TWI388556B - 醫療組合物 - Google Patents
醫療組合物 Download PDFInfo
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- TWI388556B TWI388556B TW096131928A TW96131928A TWI388556B TW I388556 B TWI388556 B TW I388556B TW 096131928 A TW096131928 A TW 096131928A TW 96131928 A TW96131928 A TW 96131928A TW I388556 B TWI388556 B TW I388556B
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- compound
- inhibitory properties
- formula
- pde5 inhibitory
- pharmaceutically acceptable
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- 239000000203 mixture Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 82
- 230000002401 inhibitory effect Effects 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 28
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 28
- 229960000835 tadalafil Drugs 0.000 claims description 17
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims description 17
- 229960003310 sildenafil Drugs 0.000 claims description 14
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
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- 208000002815 pulmonary hypertension Diseases 0.000 claims description 11
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 206010047139 Vasoconstriction Diseases 0.000 claims description 8
- 230000025033 vasoconstriction Effects 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 206010002383 Angina Pectoris Diseases 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 6
- 201000001881 impotence Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 5
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 claims description 5
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- 200000000007 Arterial disease Diseases 0.000 claims description 3
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- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229960000438 udenafil Drugs 0.000 claims description 2
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 claims description 2
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 claims 10
- 101150098694 PDE5A gene Proteins 0.000 claims 10
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 claims 10
- 230000036772 blood pressure Effects 0.000 description 15
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
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- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 2
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- RGTMHUKTLKJHNW-UHFFFAOYSA-N 1H-pyrazole 1H-pyrimidin-2-one Chemical class N1C(N=CC=C1)=O.N1N=CC=C1 RGTMHUKTLKJHNW-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
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- 235000010489 acacia gum Nutrition 0.000 description 1
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- 230000001154 acute effect Effects 0.000 description 1
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- 238000005349 anion exchange Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013928 guanylic acid Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 235000015598 salt intake Nutrition 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013300 spontaneous hypertensive rat model Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000037905 systemic hypertension Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Description
本發明係關於一種產物，其含有下式(I)之化合物
或此化合物之醫藥學上可接受之鹽與至少一種具有PDE5抑制特性之化合物或其醫藥學上可接受之鹽的組合，其係在涉及血管收縮之疾病的治療中同時地、個別地或歷經一段時間地用於治療用途。
PCT公開案WO 02/053557描述了包括式(I)化合物之內皮素受體拮抗劑及該等內皮素受體拮抗劑在涉及血管收縮之各種疾病(尤其是心臟衰竭、心絞痛、肺高壓症及全身性高血壓及勃起功能障礙)治療中之用途。
以下專利文件中已特別描述了PDE－5抑制劑：US 5,250,534(描述作為PDE－5抑制劑之吡唑幷嘧啶酮衍生物且尤其是西地那非(sildenafil)及其尤其用於高血壓及心臟衰竭之用途)及EP 1 097 711(尤其描述西地那非用於肺高壓症之用途)；WO 99/24433(尤其描述伐地那非(vardenafil)及其尤其用於高血壓、心絞痛及勃起功能障礙之用途)；US 5,859,006(尤其描述他達那非(tadalafil)及其尤其用於高血壓、肺高壓症、絞痛症及充血性心臟衰竭之用途)；WO 00/27848(尤其描述優地那非(udenafil)及其用於陽痿之用途)。
本申請者現已意外發現式(I)化合物與具有PDE5抑制特性之化合物的組合在涉及血管收縮之疾病的治療中產生意外的協同效應。
因此，本發明之一目標為一種產物，其含有如上所述之式(I)化合物或該式(I)化合物之醫藥學上可接受之鹽與至少一種(且較佳一種)具有PDE5抑制特性之化合物或其醫藥學上可接受之鹽的組合，其係在涉及血管收縮之疾病的治療中同時地、個別地或歷經一段時間地用於治療用途。
以下段落提供本專利申請案中所用之各種術語的定義且意欲在整個說明書及申請專利範圍中一致地應用，除非另外明確闡明之定義提供更廣泛或更狹隘之定義。
"PDE－5"在本申請案中代表5型環3',5'－單磷酸鳥苷(cGMP)磷酸二酯酶。
當提及治療用途時，"同時地"或"同時的"在本申請案中意謂相關治療用途係兩種或兩種以上活性成份經由相同途徑同時投藥。
當提及治療用途時，"個別地"或"個別的"在本申請案中意謂相關治療用途係兩種或兩種以上活性成份經由至少兩種不同途徑大約同時投藥。
治療性投藥"歷經一段時間"在本申請案中意謂兩種或兩種以上成份在不同時間投藥，且詳言之為活性成份之一完全投藥完成後再開始投與其他成份之投藥方法。以此方式有可能投與活性成份之一歷時數月，隨後投與其他活性成份。在此情況下，不發生同時投藥。
"涉及血管收縮之疾病"尤其意謂高血壓、肺高壓症(包括肺動脈高壓)、糖尿病性動脈病、心臟衰竭、勃起功能障礙或心絞痛。
"具有PDE5抑制特性之化合物"意謂當接受描述於本專利申請案中之"PDE5 IC50
測定測試"時，具有等於或低於1 μM之IC50
值的化合物。
具有PDE5抑制特性之化合物的特定實例包括具有以下結構(名稱)之化合物：
術語"醫藥學上可接受之鹽"係指無毒性無機或有機酸加成鹽及/或鹼加成鹽。可參考"Salt selection for basic drugs",Int.J.Pharm.
(1986),33,201－217。
此外，應瞭解若適當及有利任何對式(I)化合物或對具有PDE5抑制特性之化合物的提及均如同亦提及其醫藥學上可接受之鹽。
較佳地，根據本發明之產物將使得式(I)化合物與具有PDE5抑制特性之化合物意欲用於同時或歷經一段時間發生的治療用途。
根據本發明之一較佳變體，式(I)化合物與具有PDE5抑制特性之化合物將意欲同時投與。
根據本發明之另一較佳變體，式(I)化合物與具有PDE5抑制特性之化合物將意欲歷經一段時間投與。
為達成根據本發明之產物的治療用途，意欲該段時間將至少為一週，且較佳為至少一個月或多個月(例如6個月)。此段時間亦可能為接受該產物之患者的終生。較佳地，式(I)化合物可與具有PDE5抑制特性之化合物交替投藥，且此投藥之間的時間間隔將不超過兩天或三天(且更佳不超過一天)。
具有PDE5抑制特性之化合物較佳係選自西地那非、伐地那非、他達那非及優地那非。具有PDE5抑制特性之化合物更佳為西地那非或他達那非。
根據本發明之一尤其較佳之變體，具有PDE5抑制特性之化合物為西地那非。
根據本發明之另一尤其較佳之變體，具有PDE5抑制特性之化合物為他達那非。
式(I)化合物與具有PDE5抑制特性之化合物的投藥途徑較佳相同。詳言之，式(I)化合物及具有PDE5抑制特性之化合物的常見投藥途徑為靜脈內途徑或口服途徑(且尤其為口服途徑)。
儘管將必須由治療醫師來確定根據本發明之產物的精確投藥劑量，但預期0.05 mg至2 mg(且較佳0.1 mg至1 mg)式(I)化合物/公斤患者體重之劑量與0.01 mg至1 mg(且較佳0.05 mg至0.5 mg)他達那非/公斤患者體重之劑量的組合(兩種化合物均意欲藉由口服途徑來投藥)，或與0.1 mg至2 mg(且較佳0.2 mg至1 mg)西地那非/公斤患者體重之劑量的組合(兩種化合物亦均意欲藉由口服途徑來投藥)將為適當的。
意欲以根據本發明之產物來治療的疾病較佳選自高血壓、肺高壓症、糖尿病性動脈病、心臟衰竭、勃起功能障礙及心絞痛。意欲以根據本發明之產物來治療的疾病更佳選自高血壓及肺高壓症。特定言之，意欲以根據本發明之產物來治療的疾病為肺高壓症(且尤其為肺動脈高壓)。
本發明亦係關於一種醫藥組合物，其含有作為活性成份之下式(I)之化合物
或此化合物之醫藥學上可接受之鹽與至少一種(且較佳一種)具有PDE5抑制特性之化合物或其醫藥學上可接受之鹽的組合，以及至少一種賦形劑。
本發明另外係關於下式(I)之化合物
或此化合物之醫藥學上可接受之鹽與至少一種(且較佳一種)具有PDE5抑制特性之化合物或其醫藥學上可接受之鹽的組合用於製造意欲治療需要血管擴張之疾病的藥物之用途。
此外，所指示之根據本發明之較佳產物當然亦可在經必要之修改後適用於本發明之醫藥組合物及用途。
以下實例描述本發明之特定實施例，其係用以更詳細地闡明本發明而不以任何方式限制其範疇。
為闡明本發明之有效性，在兩個不同高血壓模型(亦即Dahl鹽敏感性大鼠模型及自發性高血壓大鼠模型)中研究以0.3 mg/kg之劑量經口投與之式(I)化合物與以10 mg/kg之劑量經口投與之他達那非之組合。此外，在自發性高血壓大鼠模型中研究以0.3 mg/kg之劑量經口投與之式(I)化合物與以30 mg/kg之劑量經口投與之西地那非之組合。在下文題為"本發明化合物之藥理學特性"之部分中詳述所用方案。
本發明化合物之藥理學特性
可使用下文所述之實驗方法展示本發明化合物之藥理學特性。
Dahl鹽敏感性大鼠模型
自Harlan(Netherlands)購得Dahl鹽敏感性(Dahl－S)大鼠。在環境適應期間將大鼠成群安置且在植入遙測裝置之後單個安置。所有動物維持於相同條件下且可自由獲取普通球粒大鼠食物及水。Dahl鹽敏感性大鼠僅在暴露於鹽攝取後才出現高血壓。對其投與高鹽(8%)飲食(Purina系列5500)。開始投與鹽後5週，在經吸入2.5%異氟烷(於70%O2
＋30% N2
O中)而麻醉下植入遙測系統。在無菌條件下，將壓力射頻傳輸器植入腹腔內，且在降主動脈中插入感應導管且將其朝上游推進以略微處於腎動脈分叉以下。將傳輸器縫合於腹部肌肉組合且使皮膚閉合。接收器平臺將無線電信號轉換為數位化輸入，將其輸送至專用個人電腦(Compaq,deskpro)。藉由使用來自周圍壓力參照監測器之輸入來校準動脈血壓量測值。遙測單元係自Data Sciences(St.Paul,MN,USA)獲得。
在遙測系統植入後至少2週投與化合物。在5%阿拉伯膠中製備式(I)化合物及具有PDE5抑制特性之化合物且藉由口腔管飼法來投藥。藉由在經口投藥後每隔5分鐘收集資料歷時長達72 h來量測式(I)化合物、具有PDE5抑制特性之化合物及其組合對血壓之急性效應。計算各大鼠血壓之每小時平均值。藉由使用投藥前最後24小時之血壓資料，各大鼠以自身作對照。將兩條曲線(對照期血壓及治療期血壓)一起作圖且計算0小時至72小時之曲線間面積(ABC)。ABC愈高，經測試用於降低血壓之物品的作用愈強。
自發性高血壓大鼠模型
除用自發性高血壓大鼠(SHR)替代Dahl－S大鼠且SHR大鼠不接受任何鹽飲食以外，使用與Dahl鹽敏感性大鼠模型相同之方案。SHR大鼠係自Harlan(Netherlands)購得。
PDE5 IC 50 測定測試：
為評估測試化合物對PDE5活性之抑制程度，進行以下測試。自人類海綿體組織分離磷酸二酯酶－5酵素(PDE5)。在4℃將約3 g此組織以12 ml HEPES緩衝液(20 mM HEPES、250 mM蔗糖、1 mM EDTA、1 mM PMSF,pH值7.2)均質化。以雙層紗布過濾溶液且在4℃離心(100,000×g)60 min。以0.2 μm濾紙過濾上清液且藉由HPLC(Mono Q陰離子交換管柱)使用0 mM－500 mM NaCl之濃度梯度溶離PDE同功酶來進行分離。藉由以下方法量測各管柱溶離份之酶活性以分離PDE5溶離份且使用PDE5溶離份來量測測試化合物之PDE5抑制作用。將100 μl反應混合物(15 mM Tris－HCl、5 mM MgCl2
、0.5 mg/ml BSA，pH值7.4)及適量測試化合物溶離份及測試化合物添加至1.5 ml管中且使混合物充分混合。將3
H－cAMP或3
H－Cgmp(500 nM,2μCi/ml)添加至此溶液中，使混合物在30℃恆溫箱中反應約1小時且藉由將管放入沸水中歷時約45秒鐘至2分鐘來終止反應。接著在冰浴中將管冷卻約5 min。將蛇毒(1 mg/ml,100 μl)或5－核苷酸酶(0.1單位/管)添加至此管中且使混合物在37℃恆溫箱中反應10 min且在冰浴中冷卻。將樹脂3倍體積之甲醇添加至陰離子交換樹脂(Bio－Rad樹脂，AG1－X2,200目－400目)，其係已依次經0.5 N HCl、H2
O、0.5 N NaOH、H2
O、0.5 N HCl及H2
O洗滌且調節至pH 5。接著將1 ml經預處理之樹脂經攪拌分配至各管中。伴隨偶爾攪拌將混合物置於4℃歷時15 min且離心(10,000 rpm)歷時約5 min以使樹脂沈降。將上清液(700 μl)轉移至液體閃爍小瓶中，且與10 ml閃爍混合液混合。在經置放隔夜而使溶液穩定後，以β－計數器來量測管之放射能。
若測試化合物具有等於或低於1 μM之IC50
值，則認為其具有用於本專利申請案之目的之PDE5抑制特性。若測試化合物具有高於1 μM之IC50
值，則認為其不具有用本專利申請案之目的之PDE5抑制特性。
根據先前描述於題為"Dahl鹽敏感性大鼠模型"部分之測試方案，經口投與式(I)化合物及他達那非均降低Dahl－S大鼠之血壓：式(I)化合物(0.3 mg/kg)以256之ABC降低血壓且他達那非(10 mg/kg)以310之ABC降低血壓。經口投與組合(式(I)化合物為0.3 mg/kg且他達那非為10 mg/kg)後ABC為923，證明具有協同效應。
根據先前描述於題為"自發性高血壓大鼠模型"部分之測試方案，經口投與式(I)化合物及他達那非均降低SHR大鼠之血壓：式(I)化合物(0.3 mg/kg)以44之ABC降低血壓且他達那非(10 mg/kg)以286之ABC降低血壓。口腔管飼組合(式(I)化合物為0.3 mg/kg且他達那非為10 mg/kg)後ABC為444，證實具有協同效應。
根據先前描述於題為"自發性高血壓大鼠模型"部分之測試方案，經口投與式(I)化合物及西地那非均降低SHR大鼠之血壓：式(I)化合物(0.3 mg/kg)以38之ABC降低血壓且西地那非(30 mg/kg)以229之ABC降低血壓。口腔管飼組合(式(I)化合物為0.3 mg/kg且西地那非為30 mg/kg)後ABC為317，證實具有協同效應。
Claims (12)
- 一種產物，其含有下式(I)之化合物
- 如請求項1之產物，其中該具有PDE5抑制特性之化合物係選自西地那非(sildenafil)、伐地那非(vardenafil)、他達那非(tadalafil)及優地那非(udenafil)。
- 如請求項2之產物，其中該具有PDE5抑制特性之化合物為他達那非。
- 如請求項2之產物，其中該具有PDE5抑制特性之化合物為西地那非。
- 如請求項1之產物，其中該涉及血管收縮之疾病係選自高血壓、肺高壓症、糖尿病性動脈病、心臟衰竭、勃起功能障礙及心絞痛。
- 一種醫藥組合物，其含有作為活性成份之如請求項1之式(I)化合物或該式(I)化合物之醫藥學上可接受之鹽與至少一種具有PDE5抑制特性之化合物或其醫藥學上可接受之鹽的組合，以及至少一種賦形劑。
- 如請求項6之醫藥組合物，其中該具有PDE5抑制特性之化合物係選自西地那非、伐地那非、他達那非及優地那非。
- 如請求項7之醫藥組合物，其中該具有PDE5抑制特性之化合物為他達那非。
- 如請求項7之醫藥組合物，其中該具有PDE5抑制特性之化合物為西地那非。
- 一種如請求項1之式(I)化合物或該式(I)化合物之醫藥學上可接受之鹽與至少一種具有PDE5抑制特性之化合物或其醫藥學上可接受之鹽之組合的用途，其係用於製造意欲治療涉及血管收縮之疾病的藥物。
- 如請求項10之用途，其中該具有PDE5抑制特性之化合物係選自西地那非、伐地那非、他達那非及優地那非。
- 如請求項10之用途，其中該意欲接受治療之疾病係選自高血壓及肺高壓症。
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2007
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- 2007-08-27 CL CL200702494A patent/CL2007002494A1/es unknown
- 2007-08-28 SI SI200731367T patent/SI2059246T1/sl unknown
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- 2007-08-28 ES ES07826167.4T patent/ES2438792T3/es active Active
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- 2007-08-28 JP JP2009526239A patent/JP5208113B2/ja active Active
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- 2007-08-28 EP EP07826167.4A patent/EP2059246B1/en active Active
- 2007-08-28 WO PCT/IB2007/053448 patent/WO2008026156A2/en not_active Ceased
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- 2009-02-25 IL IL197235A patent/IL197235A/en active IP Right Grant
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- 2009-03-26 NO NO20091254A patent/NO342554B1/no unknown
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2012
- 2012-09-05 US US13/604,148 patent/US20130210830A9/en not_active Abandoned
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2013
- 2013-12-27 CY CY20131101163T patent/CY1114735T1/el unknown
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2014
- 2014-01-23 US US14/162,280 patent/US20140148460A1/en not_active Abandoned
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2018
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2019
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2020
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