TW201934536A - 用於預防或治療眼部疾病的中性肽鏈內切酶(NEP)及人類可溶性肽鏈內切酶(hSEP)之抑制劑 - Google Patents
用於預防或治療眼部疾病的中性肽鏈內切酶(NEP)及人類可溶性肽鏈內切酶(hSEP)之抑制劑 Download PDFInfo
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Abstract
本發明係關於同時具有中性肽鏈內切酶(NEP)及/或人類可溶性肽鏈內切酶(hSEP)及內皮素轉化酶(ECE)抑制活性的苯并吖庚因(benzazepine)、苯並氧氮雜(benzoxazepine)、苯并硫-N-乙酸(benzothiazepine-N-acetic acid)以及膦醯基取代的苯並氮雜酮衍生物(phosphono-substituted benzazepinone derivatives)的新用途。本發明中的化合物對於製備用於預防及治療眼部疾病的藥學成分是有用的。
Description
本發明係關於內皮素轉化酶(endothelin converting enzyme-1，ECE-1)及中性肽鏈內切酶(neutral endopeptidase，NEP)及/或人類可溶性肽鏈內切酶(human soluble endopeptidase，hSEP)的雙重抑制劑，以及其組成物，所述之藥學成分可以選擇性包含用於預防及/或治療眼部疾病的一種或多種或不包含以下成分：碳酸酐酶抑制劑(carbonic anhydrase inhibitors)，例如：布林佐胺(brinzolamide)，α2
-腎上腺素促效劑(α2
-adrenergic agonist)，例如：溴莫尼定(brimonidine)，β-阻斷劑(β-blockers)，例如：第莫洛(timolol)，前列腺素類似物(prostaglandin analogs)，例如：比馬前列素(bimatoprost)，rho激酶抑製劑(rho kinase inhibitors)，例如：2,4-二甲基苯甲酸[4-[(1S)-1-(氨基甲基)-2-(6-異喹基氨基)-2-氧代乙基]苯基]甲基酯二鹽酸鹽(netarsudil)，腺甘酸A1
受器促效劑 (adenosine A1
receptor agonists)，例如：[(2R,3S,4R,5R)-5-[6-(環戊基氨基)-9H-嘌呤-9-基]-3,4-二羥基環氧乙烷-2-基]甲基硝酸酯(trabodenoson)，ETA
內皮素受器拮抗劑(ETA
endothelin receptor antagonists)，例如：N-(4-氯-3-甲基-1,2-噁唑-5-基)-2-[2-(6-甲基-2H-1,3-苯並二氧戊-5-基)乙酰基]噻吩-3-甲磺胺(sitaxentan)，雙重內皮素受器拮抗劑(dual endothelin receptor antagonists)，例如：波生坦(bosentan)，一氧化氮予體(nitric oxide donors)，例如：丁二醇(butanediol)，擬副交感神經劑(parasympathomimetics)，例如：毛果芸香鹼(pilocarpine)、乙醯膽鹼(acetylcholine)，兒茶酚胺(catecholamines)，例如：腎上腺素(adrenaline)，毒蕈素受體拮抗劑(muscarinic receptor antagonists)，例如：阿托平(atropine)，血管內皮生長因子抑制劑(vascular endothelial growth factor inhibitors)，例如：雷珠單抗(ranibizumab)，皮質類固醇(corticosteroids)，例如：地塞米松(dexamethasone)，抗生素(antibiotics)，例如：萬古黴素(vancomycin)，組織再生試劑(tissue regenerating agents)，例如：聚羧甲基葡萄糖(poly-carboxymethylglucose)，維生素及原維生素(provitamins)，例如：泛醇(panthenol)及軟脂酸視網酯(retinyl palmitate)，化學治療劑(chemotherapeutic agents)，例如：絲裂霉素(mitomycin)，非類固醇消炎藥(nonsteroidal anti-inflammatory drugs)，例如：克多羅多克(ketorolac)，H1
受體拮抗劑(H1
receptor antagonists)，例如：鹽酸西替利嗪(cetirizine)，單株抗體(monoclonal antibodies)，例如：阿達木單抗(adalimumab)，蛋白酶(proteases)，例如：奧克纖溶酶(ocriplasmin)，免疫抑制劑(immunosuppressive agents)，例如：環孢素(cyclosporine)。
眼壓升高及眼部血流量減少是造成人類青光眼的主要危險因子。青光眼是最常見的視神經頭神經病變(optic nerve head neuropathy)，並且與形態學上失去視網膜節細胞(retinal ganglion cells)以及臨床上視野惡化(visual field deterioration)相關。青光眼的治療以降低眼壓(intraocular pressure)並防止視神經病變(optic neuropathy)的發生或進展為主。目前尚無治療方法可於青光眼期間緩和眼部血流變化，或在青光眼的過程中藉由細胞凋亡限制視網膜節細胞(retinal ganglion cells)的死亡(B.C. Chauhan (2008) Can. J. Ophthalmol. 43, 356–360)。
內皮素(endothelin)是目前為止已知人體中最有效的血管活性肽(vasoactive peptide)。如同「血管活性肽」一詞所意味，此胜肽藉由血管收縮劑活性(vasoconstrictor activity)參與眼內血壓的調控。內皮素一經釋放會造成眼部血流減少，其次是出現於視網膜(retina)及視神經頭(optic nerve head)的病狀。
內皮素除了其血管收縮劑活性外，還藉由影響小梁外流(trabecular outflow)來參與眼內壓力的調控。小梁外流是液體流出眼睛的主要途徑。內皮素增加小梁網(trabecular meshwork)的收縮性，因此減少從眼睛流出的液體使眼壓提升，接著出現於視網膜(retina)及視神經頭(optic nerve head)的病狀。
內皮素除了影響眼內血壓及調控眼內液壓外，還影響藉由ETB
受體(ETB
receptors)而作用之視網膜節細胞(retinal ganglion cells)的細胞凋亡，以及藉由誘發ETA
受體與ETB
受體而作用之人類視神經頭星狀細胞(optic nerve head astrocytes)的增殖(G. Prasanna, R. Krishnamoorthy, A.F. Clark, R.J. Wordinger & T. Yorio (2002) Invest. Ophthalmol. Vis. Sci. 43, 2704-2713)。
內皮素(endothelin)為一種由21種胺基酸所組成的胜肽，此種胜肽由內皮細胞(endothelium)合成並釋放。內皮素由切斷前體胜肽之大內皮素(big endothelin，Big ET-1)中的Trp-Val鍵而產生。內皮素轉化酶-1(Endothelin converting enzyme-1，ECE-1)為一種膜上金屬蛋白酶，其催化大內皮素-1(Big ET-1)的蛋白水解活性以成為內皮素，並構成控制活性胜肽生產的調控點。
中性肽鏈內切酶(neutral endopeptidase，NEP)為一種含鋅的金屬胜肽酶，其降解心房排鈉肽(atrial natriuretic peptide，ANP)並構成控制活性胜肽濃度的調控點。在血清剝除性嗜鉻細胞瘤細胞(serum-deprived pheochromocytoma cells)中，ANP藉由使cGMP提升來抑制細胞凋亡。皮質傳播性抑制(spreading depression in the cortex)後，接著是ANP的表現與細胞內cGMP的濃度持續升高。排鈉肽受體(natriuretic peptide receptor，NPrA)藉由刺激活化cGMP蛋白激酶G路徑(cGMP-dependent protein kinase G pathway)的顆粒鳥苷酸環化酶(particulate guanylyl cyclase，pGC)，來調控細胞內cGMP濃度。
據報導，由於ET-1受體的上調控與ANP受體的下調控發生於受到代謝或氧化損傷的細胞中，這促使我們探討雙重ECE/NEP抑制對於經歷細胞凋亡的齧齒動物細胞的影響，該細胞凋亡被報導為類似人類患有眼部疾病時的細胞凋亡，例如：青光眼(glaucoma)。
本發明係關於具有中性肽鏈內切酶(neutral endopeptidase，NEP)及/或人類可溶性肽鏈內切酶(human soluble endopeptidase，hSEP)之抑制活性的苯并吖庚因(benzazepine)、苯並氧氮雜(benzoxazepine)、苯并硫-N-乙酸(benzothiazepine-N-acetic acid)以及膦醯基取代的苯並氮雜酮衍生物(phosphono-substituted benzazepinone derivatives)的新用途。本發明中的化合物可用於製備用於預防及治療眼部疾病的藥學成分。
本發明係關於專利文獻EP1706121B1中所揭露用於製造具有有益效果之藥物的化合物的用途。有益效果揭露於此或對該技術領域中具有通常知識者由說明書及通常知識能顯而易見。本發明也關於製造用於治療或預防疾病或狀況的藥物之化合物的用途。尤其，本發明係關於一種用於治療疾病或狀態的新用途，疾病或狀況揭露於此或對該技術領域中具有通常知識者由說明書及通常知識能顯而易見。本發明實施例中所揭露於此的特定化合物為用於藥品的製造。
專利文獻EP1706121B1係關於對中性肽鏈內切酶(neutral endopeptidase)及/或人類可溶性肽鏈內切酶(human soluble endopeptidase，hSEP)及內皮素轉化酶(endothelin converting enzyme，ECE)具有抑制活性之某些化合物的用途，用於治療及/或預防神經變性疾病(neurodegenerative diseases)，例如：外傷性腦損傷(traumatic brain injury)、急性瀰漫性腦脊髓炎(acute disseminated encephalomyelitis)、癲癇相關腦部損傷(epilepsy related brain damage)、脊椎損傷、細菌性或病毒性腦膜炎(bacterial or viral meningitis)、腦膜腦炎(meningoencephalitis)、普里昂疾病(prion diseases)、神經毒性化合物中毒以及輻射誘發腦部損傷，以及用於預防缺血性腦中風(ischemic stroke)，所述藥學成分不包含醛固酮受體拮抗劑(aldosterone receptor antagonist)。
於2004年03月18日提交、2004年09月30日公開的專利文獻WO2004082637，揭露了一種方法用於預防或治療多種病理情況，包含給予醛固酮受體拮抗劑(aldosterone receptor antagonist)以及ECE抑制劑。所列病理情況為青光眼、高血壓或糖尿病視網膜病變(hypertensive or diabetic retinopathy)及眼壓升高。然而，沒有文獻揭露關於對於這些症狀之較佳化合物的益處。
本發明的目標為辨別特定的金屬蛋白酶抑制劑，當施用於不含醛固酮受體拮抗劑的藥學成分時具有治療價值。
令人驚訝的是，現在發現具有中性肽鏈內切酶(NEP)及人類可溶性肽鏈內切酶(hSEP)之抑制活性的苯并吖庚因(benzazepine)、苯並氧氮雜(benzoxazepine)、苯并硫-N-乙酸(benzothiazepine-N-acetic acid)以及膦醯基取代的苯並氮雜酮衍生物(phosphono-substituted benzazepinone derivatives)會阻止囓齒動物模型的細胞凋亡，該細胞凋亡類似人類於眼部疾病過程中的細胞凋亡。此性質使該些化合物可用於治療及/或預防及/或製備用於治療及/或預防視覺及/或眼睛疾病的藥學成分，疾病為選自由下述所組成的群組，例如：(i) 原發性青光眼與續發性青光眼(primary and secondary glaucoma)的所有形式，例如：隅角開放性青光眼(primary open-angle glaucoma)、正常張力青光眼(normal-tension glaucoma)、隅角閉鎖性青光眼(primary angle-closure glaucoma)、假性剝落症候群與青光眼(pseudoexfoliation syndrome and glaucoma)、色素分散症候群與青光眼(pigment dispersion syndrome and glaucoma)、血管新生青光眼(neovascular glaucoma)、炎性青光眼(inflammatory glaucoma) 水晶體相關青光眼(lens-related glaucoma)、創傷性青光眼(traumatic glaucoma)、原發性先天青光眼(primary congenital glaucoma)、醫源性誘發青光眼(iatrogenic induced glaucoma)以及惡性青光眼(malignant glaucoma)；(ii) 後天黃斑點異常(acquired macular disorders)，例如：老年性黃斑點退化(age-related macular degeneration)、自發性脈絡膜血管新生疾病(idiopathic choroidal neovascularisation)、中心性漿液性脈絡膜視網膜病變(central serous chorioretinopathy)、玻璃體界面異常(vitreomacular interface disorders)、醫源性黃斑點毛細血管擴張(idiopathic macular telangiectasia)、囊狀黃斑點水腫(cystoid macular oedema)以及微囊狀黃斑點水腫(microcystic macular oedema)；(iii) 視神經病變(optic neuropathy)，例如：前方或後方視神經病變(anterior or posterior ischemic optic neuropathy)；(iv) 視神經炎(optic neuritis)；(v) 眼色素層炎(uveitis)，例如：前眼色素層炎(anterior uveitis)、中眼色素層炎(intermediate uveitis)、後眼色素層炎(posterior uveitis)、以及全眼色素層炎(panuveitis)；(vi) 遺傳性眼底異常(hereditary fundus dystrophies)，例如：色素性視網膜炎(retinitis pigmentosa)、視錐異常(cone dystrophy)、錐桿異常(cone-rod dystrophy)、視桿異常(rod dystrophy)、Stargardt's氏症(Stargardt's disease)、Bietti結晶角膜失養症(Bietti's crystalline corneoretinal dystrophy)、家族性良性斑點視網膜(familial benign fleck retina)、貝斯特氏卵黃樣黃斑失養症(Best vitelliform macular dystrophy)、成年發病卵黃樣黃斑失養症(adult-onset vitelliform macular dystrophy)、北卡羅來納黃斑失養症(North Carolina macular dystrophy)、家族性顯性隱結(familial dominant drusen)以及同心環形黃斑失養症(concentric annular macular dystrophy)；(vii) 視網膜血管疾病(retinal vascular diseases)，例如：糖尿病視網膜病變(diabetic retinopathy)、非糖尿病視網膜病變(non-diabetic retinopathy)、視網膜靜脈閉塞病(retinal venous occlusive disease)、視網膜動脈閉塞病(retinal arterial occlusive disease)、眼缺血症候群(ocular ischemic syndrome)、高眼壓疾病(hypertensive eye disease)、鐮狀細胞視網膜病變(sickle cell retinopathy)、地中海型貧血視網膜病變(thalassemia retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、視網膜大動脈瘤(retinal artery macroaneurysm)、原發性視網膜毛細血管擴張(primary retinal telangiectasiam)、Eales病(Eales disease)以及放射性視網膜病變(radiation retinopathy)；(viii) 鞏膜炎(scleritis)以及上鞏膜炎(episcleritis)；(ix) 視網膜剝離(retinal detachments)；(x) 眼球創傷 (trauma to the eye globe)；(xi) 玻璃體混濁(vitreous opacities)，例如：玻璃體出血(vitreous hemorrhage)以及星狀玻璃體症(asteroid hyalosis)；(xii) 近視(myopia)以及退化性近視(degenerative myopia)；(xiii) 術後創傷(postsurgical trauma)，例如：由一般手術造成的機械創傷(mechanical trauma)、由雷射手術造成的熱創傷(thermotrauma)、以及冷凍手術誘導創傷(trauma induced by cryosurgery)；(xiv) 乾眼症(dry eye disease)；(xv) 角膜疾病(corneal disorders)，例如：剝落(abrasions)、撕裂(lacerations)、潰瘍(ulcerations)、失養(dystrophies)、混濁(opacities)、內皮與上皮衰退(endothelial and epithelial decompensation)、術後水腫(post-surgical oedema)、角膜退化(corneal degenerations)、角膜血管形成(corneal vascularisation)；以及角膜擴張(corneal ectasias)，例如：圓錐角膜(keratoconus)。
從歐洲專利文獻EP0733642、EP0916679及EP1468010中已知本發明之化合物包含詳細的合成方式，本發明之化合物可以化學通式(1)表示：
其中：
R1代表化學式(2)或化學式(3)之取代基：A表示CH2 、O或S，R2與R3各自表示氫或鹵素，R4與R6各自表示氫或生物不穩定的成羧酸酯基，R5為選自由可以被取代為(C1-C6)-烷氧基((C1-C6)-alkoxy)的(C1-C6)-烷氧-(C1-C6)-烷基((C1-C6)-alkoxy-(C1-C6)-alkyl)、苯-(C1-C6)-烷基(phenyl-(C1-C6)-alkyl)及苯氧-(C1-C6)-烷基(phenyloxy-(C1-C6)-alkyl)所組成之取代基群組，其中苯基可以被取代為(C1-C6)-烷基((C1-C6)-alkyl)、(C1-C6)-烷氧基((C1-C6)-alkoxy)或鹵素及萘-(C1-C6)-烷基(naphtyl-(C1-C6)-alkyl)， R7與R8各自表示氫或形成生物不穩定膦酸酯(biolabile phosphonic acid ester)的取代基。
其中：
R1代表化學式(2)或化學式(3)之取代基：A表示CH2 、O或S，R2與R3各自表示氫或鹵素，R4與R6各自表示氫或生物不穩定的成羧酸酯基，R5為選自由可以被取代為(C1-C6)-烷氧基((C1-C6)-alkoxy)的(C1-C6)-烷氧-(C1-C6)-烷基((C1-C6)-alkoxy-(C1-C6)-alkyl)、苯-(C1-C6)-烷基(phenyl-(C1-C6)-alkyl)及苯氧-(C1-C6)-烷基(phenyloxy-(C1-C6)-alkyl)所組成之取代基群組，其中苯基可以被取代為(C1-C6)-烷基((C1-C6)-alkyl)、(C1-C6)-烷氧基((C1-C6)-alkoxy)或鹵素及萘-(C1-C6)-烷基(naphtyl-(C1-C6)-alkyl)， R7與R8各自表示氫或形成生物不穩定膦酸酯(biolabile phosphonic acid ester)的取代基。
所有具有化學通式(1)的化合物、消旋化合物(racemates)、非鏡像異構物的混合物以及單獨的立體異構物，也包含該等化合物藥學上可接受的鹽類皆屬於本發明。因此，取代基在不對稱碳原子上為R-構型或S-構型的化合物皆屬於本發明。
藥學上可接受的鹽類可以使用該技術領域中已知的標準程序來獲得，例如：藉由混合本發明的一化合物與適當的金屬陽離子或是有機鹼(例如：胺類)。
此目標可以由製備如上所述具有化學通式(1)之化合物的金屬鹽類達成，其中金屬離子可以為鋰離子或二價金屬離子。較佳的二價金屬鹽類為鈣鹽、鎂鹽及鋅鹽。最佳為鈣鹽。
本發明係關於如上述所定義具有化學通式(1)之化合物的用途，用於治療及/或預防及/或製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病為選自由下述所組成的群組，例如：(i) 原發性青光眼與續發性青光眼(primary and secondary glaucoma)的所有形式，例如：隅角開放性青光眼(primary open-angle glaucoma)、正常張力青光眼(normal-tension glaucoma)、隅角閉鎖性青光眼(primary angle-closure glaucoma)、假性剝落症候群與青光眼(pseudoexfoliation syndrome and glaucoma)、色素分散症候群與青光眼(pigment dispersion syndrome and glaucoma)、血管新生青光眼(neovascular glaucoma)、炎性青光眼(inflammatory glaucoma) 水晶體相關青光眼(lens-related glaucoma)、創傷性青光眼(traumatic glaucoma)、原發性先天青光眼(primary congenital glaucoma)、醫源性誘發青光眼(iatrogenic induced glaucoma)以及惡性青光眼(malignant glaucoma)；(ii) 後天黃斑點異常(acquired macular disorders)，例如：老年性黃斑點退化(age-related macular degeneration)、自發性脈絡膜血管新生疾病(idiopathic choroidal neovascularisation)、中心性漿液性脈絡膜視網膜病變(central serous chorioretinopathy)、玻璃體界面異常(vitreomacular interface disorders)、醫源性黃斑點毛細血管擴張(idiopathic macular telangiectasia)、囊狀黃斑點水腫(cystoid macular oedema)以及微囊狀黃斑點水腫(microcystic macular oedema)；(iii) 視神經病變(optic neuropathy)，例如：前方或後方視神經病變(anterior or posterior ischemic optic neuropathy)；(iv) 視神經炎(optic neuritis)；(v) 眼色素層炎(uveitis)，例如：前眼色素層炎(anterior uveitis)、中眼色素層炎(intermediate uveitis)、後眼色素層炎(posterior uveitis)、以及全眼色素層炎(panuveitis)；(vi) 遺傳性眼底異常(hereditary fundus dystrophies)，例如：色素性視網膜炎(retinitis pigmentosa)、視錐異常(cone dystrophy)、錐桿異常(cone-rod dystrophy)、視桿異常(rod dystrophy)、Stargardt's氏症(Stargardt's disease)、Bietti結晶角膜失養症(Bietti's crystalline corneoretinal dystrophy)、家族性良性斑點視網膜(familial benign fleck retina)、貝斯特氏卵黃樣黃斑失養症(Best vitelliform macular dystrophy)、成年發病卵黃樣黃斑失養症(adult-onset vitelliform macular dystrophy)、北卡羅來納黃斑失養症(North Carolina macular dystrophy)、家族性顯性隱結(familial dominant drusen)以及同心環形黃斑失養症(concentric annular macular dystrophy)；(vii) 視網膜血管疾病(retinal vascular diseases)，例如：糖尿病視網膜病變(diabetic retinopathy)、非糖尿病視網膜病變(non-diabetic retinopathy)、視網膜靜脈閉塞病(retinal venous occlusive disease)、視網膜動脈閉塞病(retinal arterial occlusive disease)、眼缺血症候群(ocular ischemic syndrome)、高眼壓疾病(hypertensive eye disease)、鐮狀細胞視網膜病變(sickle cell retinopathy)、地中海型貧血視網膜病變(thalassemia retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、視網膜大動脈瘤(retinal artery macroaneurysm)、原發性視網膜毛細血管擴張(primary retinal telangiectasiam)、Eales病(Eales disease)以及放射性視網膜病變(radiation retinopathy)；(viii) 鞏膜炎(scleritis)以及上鞏膜炎(episcleritis)；(ix) 視網膜剝離(retinal detachments)；(x) 眼球創傷 (trauma to the eye globe)；(xi) 玻璃體混濁(vitreous opacities)，例如：玻璃體出血(vitreous hemorrhage)以及星狀玻璃體症(asteroid hyalosis)；(xii) 近視(myopia)以及退化性近視(degenerative myopia)；(xiii) 術後創傷(postsurgical trauma)，例如：由一般手術造成的機械創傷(mechanical trauma)、由雷射手術造成的熱創傷(thermotrauma)、以及冷凍手術誘導創傷(trauma induced by cryosurgery)；(xiv) 乾眼症(dry eye disease)；(xv) 角膜疾病(corneal disorders)，例如：剝落(abrasions)、撕裂(lacerations)、潰瘍(ulcerations)、失養(dystrophies)、混濁(opacities)、內皮與上皮衰退(endothelial and epithelial decompensation)、術後水腫(post-surgical oedema)、角膜退化(corneal degenerations)、角膜血管形成(corneal vascularisation)；以及角膜擴張(corneal ectasias)，例如：圓錐角膜(keratoconus)，附帶條件為該藥學成分不包含醛固酮受體拮抗劑(aldosterone receptor antagonist)。
本發明更進一步的實施例定義於附屬項中。
本發明更關於具有化學通式(4)之化合物的用途：
其中，R2~R6與上述相同。
其中，R2~R6與上述相同。
尤其，本發明係關於具有化學通式(5)之化合物的用途：
其中，R4、R7和R8與上述相同。
其中，R4、R7和R8與上述相同。
本發明還關於一種化合物(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-側氧-2,3,4,5-四氫-1H-1-苯并吖庚因-3-基]胺基}羰基)環戊基]甲基}-4-苯丁酸((2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-phenylbutanoic acid)，具有化學式(6)：
本發明還關於一種化合物(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-側氧-2,3,4,5-四氫-1H-1-苯并吖庚因-3-基]胺基}羰基)環戊基]甲基}-4-(1-萘基)丁酸((2R)-2-{(1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-(1-naphthyl)butanoic acid)，具有化學式(7)：
本發明還關於一種化合物三級丁基-((3S)-3-{[1-{[(苄氧)(乙氧)磷醯]甲基}環戊基]-羰基]胺基)-2-側氧-2,3,4,5-四氫-1H-1-苯并吖庚因-1-基)醋酸鹽(tert-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl}cyclopentyl)- carbonyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate)，具有化學式(8)：
藥學成分
本發明之化合物可以藉由使用輔助物質例如液體或載體材料的常見方式來製成適合給藥的形式。本發明之藥學成分可以局部及/或系統性施藥，特別例如：局部施藥至眼睛，其中施藥的方式有從結膜下(subconjunctival)、眼球筋膜下(subtenon)、眼球後(retrobulbar)或眼球周圍(peribulbar)至眼睛周圍的方式局部施藥至眼內。此外，也可以腸內(enterally)、口服(orally)、腸胃外(parenterally)(肌內(intramuscularly)或靜脈內(intravenously))、皮下(subcutaneously)或直腸(rectally)的方式施以藥物。這些藥學成分可以是採用液體、懸浮體、軟膏(乳膏、凝膠、成凝膠溶液、噴霧、眼部插入/沉澱劑、隱形眼鏡)、眼部注射的形式給藥，也可以錠劑、膠囊、軟凝膠、粉末、栓劑、奈米製劑或通過離子電滲法(iontophoresis)的形式，或藉由基於奈米粒子載體系統的藥學組成的形式給藥。用於此類製劑的適當賦形劑為藥學上常用的液體或固體填充劑、增量劑、溶劑、乳化劑、潤滑劑、調味劑、色素及/或緩衝物質。前述所提及常用的輔助物質為碳酸鎂(magnesium carbonate)、二氧化鈦(titanium dioxide)、乳糖(lactose)、甘露醇(mannitol)及其他醣類，滑石(talc)、乳蛋白質(lactoprotein)、明膠(gelatin)、澱粉、纖維素及其衍生物、動物與植物油(animal and vegetable oils)，例如：魚肝油、葵花油、花生油或芝麻油、聚乙烯乙二醇(polyethylene glycol)以及溶劑，例如：無菌水(sterile water)及單元醇或多元醇，例如：甘油。
本發明之化合物通常作為藥學成分。藥學成分的類型可以包含但不限於液體、懸浮體、軟膏(乳膏、凝膠或噴霧)，也可以包含但不限於錠劑、咀嚼片、膠囊、軟凝膠、注射用溶液、栓劑，以及其他揭露於此的類型或對於該技術領域中具有通常知識者可以從說明書及通常知識中顯而易見者。本發明之藥學成分不包含醛固酮受體拮抗劑(aldosterone receptor antagonist)。
本發明之實施例中，提供了一種藥學組合或套組包含一個或多個容器，其中填充了一種或多種本發明之藥學成分。與這些容器相關的書面資料，例如：以由規範該藥學產品製造、使用或販賣的政府機構所規定的形式發出的通知或使用說明，該通知反映了由政府機構批准該藥學產品用於人類或獸醫施藥的製造、使用或販賣。
適合本發明化合物的特定製劑描述於專利文獻WO03068266與WO04062692中。
上述特定化合物旨在更詳細說明本發明，因此不以任何方式限制本發明的範圍。
眼部疾病：延遲人類視網膜細胞死亡以及實驗模組
細胞凋亡為視覺及/或眼睛疾病中細胞死亡的重要部分，眼部疾病包含：(i) 原發性青光眼與續發性青光眼(primary and secondary glaucoma)的所有形式，例如：隅角開放性青光眼(primary open-angle glaucoma)、正常張力青光眼(normal-tension glaucoma)、隅角閉鎖性青光眼(primary angle-closure glaucoma)、假性剝落症候群與青光眼(pseudoexfoliation syndrome and glaucoma)、色素分散症候群與青光眼(pigment dispersion syndrome and glaucoma)、血管新生青光眼(neovascular glaucoma)、炎性青光眼(inflammatory glaucoma) 水晶體相關青光眼(lens-related glaucoma)、創傷性青光眼(traumatic glaucoma)、原發性先天青光眼(primary congenital glaucoma)、醫源性誘發青光眼(iatrogenic induced glaucoma)以及惡性青光眼(malignant glaucoma) (R. Agarwal, S.K. Gupta, P. Agarwal, R. Saxena & S.S. Agrawal (2009) Indian J. Ophthalmol. 57, 257-266)；(ii) 後天黃斑點異常(acquired macular disorders)，例如：老年性黃斑點退化(age-related macular degeneration)、自發性脈絡膜血管新生疾病(idiopathic choroidal neovascularisation)、中心性漿液性脈絡膜視網膜病變(central serous chorioretinopathy)、玻璃體界面異常(vitreomacular interface disorders)、醫源性黃斑點毛細血管擴張(idiopathic macular telangiectasia)、囊狀黃斑點水腫(cystoid macular oedema)以及微囊狀黃斑點水腫(microcystic macular oedema) (J.L. Dunaief, T. Dentchev, G.-S. Ying & A.H. Milam (2002) Arch. Ophthalmol. 120, 1435-1442)；(iii) 視神經病變(optic neuropathy)，例如：前方或後方視神經病變(anterior or posterior ischemic optic neuropathy) (B.J. Slater, Z. Mehrabian, Y. Guo, A. Hunter & S.L. Bernstein (2008) Invest. Ophthalmol. Vis. Sci. 49, 3671-3676)；(iv) 視神經炎(optic neuritis) (K.S. Shindler, E. Ventura, M. Dutt & A. Rostami (2008) Exp.Eye Res. 87, 208-213)；(v) 眼色素層炎(uveitis)，例如：前眼色素層炎(anterior uveitis)、中眼色素層炎(intermediate uveitis)、後眼色素層炎(posterior uveitis)、以及全眼色素層炎(panuveitis) (C.-C. Chan, D.M. Matteson, Q. Li, S.M. Whitcup & R.B. Nussenblatt (1997) Arch. Ophthalmol. 115, 1559-1567)；(vi) 遺傳性眼底異常(hereditary fundus dystrophies)，例如：色素性視網膜炎(retinitis pigmentosa)、視錐異常(cone dystrophy)、錐桿異常(cone-rod dystrophy)、視桿異常(rod dystrophy)、Stargardt's氏症(Stargardt's disease)、Bietti結晶角膜失養症(Bietti's crystalline corneoretinal dystrophy)、家族性良性斑點視網膜(familial benign fleck retina)、貝斯特氏卵黃樣黃斑失養症(Best vitelliform macular dystrophy)、成年發病卵黃樣黃斑失養症(adult-onset vitelliform macular dystrophy)、北卡羅來納黃斑失養症(North Carolina macular dystrophy)、家族性顯性隱結(familial dominant drusen)以及同心環形黃斑失養症(concentric annular macular dystrophy) (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) 視網膜血管疾病(retinal vascular diseases)，例如：糖尿病視網膜病變(diabetic retinopathy)、非糖尿病視網膜病變(non-diabetic retinopathy)、視網膜靜脈閉塞病(retinal venous occlusive disease)、視網膜動脈閉塞病(retinal arterial occlusive disease)、眼缺血症候群(ocular ischemic syndrome)、高眼壓疾病(hypertensive eye disease)、鐮狀細胞視網膜病變(sickle cell retinopathy)、地中海型貧血視網膜病變(thalassemia retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、視網膜大動脈瘤(retinal artery macroaneurysm)、原發性視網膜毛細血管擴張(primary retinal telangiectasiam)、Eales病(Eales disease)以及放射性視網膜病變(radiation retinopathy) (G. Donati, A. Kapetanios, M. Dubois-Dauphin & C.J. Pournaras (2008) Acta Ophthalmol. 86, 302-306)；(viii) 鞏膜炎(scleritis)以及上鞏膜炎(episcleritis) (C. Heinz, N. Bograd, J. Koch & A. Heiligenhaus (2013) Graefes Arch. Clin. Exp. Ophthalmol. 251, 139-142)；(ix) 視網膜剝離(retinal detachments) (J.G. Arroyo, L. Yang, D. Bula & D.F. Chen (2005) Am. J. Ophthalmol. 139, 605-610)；(x) 眼球創傷 (trauma to the eye globe) (H.-C.H. Wang, J.-H. Choi, W.A. Greene, M.L. Plamper, H.E. Cortez, M. Chavko, Y. Li, J.J. Dalle Lucca & A.J. Johnson (2014) Military Med. 179, S34-S40)；(xi) 玻璃體混濁(vitreous opacities)，例如：玻璃體出血(vitreous hemorrhage)以及星狀玻璃體症(asteroid hyalosis) (A. Alamri, H. Alkatan & I. Aljadaan (2016) Middle East African J. Ophthalmol. 23, 271-273)；(xii) 近視(myopia)以及退化性近視(degenerative myopia) (G.Z. Xu, W.W. Li & M.O. Tso (1996) Trans. Am. Ophthalmol. Soc. 94, 411-431)；(xiii) 術後創傷(postsurgical trauma)，例如：由一般手術造成的機械創傷(mechanical trauma)、由雷射手術造成的熱創傷(thermotrauma)、以及冷凍手術誘導創傷(trauma induced by cryosurgery) (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) 乾眼症(dry eye disease) (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(corneal disorders)，例如：剝落(abrasions)、撕裂(lacerations)、潰瘍(ulcerations)、失養(dystrophies)、混濁(opacities)、內皮與上皮衰退(endothelial and epithelial decompensation)、術後水腫(post-surgical oedema)、角膜退化(corneal degenerations)、角膜血管形成(corneal vascularisation)；以及角膜擴張(corneal ectasias)，例如：圓錐角膜(keratoconus) (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)。藉由使用螢光染劑DY-776標記annexin 5於視網膜節細胞(retinal ganglion cells)即時成像，細胞凋亡已被證實發生於視網膜節細胞(retinal ganglion cells)在人類青光眼的過程中(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)。為了在非人體實驗中模擬這種細胞凋亡，對老鼠系統性施予阿黴素(doxorubicin)，並評估在大器官如肝臟、心臟中的細胞凋亡(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)，或對老鼠的眼睛施予作用阿黴素(doxorubicin)，並評估視網膜節細胞(retinal ganglion cells)中的細胞凋亡(I.M. Parhad, J.W. Griffin, A.W. Clark & J.F. Koves (1984) J. Neuropathol. Exp. Neurol. 43, 188-200)。我們利用阿黴素(doxorubicin)誘發老鼠細胞凋亡以評估系統性給予此化合物的實施例是否阻止細胞凋亡。
實施例
方法：200-250 g的韋斯大鼠(Wistar rats)以400 mg/kg的水合氯醛(chloral hydrate)麻醉，滲透微型泵(osmotic minipumps)在注入前裝填載體或作為代表本發明化合物的化合物(6)，並以60 mg/kg/d的劑量皮下注入。其後，老鼠(n=7)在第1、2、3天受到一天三次腹腔內注射劑量為5 mg/kg的阿黴素(doxorubicin)，或者老鼠(n=8)在第1天由微量注射器(Hamilton microsyringe)在眼睛玻璃體(vitreous body)注入劑量為5 µg的阿黴素(doxorubicin)或體積為5µL的載體超過五分鐘。老鼠在第一次腹腔注射阿黴素的五天後或是在玻璃體給予阿黴素的五天後被安樂死，並且心臟注入包含4%三聚甲醛(paraformaldehyde)的磷酸緩衝溶液。肝臟及眼睛隨後移除並嵌入石蠟。為了視覺化細胞凋亡，於10 µm的石蠟切片進行基於末端脫氧核苷酸轉移酶脫氧尿苷三磷酸切口末端標記(terminal deoxynucleotide transferase-mediated dUTP nick end-label，TUNEL)的染色法。立體分節(stereological dissector)方法(L.M. Cruz-Orive & E.R. Weibel (1990) Am. J. Physiol. 258, L148-L156)用於量化細胞凋亡。一無偏差的計算框(0.05 x 0.05 mm,體視框(disector)高0.01 mm)用於肝臟，以及另一計算框(0.10 x 0.025 mm, 體視框(disector)高0.01 mm)用於視網膜節細胞取樣。TUNEL陽性細胞的Nv值由8-10個體視框決定，且Nv值表示肝臟中TUNEL陽性細胞的數目x 102
/mm3
以及視網膜節細胞中TUNEL陽性細胞的數目x 103
/mm3
。以學生T檢定(Student’s test)進行統計評估(表1)。
結果：TUNEL陽性細胞證明了阿黴素造成肝臟或視網膜節細胞的細胞凋亡(表1)。TUNEL陽性細胞數Nv值於載體處理細胞(vehicle-treated subjects)的減少證明了化合物(6)給予對抗肝臟及視網膜中阿黴素誘導的細胞凋亡重要的保護作用(表1)。
結論：化合物(6)降低了老鼠肝臟中23.46%之細胞凋亡的密度，在視網膜則降低了8.21% (表1)。肝臟中阿黴素誘發的細胞凋亡其特點為形態學上的許多特徵與視網膜節細胞中的細胞凋亡相似。
表1，阿黴素誘發細胞凋亡的影響
*P＜0.05, **P＜0.01 對於阿黴素+載體；學生T檢定(Student's t-test)；RGC，視網膜節細胞(retinal ganglion cells)；Nv，TUNEL陽性細胞/mm3
± 平均值標準誤差(SEM)
無。
無。
Claims (16)
- 一種具有化學通式(1)之化合物，其中：R1代表化學式(2)或化學式(3)之取代基：A表示CH2 、O或S，R2與R3各自表示氫或鹵素，R4與R6各自表示氫或生物不穩定的成羧酸酯基，R5為選自由可以被取代為(C1-C6)-烷氧基的(C1-C6)-烷氧-(C1-C6)-烷基、苯-(C1-C6)-烷基及苯氧-(C1-C6)-烷基所組成之取代基群組，其中苯基可以被取代為(C1-C6)-烷基、(C1-C6)-烷氧基或鹵素、及萘-(C1-C6)-烷基，R7與R8各自表示氫或形成生物不穩定膦酸酯的取代基，所述化合物的所有立體異構物以及其藥學上可接受的鹽類是用於預防及/或治療，及/或用於製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病為選自下述所組成的群組：(i) 原發性青光眼與續發性青光眼(primary and secondary glaucoma)的所有形式，隅角開放性青光眼(primary open-angle glaucoma)、正常張力青光眼(normal-tension glaucoma)、隅角閉鎖性青光眼(primary angle-closure glaucoma)、假性剝落症候群與青光眼(pseudoexfoliation syndrome and glaucoma)、色素分散症候群與青光眼(pigment dispersion syndrome and glaucoma)、血管新生青光眼(neovascular glaucoma)、炎性青光眼(inflammatory glaucoma) 水晶體相關青光眼(lens-related glaucoma)、創傷性青光眼(traumatic glaucoma)、原發性先天青光眼(primary congenital glaucoma)、醫源性誘發青光眼(iatrogenic induced glaucoma)以及惡性青光眼(malignant glaucoma)；(ii) 後天黃斑點異常(acquired macular disorders)，老年性黃斑點退化(age-related macular degeneration)、自發性脈絡膜血管新生疾病(idiopathic choroidal neovascularisation)、中心性漿液性脈絡膜視網膜病變(central serous chorioretinopathy)、玻璃體界面異常(vitreomacular interface disorders)、醫源性黃斑點毛細血管擴張(idiopathic macular telangiectasia)、囊狀黃斑點水腫(cystoid macular oedema)以及微囊狀黃斑點水腫(microcystic macular oedema)；(iii) 視神經病變(optic neuropathy)，前方或後方視神經病變(anterior or posterior ischemic optic neuropathy)；(iv) 視神經炎(optic neuritis)；(v) 眼色素層炎(uveitis)，前眼色素層炎(anterior uveitis)、中眼色素層炎(intermediate uveitis)、後眼色素層炎(posterior uveitis)、以及全眼色素層炎(panuveitis)；(vi) 遺傳性眼底異常(hereditary fundus dystrophies)，色素性視網膜炎(retinitis pigmentosa)、視錐異常(cone dystrophy)、錐桿異常(cone-rod dystrophy)、視桿異常(rod dystrophy)、Stargardt's氏症(Stargardt's disease)、Bietti結晶角膜失養症(Bietti's crystalline corneoretinal dystrophy)、家族性良性斑點視網膜(familial benign fleck retina)、貝斯特氏卵黃樣黃斑失養症(Best vitelliform macular dystrophy)、成年發病卵黃樣黃斑失養症(adult-onset vitelliform macular dystrophy)、北卡羅來納黃斑失養症(North Carolina macular dystrophy)、家族性顯性隱結(familial dominant drusen)以及同心環形黃斑失養症(concentric annular macular dystrophy)；(vii) 視網膜血管疾病(retinal vascular diseases)，糖尿病視網膜病變(diabetic retinopathy)、非糖尿病視網膜病變(non-diabetic retinopathy)、視網膜靜脈閉塞病(retinal venous occlusive disease)、視網膜動脈閉塞病(retinal arterial occlusive disease)、眼缺血症候群(ocular ischemic syndrome)、高眼壓疾病(hypertensive eye disease)、鐮狀細胞視網膜病變(sickle cell retinopathy)、地中海型貧血視網膜病變(thalassemia retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、視網膜大動脈瘤(retinal artery macroaneurysm)、原發性視網膜毛細血管擴張(primary retinal telangiectasiam)、Eales病(Eales disease)以及放射性視網膜病變(radiation retinopathy)；(viii) 鞏膜炎(scleritis)以及上鞏膜炎(episcleritis)；(ix) 視網膜剝離(retinal detachments)；(x) 眼球創傷 (trauma to the eye globe)；(xi) 玻璃體混濁(vitreous opacities)，玻璃體出血(vitreous hemorrhage)以及星狀玻璃體症(asteroid hyalosis)；(xii) 近視(myopia)以及退化性近視(degenerative myopia)；(xiii) 術後創傷(postsurgical trauma)，由一般手術造成的機械創傷(mechanical trauma)、由雷射手術造成的熱創傷(thermotrauma)、以及冷凍手術誘導創傷(trauma induced by cryosurgery)；(xiv) 乾眼症(dry eye disease)；(xv) 角膜疾病(corneal disorders)，剝落(abrasions)、撕裂(lacerations)、潰瘍(ulcerations)、失養(dystrophies)、混濁(opacities)、內皮與上皮衰退(endothelial and epithelial decompensation)、術後水腫(post-surgical oedema)、角膜退化(corneal degenerations)、角膜血管形成(corneal vascularisation)以及圓錐角膜(keratoconus)的角膜擴張(corneal ectasias)；該藥學成分不包含醛固酮受體拮抗劑(aldosterone receptor antagonist)，但可選擇性包含一種或多種或不包含以下成分：碳酸酐酶抑制劑(carbonic anhydrase inhibitors)，布林佐胺(brinzolamide)，α2 -腎上腺素促效劑(α2 -adrenergic agonist)，溴莫尼定(brimonidine)，β-阻斷劑(β-blockers)，第莫洛(timolol)，前列腺素類似物(prostaglandin analogs)，比馬前列素(bimatoprost)，rho激酶抑製劑(rho kinase inhibitors)，2,4-二甲基苯甲酸[4-[(1S)-1-(氨基甲基)-2-(6-異喹基氨基)-2-氧代乙基]苯基]甲基酯二鹽酸鹽(netarsudil)，腺甘酸A1 受器促效劑 (adenosine A1 receptor agonists)， [(2R,3S,4R,5R)-5-[6-(環戊基氨基)-9H-嘌呤-9-基]-3,4-二羥基環氧乙烷-2-基]甲基硝酸酯(trabodenoson)，ETA 內皮素受器拮抗劑(ETA endothelin receptor antagonists)，N-(4-氯-3-甲基-1,2-噁唑-5-基)-2-[2-(6-甲基-2H-1,3-苯並二氧戊-5-基)乙酰基]噻吩-3-甲磺胺(sitaxentan)，雙重內皮素受器拮抗劑(dual endothelin receptor antagonists)，波生坦(bosentan)，一氧化氮予體(nitric oxide donors)，丁二醇(butanediol)，擬副交感神經劑(parasympathomimetics)，毛果芸香鹼(pilocarpine)、乙醯膽鹼(acetylcholine)，兒茶酚胺(catecholamines)，腎上腺素(adrenaline)，毒蕈素受體拮抗劑(muscarinic receptor antagonists)，阿托平(atropine)，血管內皮生長因子抑制劑(vascular endothelial growth factor inhibitors)，雷珠單抗(ranibizumab)，皮質類固醇(corticosteroids)，地塞米松(dexamethasone)，抗生素(antibiotics)，萬古黴素(vancomycin)，組織再生試劑(tissue regenerating agents)，聚羧甲基葡萄糖(poly-carboxymethylglucose)，維生素及原維生素(provitamins)，泛醇(panthenol)及軟脂酸視網酯(retinyl palmitate)，化學治療劑(chemotherapeutic agents)，絲裂霉素(mitomycin)，非類固醇消炎藥(nonsteroidal anti-inflammatory drugs)，克多羅多克(ketorolac)，H1 受體拮抗劑(H1 receptor antagonists)，鹽酸西替利嗪(cetirizine)，單株抗體(monoclonal antibodies)，阿達木單抗(adalimumab)，蛋白酶(proteases)，奧克纖溶酶(ocriplasmin)，以及免疫抑制劑(immunosuppressive agents)，環孢素(cyclosporine)。
- 一種具有化學通式(4)之化合物：其中，R2~R6的表示如請求項1所述，所述化合物的所有立體異構物以及其藥學上可接受的鹽類是用於預防及/或治療，及/或用於製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病如請求項1所述。
- 一種具有化學通式(5)之化合物：其中，R4、R7和R8的表示如請求項1所述，所述化合物的所有立體異構物以及其藥學上可接受的鹽類，用於預防及/或治療，及/或用於製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病如請求項1所述。
- 一種具有化學式(6)之化合物(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-側氧-2,3,4,5-四氫-1H-1-苯并吖庚因-3-基]胺基}羰基)環戊基]甲基}-4-苯丁酸((2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-phenylbutanoic acid)，其中：所述化合物的藥學上可接受的鹽類是用於預防及/或治療，及/或用於製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病如請求項1所述。
- 一種具有化學式(7)之化合物(2R)-2-{[1-({[(3S)-1-(羧甲基)-2-側氧-2,3,4,5-四氫-1H-1-苯并吖庚因-3-基]胺基}羰基)環戊基]甲基}-4-(1-萘基)丁酸((2R)-2-{(1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-(1-naphthyl)butanoic acid)，其中：所述化合物的藥學上可接受的鹽類是用於預防及/或治療，及/或用於製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病如請求項1所述。
- 一種具有化學式(8)之化合物三級丁基-((3S)-3-{[1-{[(苄氧)(乙氧)磷醯]甲基}環戊基]-羰基]胺基)-2-側氧-2,3,4,5-四氫-1H-1-苯并吖庚因-1-基)醋酸鹽(tert-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl}cyclopentyl)- carbonyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate)，其中：所述化合物的藥學上可接受的鹽類是用於預防及/或治療，及/或用於製備於預防及/或治療視覺及/或眼睛疾病的藥學成分，疾病如請求項1所述。
- 如請求項1至6中任一項之化合物的用途，其特徵在於藥學上可接受的鹽類為選自由鋰鹽、鈣鹽、鎂鹽及鋅鹽所組成之群組。
- 如請求項7所述之化合物的用途，其特徵在於藥學上可接受的鹽類為鈣鹽。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對原發性青光眼與續發性青光眼的所有形式，隅角開放性青光眼、正常張力青光眼、隅角閉鎖性青光眼、假性剝落症候群、色素分散症候群、血管新生青光眼、炎性青光眼、水晶體相關青光眼、創傷性青光眼、原發性先天青光眼、醫源性誘發青光眼或惡性青光眼。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對後天黃斑點異常，老年性黃斑點退化、自發性脈絡膜血管新生疾病、中心性漿液性脈絡膜視網膜病變、玻璃體界面異常、醫源性黃斑點毛細血管擴張、囊狀黃斑點水腫或、微囊狀黃斑點水腫。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對視神經病變，前方或後方視神經病變；或針對鞏膜炎或上鞏膜炎；或針對視神經炎；或針對眼色素層炎，前眼色素層炎、中眼色素層炎、後眼色素層炎或全眼色素層炎。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對遺傳性眼底異常，色素性視網膜炎、視錐異常、錐桿異常、視桿異常、Stargardt's氏症、Bietti結晶角膜失養症、家族性良性斑點視網膜、貝斯特氏卵黃樣黃斑失養症、成年發病卵黃樣黃斑失養症、北卡羅來納黃斑失養症、家族性顯性隱結或同心環形黃斑失養症。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對視網膜血管疾病，糖尿病視網膜病變、非糖尿病視網膜病變、視網膜靜脈閉塞病、視網膜動脈閉塞病、眼缺血症候群、高眼壓疾病、鐮狀細胞視網膜病變、地中海型貧血視網膜病變、早產兒視網膜病變、視網膜大動脈瘤、原發性視網膜毛細血管擴張、Eales病或放射性視網膜病變。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對近視或退化性近視；或針對乾眼症。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對眼球創傷；或針對術後創傷，由一般手術造成的機械創傷、由雷射手術造成的熱創傷或冷凍手術誘導創傷；或針對玻璃體混濁，玻璃體出血或星狀玻璃體症；或針對視網膜剝離。
- 如請求項1至6中任一項之化合物的用途，其特徵在於所述預防及/或治療為針對角膜疾病，剝落、撕裂、潰瘍、失養、混濁、內皮與上皮衰退、術後水腫、角膜退化或角膜血管形成；或針對角膜擴張，圓錐角膜。
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| 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 |
| ATE400277T1 (de) * | 1998-03-05 | 2008-07-15 | Senju Pharma Co | Pharmazeutische zusammenstellung zur vorbeugung und behandlung von mit zellkrankheiten des augenhintergrundes zusammenhängenden krankheiten |
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| 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 |
| SA04250283B1 (ar) * | 2003-09-26 | 2008-05-26 | سولفاي فارماسيتيكالز جي أم بي أتش | مشتقات من amidomethy1-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid |
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2018
- 2018-01-31 PL PL424452A patent/PL424452A1/pl unknown
-
2019
- 2019-01-31 US US16/963,234 patent/US20210046097A1/en not_active Abandoned
- 2019-01-31 EP EP19747023.0A patent/EP3746106B1/en active Active
- 2019-01-31 HR HRP20240728TT patent/HRP20240728T1/hr unknown
- 2019-01-31 CA CA3088966A patent/CA3088966A1/en active Pending
- 2019-01-31 RS RS20240670A patent/RS65651B1/sr unknown
- 2019-01-31 TW TW108103768A patent/TWI762760B/zh active
- 2019-01-31 PL PL19747023.0T patent/PL3746106T3/pl unknown
- 2019-01-31 CN CN201980011177.2A patent/CN111757750A/zh active Pending
- 2019-01-31 WO PCT/PL2019/000012 patent/WO2019151882A1/en active Application Filing
- 2019-01-31 KR KR1020207025030A patent/KR20200116145A/ko not_active Application Discontinuation
- 2019-01-31 RU RU2020125048A patent/RU2758771C1/ru active
- 2019-01-31 MX MX2020007989A patent/MX2020007989A/es unknown
- 2019-09-10 ZA ZA2019/05959A patent/ZA201905959B/en unknown
-
2020
- 2020-07-12 IL IL275984A patent/IL275984A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL275984A (en) | 2020-08-31 |
| ZA201905959B (en) | 2021-07-28 |
| TWI762760B (zh) | 2022-05-01 |
| MX2020007989A (es) | 2020-09-09 |
| EP3746106B1 (en) | 2024-03-27 |
| HRP20240728T1 (hr) | 2024-08-30 |
| EP3746106A4 (en) | 2021-11-03 |
| WO2019151882A4 (en) | 2019-09-26 |
| US20210046097A1 (en) | 2021-02-18 |
| CN111757750A (zh) | 2020-10-09 |
| EP3746106C0 (en) | 2024-03-27 |
| RS65651B1 (sr) | 2024-07-31 |
| PL3746106T3 (pl) | 2024-06-24 |
| WO2019151882A1 (en) | 2019-08-08 |
| PL424452A1 (pl) | 2019-08-12 |
| CA3088966A1 (en) | 2019-08-08 |
| KR20200116145A (ko) | 2020-10-08 |
| EP3746106A1 (en) | 2020-12-09 |
| RU2758771C1 (ru) | 2021-11-01 |
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