv，且对于肝脏Nv表示为TUNEL阳性细胞的数目x102/mm3且对于视网膜神经节细胞Nv表示为TUNEL阳性细胞的数目x103/mm3。以学生T检验进行统计学评估(表1)。
结果：TUNEL阳性细胞的存在证明了多柔比星造成了肝脏或视网膜中的细胞凋亡(表1)。相比于载体处理细胞受试者TUNEL阳性细胞的Nv的减少证明了实例(6)赋予了对抗肝脏及视网膜中多柔比星诱导的细胞凋亡的重要保护作用(表1)。
结论：实例(6)在大鼠肝脏中降低了23.46％的细胞凋亡的密度，且在视网膜中降低了8.21％(表1)。肝脏中多柔比星诱发的细胞凋亡的特点在于许多与视网膜神经节细胞中看到的细胞凋亡的那些相似的形态学特征。
表1.对多柔比星诱发的细胞凋亡的影响
*P<0.05，**P<0.01对比多柔比星+载体；学生T检验；RGC，视网膜神经节细胞；Nv，TUNEL阳性细胞数/mm3±SEM
Claims (15)
1.通式(1)的化合物，其中：
R1代表式(2)或式(3)的基团：
A表示CH2、O或S，
R2与R3独立地表示氢或卤素，
R4与R6独立地表示氢或形成生物不稳定羧酸酯的基团，
R5选自由如下各项组成的组：可以被(C1-C6)-烷氧基取代的(C1-C6)-烷氧基-(C1-C6)-烷基，苯基-(C1-C6)-烷基及苯氧基-(C1-C6)-烷基，其中苯基可以被(C1-C6)-烷基、(C1-C6)-烷氧基或卤素取代，以及萘基-(C1-C6)-烷基，
R7与R8独立地表示氢或形成生物不稳定膦酸酯的基团，
其所有立体异构体以及药学上可接受的盐，其用于预防和/或治疗视力和/或眼睛疾病和/或用于制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物，所述的视力和/或眼睛疾病选自由如下各项组成的组：这类疾病例如(i)所有形式的原发性青光眼与继发性青光眼，优选例如原发性开角型青光眼、正常张力青光眼、原发性闭角型青光眼、假表皮脱落综合征与青光眼、色素分散综合征与青光眼、新生血管性青光眼、炎性青光眼、晶状体相关青光眼、创伤性青光眼、原发性先天青光眼、医源性诱发青光眼以及恶性青光眼；(ii)获得性黄斑障碍，优选例如年龄相关性黄斑变性、自发性脉络膜新血管发生、中心浆液性脉络膜视网膜病变、玻璃体界面障碍、自发性黄斑毛细血管扩张、囊状黄斑水肿以及微囊状黄斑水肿；(iii)视神经病变，优选例如前部或后部缺血性视神经病变；(iv)视神经炎；(v)葡萄膜炎，优选例如前葡萄膜炎、中葡萄膜炎、后葡萄膜炎以及全葡萄膜炎；(vi)遗传性眼底营养不良，优选例如视网膜色素变性、锥体营养不良、锥体-视网膜杆营养不良、视网膜杆营养不良、施塔加特病、Bietti晶状体角膜视网膜营养不良、家族性良性斑点视网膜、贝斯特氏卵黄样黄斑营养不良、成年发病卵黄样黄斑营养不良、北卡罗来纳黄斑营养不良、家族性显性脉络膜小疣以及同心环形黄斑营养不良；(vii)视网膜血管疾病，优选例如糖尿病视网膜病变、非糖尿病视网膜病变、视网膜静脉闭塞性疾病、视网膜动脉闭塞性疾病、眼缺血综合征、高血压眼病、镰状细胞视网膜病变、地中海贫血视网膜病变、早产儿视网膜病变、视网膜动脉大动脉瘤、原发性视网膜毛细血管扩张、伊尔斯病以及辐射性视网膜病变；(viii)巩膜炎以及巩膜外层炎；(ix)视网膜脱离；(x)眼球创伤；(xi)玻璃体混浊，优选例如玻璃体出血以及星状玻璃体变性；(xii)近视以及变性近视；(xiii)手术后创伤，优选例如由常规手术造成的机械创伤、由激光手术造成的热创伤以及冷冻手术诱导的创伤；(xiv)干眼病；(xv)角膜疾病，优选例如擦伤、撕裂、溃疡、营养不良、混浊、内皮与上皮代偿失调、手术后水肿、角膜退化、角膜血管形成，以及角膜扩张，优选例如圆锥角膜；条件是所述的药物组合物不包含醛固酮受体拮抗剂，但可任选包含或不含以下药剂中的一种或多种：碳酸酐酶抑制剂，例如布林唑胺，α2-肾上腺素激动剂，例如溴莫尼定，β-阻断剂，例如噻吗洛尔，前列腺素类似物，例如比马前列素，rho激酶抑制剂，例如奈妥舒迪，腺苷A1受体激动剂，例如trabodenoson，ETA内皮素受体拮抗剂，例如西他生坦，双重内皮素受体拮抗剂，例如波生坦，一氧化氮供体，例如丁二醇，拟副交感神经药，例如毛果芸香碱、乙酰胆碱，儿茶酚胺类，例如肾上腺素，毒蕈碱型受体拮抗剂，例如阿托平，血管内皮生长因子抑制剂，例如雷珠单抗，皮质类固醇类，例如地塞米松，抗生素，例如万古霉素，组织再生剂，例如聚羧甲基葡萄糖，维生素及维生素原，例如泛醇及棕榈酸视黄酯，化学治疗剂，例如丝裂霉素，非甾类抗炎药，例如酮咯酸，H1受体拮抗剂，例如盐酸西替利嗪，单克隆抗体，例如阿达木单抗，蛋白酶，例如奥克纤溶酶，以及免疫抑制剂，例如环孢素。
2.通式(4)的化合物、其所有立体异构体以及药学上可接受的盐：
式中符号具有权利要求1中所给出的含义，用于预防和/或治疗权利要求1中所要求保护的视力和/或眼睛疾病，和/或用于制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物。
3.通式(5)的化合物、其所有立体异构体以及药学上可接受的盐：
式中符号具有权利要求1中所给出的含义，用于预防和/或治疗权利要求1中所要求保护的视力和/或眼睛疾病，和/或用于制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物。
4.具有式(6)的化合物(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-氧代-2,3,4,5-四氢-1H-1-苯并氮杂
-3-基]氨基}羰基)环戊-基]甲基}-4-苯基丁酸：
以及其药学上可接受的盐，用于预防和/或治疗权利要求1中所要求保护的视力和/或眼睛疾病，和/或用于制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物。
5.具有式(7)的化合物(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-氧代-2,3,4,5-四氢-1H-1-苯并氮杂
-3-基]氨基}羰基)环戊-基]甲基}-4-(1-萘基)丁酸：
以及其药学上可接受的盐，用于预防和/或治疗权利要求1中所要求保护的视力和/或眼睛疾病，和/或用于制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物。
6.具有式(8)的化合物((3S)-3-{[1-{[(苄氧基)(乙氧基)磷酰基]甲基}环戊基]-羰基]氨基)-2-氧代-2,3,4,5-四氢-1H-1-苯并氮杂
-1-基)乙酸叔丁酯：
以及其药学上可接受的盐，用于预防和/或治疗权利要求1中所要求保护的视力和/或眼睛疾病，和/或用于制备用于预防和/或治疗视力和/或眼睛疾病的药物组合物。
7.权利要求1至6任一项中所要求保护的用途，其特征在于所述药学上可接受的盐选自由锂盐、钙盐、镁盐及锌盐组成的组，且所述药学上可接受的盐优选为钙盐。
8.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于所有形式的原发性青光眼与继发性青光眼，优选例如原发性开角型青光眼、正常张力青光眼、原发性闭角型青光眼、假表皮脱落综合征与青光眼、色素分散综合征与青光眼、新生血管性青光眼、炎性青光眼、晶状体相关青光眼、创伤性青光眼、原发性先天青光眼、医源性诱发青光眼或恶性青光眼。
9.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于获得性黄斑障碍，优选例如年龄相关性黄斑变性、自发性脉络膜新血管发生、中心浆液性脉络膜视网膜病变、玻璃体界面障碍、自发性黄斑毛细血管扩张、囊状黄斑水肿或微囊状黄斑水肿。
10.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于视神经病变，优选例如前部或后部缺血性视神经病变；用于巩膜炎以及巩膜外层炎；用于视神经炎；用于葡萄膜炎，优选例如前葡萄膜炎、中葡萄膜炎、后葡萄膜炎或全葡萄膜炎。
11.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于遗传性眼底营养不良，优选例如视网膜色素变性、锥体营养不良、锥体-视网膜杆营养不良、视网膜杆营养不良、施塔加特病、Bietti晶状体角膜视网膜营养不良、家族性良性斑点视网膜、贝斯特氏卵黄样黄斑营养不良、成年发病卵黄样黄斑营养不良、北卡罗来纳黄斑营养不良、家族性显性脉络膜小疣或同心环形黄斑营养不良。
12.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于视网膜血管疾病，优选例如糖尿病视网膜病变、非糖尿病视网膜病变、视网膜静脉闭塞性疾病、视网膜动脉闭塞性疾病、眼缺血综合征、高血压眼病、镰状细胞视网膜病变、地中海贫血视网膜病变、早产儿视网膜病变、视网膜动脉大动脉瘤、原发性视网膜毛细血管扩张、伊尔斯病或辐射性视网膜病变。
13.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于近视以及变性近视；或用于干眼病。
14.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于眼球创伤；或用于手术后创伤，优选例如由常规手术造成的机械创伤、由激光手术造成的热创伤以及冷冻手术诱导的创伤；或用于玻璃体混浊，优选例如玻璃体出血或星状玻璃体变性；或用于视网膜脱离。
15.权利要求1至6任一项中所要求保护的用途，其特征在于所述的预防和/或治疗用于角膜疾病，优选例如擦伤、撕裂、溃疡、营养不良、混浊、内皮与上皮代偿失调、手术后水肿、角膜退化或角膜血管形成；或用于角膜扩张，优选例如圆锥角膜。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL424452A PL424452A1 (pl) | 2018-01-31 | 2018-01-31 | Inhibitory obojętnej endopeptydazy (NEP) i ludzkiej rozpuszczalnej endopeptydazy (hSEP) do profilaktyki i leczenia chorób oczu |
| PLP.424452 | 2018-01-31 | ||
| PCT/PL2019/000012 WO2019151882A1 (en) | 2018-01-31 | 2019-01-31 | Neutral endopeptidase (nep) and human soluble endopeptidase (hsep) inhibitors for prophylaxis and treatment of eye diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111757750A true CN111757750A (zh) | 2020-10-09 |
Family
ID=67478423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980011177.2A Pending CN111757750A (zh) | 2018-01-31 | 2019-01-31 | 用于预防和治疗眼病的中性内肽酶(nep)及人类可溶性内肽酶(hsep)的抑制剂 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US20210046097A1 (zh) |
| EP (1) | EP3746106B1 (zh) |
| KR (1) | KR20200116145A (zh) |
| CN (1) | CN111757750A (zh) |
| CA (1) | CA3088966A1 (zh) |
| IL (1) | IL275984A (zh) |
| MX (1) | MX2020007989A (zh) |
| PL (1) | PL424452A1 (zh) |
| RU (1) | RU2758771C1 (zh) |
| TW (1) | TWI762760B (zh) |
| WO (1) | WO2019151882A1 (zh) |
| ZA (1) | ZA201905959B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024088156A1 (zh) * | 2022-10-24 | 2024-05-02 | 景泽生物医药(合肥)有限公司 | 重组人奥克纤溶酶在制备治疗脉络膜血管疾病药物中的用途 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102647920B1 (ko) | 2021-10-13 | 2024-03-13 | 영남대학교 산학협력단 | 거짓비늘 녹내장 바이오 마커 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298304A (zh) * | 1998-03-05 | 2001-06-06 | 千寿制药株式会社 | 用于预防和治疗由眼底组织细胞病变引起的疾病的药物组合物 |
| WO2002094176A2 (en) * | 2001-05-18 | 2002-11-28 | Solvay Pharmaceuticals Gmbh | Use of compounds with combined nep/mp-inhibitory activity on the preparation of medicaments |
| WO2005030795A1 (en) * | 2003-09-26 | 2005-04-07 | Solvay Pharmaceuticals Gmbh | Amidomethyl substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-n-acetic acid derivatives, process and intermediate products for their preparation and medicaments containing these compounds |
| CN1859924A (zh) * | 2003-10-10 | 2006-11-08 | 索尔瓦药物有限公司 | 包含选择性ⅰ1咪唑啉受体激动剂和血管紧张素ⅱ受体阻断剂的药物组合物 |
| CN101076339B (zh) * | 2004-01-12 | 2011-02-09 | 索尔瓦药物有限公司 | 用于预防和治疗神经变性疾病的中性内肽酶(NEP)和人可溶内肽酶(hSEP)抑制剂 |
| CN102625709A (zh) * | 2009-08-24 | 2012-08-01 | 康肽德生物医药技术有限公司 | 用于预防或治疗眼科病症的方法和组合物 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19510566A1 (de) | 1995-03-23 | 1996-09-26 | Kali Chemie Pharma Gmbh | Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| DE19750002A1 (de) * | 1997-11-12 | 1999-05-20 | Solvay Pharm Gmbh | Phosphonsäure-substituierte Benzazepinon-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| KR100979077B1 (ko) | 2002-01-16 | 2010-08-31 | 솔베이 파마슈티칼스 비. 브이 | 벤즈아제핀 화합물의 고체 염 및 이를 포함하는 약제학적 조성물 |
| AR038681A1 (es) | 2002-02-14 | 2005-01-26 | Solvay Pharm Bv | Formulacion oral de solucion solida de una sustancia activa pobremente soluble en agua |
| WO2004062692A1 (en) | 2003-01-13 | 2004-07-29 | Solvay Pharmaceuticals B.V. | Formulation of poorly water-soluble active substances |
| CL2004000545A1 (es) | 2003-03-18 | 2005-01-28 | Pharmacia Corp Sa Organizada B | Uso de un antagonista de los receptores de aldosterona y un antagonista de receptores de endotelina para el tratamiento o profilaxis de una condicion patologica relacionada con hipertension, disfuncion renal, insulinopatia y enfermedades cardiovascul |
| US7232813B2 (en) * | 2004-01-12 | 2007-06-19 | Solvay Pharmaceuticals B.V. | Neutral endopeptidase (NEP) and human soluble endopeptidase (hSEP) inhibitors for prophylaxis and treatment of neuro-degenerative disorders |
| JP2009514974A (ja) * | 2005-11-07 | 2009-04-09 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Ｐｐａｒモジュレーターとしての化合物および組成物 |
-
2018
- 2018-01-31 PL PL424452A patent/PL424452A1/pl unknown
-
2019
- 2019-01-31 CN CN201980011177.2A patent/CN111757750A/zh active Pending
- 2019-01-31 US US16/963,234 patent/US20210046097A1/en not_active Abandoned
- 2019-01-31 MX MX2020007989A patent/MX2020007989A/es unknown
- 2019-01-31 TW TW108103768A patent/TWI762760B/zh active
- 2019-01-31 KR KR1020207025030A patent/KR20200116145A/ko unknown
- 2019-01-31 WO PCT/PL2019/000012 patent/WO2019151882A1/en unknown
- 2019-01-31 EP EP19747023.0A patent/EP3746106B1/en active Active
- 2019-01-31 RU RU2020125048A patent/RU2758771C1/ru active
- 2019-01-31 CA CA3088966A patent/CA3088966A1/en active Pending
- 2019-09-10 ZA ZA2019/05959A patent/ZA201905959B/en unknown
-
2020
- 2020-07-12 IL IL275984A patent/IL275984A/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298304A (zh) * | 1998-03-05 | 2001-06-06 | 千寿制药株式会社 | 用于预防和治疗由眼底组织细胞病变引起的疾病的药物组合物 |
| WO2002094176A2 (en) * | 2001-05-18 | 2002-11-28 | Solvay Pharmaceuticals Gmbh | Use of compounds with combined nep/mp-inhibitory activity on the preparation of medicaments |
| WO2005030795A1 (en) * | 2003-09-26 | 2005-04-07 | Solvay Pharmaceuticals Gmbh | Amidomethyl substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-n-acetic acid derivatives, process and intermediate products for their preparation and medicaments containing these compounds |
| CN1859924A (zh) * | 2003-10-10 | 2006-11-08 | 索尔瓦药物有限公司 | 包含选择性ⅰ1咪唑啉受体激动剂和血管紧张素ⅱ受体阻断剂的药物组合物 |
| CN101076339B (zh) * | 2004-01-12 | 2011-02-09 | 索尔瓦药物有限公司 | 用于预防和治疗神经变性疾病的中性内肽酶(NEP)和人可溶内肽酶(hSEP)抑制剂 |
| CN102625709A (zh) * | 2009-08-24 | 2012-08-01 | 康肽德生物医药技术有限公司 | 用于预防或治疗眼科病症的方法和组合物 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024088156A1 (zh) * | 2022-10-24 | 2024-05-02 | 景泽生物医药(合肥)有限公司 | 重组人奥克纤溶酶在制备治疗脉络膜血管疾病药物中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2758771C1 (ru) | 2021-11-01 |
| US20210046097A1 (en) | 2021-02-18 |
| PL424452A1 (pl) | 2019-08-12 |
| WO2019151882A4 (en) | 2019-09-26 |
| ZA201905959B (en) | 2021-07-28 |
| WO2019151882A1 (en) | 2019-08-08 |
| KR20200116145A (ko) | 2020-10-08 |
| MX2020007989A (es) | 2020-09-09 |
| EP3746106C0 (en) | 2024-03-27 |
| CA3088966A1 (en) | 2019-08-08 |
| EP3746106A4 (en) | 2021-11-03 |
| EP3746106B1 (en) | 2024-03-27 |
| IL275984A (en) | 2020-08-31 |
| TWI762760B (zh) | 2022-05-01 |
| EP3746106A1 (en) | 2020-12-09 |
| TW201934536A (zh) | 2019-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Morales et al. | Intraoperative mitomycin and corneal endothelium after photorefractive keratectomy | |
| JP6946001B2 (ja) | 薬学的組成物、および１，２，４−オキサジアゾール安息香酸の塩 | |
| JP2019034947A (ja) | 眼疾患を予防または治療するための方法および組成物 | |
| KR20070061537A (ko) | 건성안 치료용 안약액 | |
| JP2009501726A (ja) | 眼科学的活性剤の製剤とその投与の方法 | |
| CA2756864A1 (en) | Prophylactic or therapeutic agent for retinal disease and method for prophylaxis or therapy of retinal disease using jnk (c-jun amino-terminal kinase)-inhibitory peptide, and use of the peptide | |
| RU2700927C2 (ru) | Офтальмологическая композиция, содержащая циклоспорин и трегалозу | |
| Wang et al. | Changes of tear film function after pterygium operation | |
| CN111757750A (zh) | 用于预防和治疗眼病的中性内肽酶(nep)及人类可溶性内肽酶(hsep)的抑制剂 | |
| US10973758B2 (en) | Methods of eye treatment using therapeutic compositions containing dipyridamole | |
| IL259562A (en) | Aminophosphine derivatives for the prevention and treatment of eye pain | |
| Curran | Bimatoprost: a review of its use in open-angle glaucoma and ocular hypertension | |
| EP1058553A2 (en) | Pharmaceutical composition for prophylaxis and therapy of diseases associated with ocular fundus tissue cytopathy | |
| WO2023042851A1 (en) | Medicament for preventing and/or treating dry eye | |
| KR20130122958A (ko) | 망막의 질환을 치료하기 위한 방법 | |
| US20230118503A1 (en) | NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES | |
| JP5079503B2 (ja) | ラジカルスカベンジャー及び活性酸素消去剤 | |
| JP2021512847A (ja) | キレート剤、浸透促進剤およびヒドロキシエチルセルロースを含む眼科疾患治療用製剤 | |
| CA2645171A1 (en) | Prenyltransferase inhibitors for ocular hypertension control and the treatment of glaucoma | |
| Mokbel et al. | Rho-Kinase Inhibitors as a novel medication for Glaucoma Treatment–A Review of the literature | |
| RU2192261C2 (ru) | Средство консервативного лечения прогрессирующей и осложненной близорукости | |
| JPH09176003A (ja) | 角膜治療剤 | |
| KR20240019817A (ko) | 퇴행성 망막 질환에 사용하기 위한 trpa1 채널 길항제 화합물 | |
| JP2023547441A (ja) | 萎縮型加齢黄斑変性、地図状萎縮および緑内障関連神経変性の処置において使用するためのｎｏ－ｐｄｅ５阻害剤 | |
| JP2008024699A (ja) | フマル酸誘導体を有効成分として含む角結膜障害の予防または治療剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40034199 Country of ref document: HK |