CN1123345C - 治疗ards或irds的组合物 - Google Patents
治疗ards或irds的组合物 Download PDFInfo
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- CN1123345C CN1123345C CN98802597A CN98802597A CN1123345C CN 1123345 C CN1123345 C CN 1123345C CN 98802597 A CN98802597 A CN 98802597A CN 98802597 A CN98802597 A CN 98802597A CN 1123345 C CN1123345 C CN 1123345C
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
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- 230000002980 postoperative effect Effects 0.000 description 1
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- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Marine Sciences & Fisheries (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Detergent Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了治疗ARDS或IRDS、含有N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和/或其可药用盐以及肺表面活性剂的组合物。
Description
技术领域
本发明涉及用于治疗称为婴儿呼吸窘迫综合征(IRDS)和急性或成人呼吸窘迫综合征(ARDS)疾病的新的组合物。
背景技术
成人呼吸窘迫综合征(ARDS)是描述性表达，如果其伴有严重的气体交换障碍(特别是动脉低氧血)，是指具有不同病因学的大量的急性、弥散浸润性肺损害。之所以用ARDS来表示，是因为其大量的临床和病理学症状与婴儿呼吸窘迫综合征(IRDS)相同。如果对于IRDS来说，由早产引起的肺表面活性剂的缺乏是主要原因，那么对于ARDS，肺表面活性剂机能不良是由基于不同病因的肺病引起的。
引发ARDS的病因可以是，例如(参见Harrison’s Principles ofInternal Medicine 10th Ed.1983 McGraw-Hill Int.Book Comp)弥散性肺感染(例如由病毒、细菌、真菌引起的感染)，吸入如胃液的吸入或淹溺时的吸入，呼吸入毒素或刺激物(例如氯气、氧化氮、烟雾)，直接或间接创伤(例如多次骨折或肺挫伤)，对肺外炎症的系统反应(例如胰腺炎出血，格兰式阴性败血症)，高血容量的输血或心肺分流术后的选择性输血。
在50％-60％的死亡率下(Schuster Chest 1995，107：1721-26中的调查结果)，ARDS病人的前景仍不妙。
ARDS的治疗主要包括可能最早使用的不同形式的换气[例如，PEEP(呼气末正压)，增加呼吸气中氧的浓度，SIMV(周期性同步强制性通气；Harrison’s Principles of Internal Medicine 10th Ed.1983 McGraw-Hill Int.Book Comp)]来进行体外膜充氧(ECMO；Zapol and Lemaire成人呼吸窘迫综合征，Marcel Dekker Inc.1991)。
具体使用不同的换气技术仅使死亡率有很小的降低，并且还带来导致恶性循环的危险。在压力和高FiO2[吸入氧气的比例；氧气在呼吸气中的比例]的换气下，肺自身会受损害，并且作为这种损害的结果，可能需要更高的压力和更高的FiO2以在血液中获得足够的充氧。
现在，为了解决这个问题也发展了不同的药物学方法。包括肺表面活性剂代替物[调查，例如B.Lachmann，D.Gommers和E.P.Eijking：在成人中进行的外源性表面活性剂治疗，Atemw-Lungenkrkh.1993，19：581-91；T.J.Gregory等人：在患有急性呼吸窘迫综合征(ARDS)的病人中补充Survanta，Am.J。Respir.Crit.Care Med.1994，149：A567]，用例如前列腺素E1(PGE1；Abraham等人Crit Care Med 1996，24：10-15)或糖皮质类固醇激素(Bernard等人，N Engl Med 1987，317：1565-70)进行纯抗炎治疗。虽然通过施用肺表面活性剂取得了一些具体成功(例如Walmrath等人，AM JResp Crit Care Med 1996，154：57-62)，但是纯抗炎治疗只有极少至没有任何效果。这与ARDS的病理学和病理组织学发现形成了鲜明对比。因此在患有ARDS的病人的肺和灌洗物中发现了大量的多形核白细胞浸润(调查，例如Thiel等人的Anesthesist 1996，45：113-130)，并且检测到了许多炎性介质。在试验中，脂质体静脉给药剂型中还含有PGE1(Abraham等人的Crit Care Med 1996，24：10-15)和目的是抑制磷脂酸的物质(例如，Lisofylline；Rice等人的Proc Natl Acad Sci 1994，91：3857-61)和重组人白介素1(IL-1)受体拮抗剂(Fish等人的JAMA 1994，271：1836-43)。然而，PGE1和IL-1受体拮抗剂都由于副作用而限制了其医疗用途。
WO 96/09831公开了治疗ARDS和IRDS的组合物，其中含有糖皮质类固醇激素和肺表面活性剂。EP-B-0 451 215描述了将药物活性化合物经肺给药的组合物。这些组合物含有包含药物活性化合物的脂质体和肺表面活性蛋白。这些组合物也被提出来治疗ARDS和IRDS。EP-B-0 055 041描述了治疗呼吸器官疾病的吸入剂或注射剂，其中含有治疗呼吸器官疾病的活性化合物和天然肺表面活性剂。其中没有公开治疗ARDS和IRDS的组合物。
发明内容
现在惊奇地发现，通过将N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和肺表面活性剂联合给药，可获得治疗IRDS和ARDS的协同效应。
因此，本发明涉及用于治疗IRDS和ARDS、含有N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和/或其可药用盐和肺表面活性剂的组合物。
本发明进一步的实施方案基于权利要求。
N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和其作为磷酸二酯酶(PDE)IV抑制剂的应用描述在WO 95/01338中。可提及的N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺的可药用盐是，例如与酸形成的水溶性和水不溶性酸加成盐，所述的酸有例如盐酸、氢溴酸、磷酸、硝酸、硫酸、乙酸、柠檬酸、D-葡萄糖酸、苯甲酸、2-(4-羟基苯甲酰基)苯甲酸、丁酸、磺基水杨酸、马来酸、月桂酸、苹果酸、富马酸、琥珀酸、草酸、酒石酸、扑酸、硬脂酸、甲苯磺酸、甲磺酸或3-羟基-2-萘甲酸，根据其是否是一元或多元酸，并且根据需要什么酸，酸以等摩尔比或非等摩尔比在盐制剂中使用。
根据本发明，肺表面活性剂是指大量已知的具有天然肺表面活性剂功能的组合物和其修饰物。天然肺表面活性剂具有表面活化性能，可降低肺中肺泡区域的表面张力。测定表面活性剂制剂的表面活性的简单快速体外定量分析法是例如Wilhelmy平衡[Goerke，J BiophysActa，344：241-261(1974)；King R.J.和Clements J.A.，Am JPhysiol 223：715-726(1972)]。此测定法依据其接近0 mN/m表面张力的能力来指示表面活性剂的性能。它是通过将表面活性剂悬浮液以确定的磷脂浓度注射到水溶液中来进行的。磷脂伸展到气-液相形成单层。此单层降低了水溶液的表面张力。将铂板小心地浸入溶液中。用灵敏的传感器可测定拉铂板的力。此拉力与表面张力成正比，并且与铂板的大小有关。另一测定表面活性剂制剂的表面活性的方法是搏动冒泡表面活性测量仪[Possmayer F.，Yu S.和Weber M.，ProgResp Res，Ed.v.Wichert，Vol.18：112-120(1984)]。表面活性剂制剂的活性也可以通过体内分析来测定，例如，在下文药理学部分中描述的方法。肺顺应性、血内气体和换气压的测定结果能提供活性指标。
根据本发明，肺表面活性剂优选指在这类测定中能显示活性的组合物。特别是指在这类测定中显示出与天然尤其是人肺表面活性剂相似或比其更高的活性的组合物。
特别是，肺表面活性剂组合物含有磷脂并且还可以含有肺表面活性蛋白。可提及的市售产品有Curosurf(Serono，Pharma GmbH，Unterschleissheim)，这是从匀化的猪肺中提取的高度纯化的天然表面活性剂，Survanta(Abbott Gmbh，Wiesbaden)和Alveofact(Dr.Karl Thomae GmbH，Biberach)，这两种产品都是从牛肺中提取的，以及Exosurf(Deutsche Wellcome GmbH，Burgwedel)，这是用辅助物合成的磷脂。可能的肺表面活性蛋白是从天然来源，例如肺的灌洗物或羊膜水提取物，和基因工程蛋白中获得的。根据本发明，指定为SP-B和SP-C的肺表面活性蛋白及其修饰衍生物是特别有效的。这些肺表面活性蛋白的氨基酸序列、其分离或基因工程制备方法是已知的(例如，参见WO-86/03408，EP-A-0 251，449，WO-89/04326，WO-87/06943，WO-88/03170，EP-A-0 368 823，和EP-A-0348 967)。通过替换一些氨基酸而制备的与人SP-C不同的SP-C的修饰衍生物公开在WO91/18015和WO95/32992的实施例中。特别提到WO95/32992的SP-C衍生物。根据本发明，特别优选的重组SP-C衍生物[下文称为r-SP-C(FF/l)]与人SP-C不同之处在于，用苯丙氨酸替代了4位和5位的两个半胱氨酸，用异亮氨酸替代了32位的蛋氨酸。EP-B-0 100 910，EP-A-0 110 498，EP-B-0 119 056，EP-B-0 145 005和EP-B-0 286 011描述了含有和不含有肺表面活性蛋白的磷脂组合物，它们适于例如用作本发明制剂中的组分。
本发明进一步涉及本发明组合物在制备用于治疗和/或预防IRDS或ARDS的药物中的应用。
本发明还涉及含有本发明组合物、用于治疗和/或预防上述疾病的药物。
本发明组合物可制成用于气管内或支气管内给药的液体剂型或吸入给药的粉剂。本发明组合物是用本领域技术人员熟悉的方法制备的，需要时，还可以使用合适的药用辅料。例如，可通过将肺表面活性剂的液体制剂如水悬浮液与N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺的水悬浮液混合，然后冷冻干燥和微粒化来制备粉剂。或，可通过将肺表面活性剂与N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺在合适溶剂如叔丁醇中的溶液冷冻干燥，然后微粒化来制备。将肺表面活性剂悬浮液与N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺的水悬浮液的混合物，或肺表面活性剂与N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺在合适的溶剂如可选择性地含有水的醇(例如甲醇、乙醇、2-丙醇)、氯仿、二氯甲烷、丙酮和其混合物中的溶液喷雾干燥，也可以获得粉剂。吸入给药也可以通过将含有本发明组合物的溶液或悬浮液雾化来进行。本发明组合物含有1％-30％重量的N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺是有利的。
具体实施方式
下面用实施例来描述通过喷雾干燥制备的粉剂。
实施例1
将8.2g 1，2-二棕榈酰基-3-sn-磷脂酰胆碱、3.46g 1-棕榈酰基-2-油酰基-3-sn-磷脂酰甘油铵、2.7g N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺、0.56g棕榈酸、0.3g氯化钙和0.2gr-SP-C(FF/l)溶于700ml 2-丙醇/水(90∶10)中，在Büchi B 191实验喷雾干燥仪中喷雾干燥。喷雾条件：无水氮气、进口温度110℃、出口温度59-61℃。获得了精细的、奶油色的粉末。
实施例2
将8.2g 1，2-二棕榈酰基-3-sn-磷脂酰胆碱、3.46g 1-棕榈酰基-2-油酰基-3-sn-磷脂酰甘油铵、0.27g N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺、0.56g棕榈酸、0.3g氯化钙和0.2g r-SP-C(FF/l)按实施例1所述方法喷雾干燥。
实施例3
将8.2g 1，2-二棕榈酰基-3-sn-磷脂酰胆碱、3.46g 1-棕榈酰基-2-油酰基-3-sn-磷脂酰甘油铵、0.027g N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺、0.56g棕榈酸、0.3g氯化钙和0.2g r-SP-C(FF/l)按实施例1所述方法喷雾干燥。实施例4
将10.0g 1，2-二棕榈酰基-3-sn-磷脂酰胆碱、2.6g N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺、0.74g泰洛沙泊(tyloxapol)和1.1g 1-十六醇溶于500ml 2-丙醇/水(90∶10)中，在Büchi B 191实验喷雾干燥仪中喷雾干燥。喷雾条件：无水氮气、进口温度110℃、出口温度58-60℃。获得白色到黄白色的粉末。下面用实施例来描述冷冻干燥的组合物制剂。
实施例5
将8.0g从牛肺中提取的纯化的肺表面活性剂和2.0g N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺加到90ml水中。将得到的悬浮液在-25℃冷冻干燥，获得了浅黄白色的蓬松状产物。
本发明进一步涉及治疗患有IRDS或ARDS的哺乳动物包括人的方法。其特征在于，将治疗活性和药理学可忍受量的本发明组合物对患有所述疾病的哺乳动物给药。
本发明进一步涉及用于治疗IRDS或ARDS的本发明组合物。
本发明组合物每天给药3-4次，给药2-4天。例如，含有4mgN-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和50mg磷脂的制剂以6小时的间隔，通过吸入或气管内或支气管内给药6次。药理学
用纯氧气在呼气末正压下(PEEP；为了保证大鼠的充氧)对成年Sprague Dawley大鼠进行人工换气，并且灌洗直到其内源性肺表面活性剂被洗出(D.Hfner，U.Kilian和R.Beume：在成人呼吸窘迫综合征(ARDS)的动物模型中比较四种肺表面活性剂制剂.Am.Rev.Respir.Dis.1993，147：A719；D.Hfner，P.-G.Germann，D.Hauschke，《肺药理学》(Pulmonary Pharmacology)(1994)7，319-332)。在这些大鼠中，动脉氧分压(PaO2)由初始值500-550mmHg(在纯氧气换气和PEEP)降到50-110mmHg，这一事实证明了内源性肺表面活性剂被洗出。没用肺表面活性剂进行治疗的对照组大鼠在整个观测期间都维持低的PaO2。PaO2降到这些低的值后60分钟，将肺表面活性剂或肺表面活性剂与N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺一起进行气管内滴注给药。滴注后30分钟和120分钟测定血内气体。
在下面的表1和表2中，横栏A中是以mmHg表示的在气管内滴注后30分钟(8cm H2O的恒定PEEP)测定的PaO2的平均值(±标准偏差)，横栏B中是在气管内滴注后120分钟测定的平均值。从表1中可以看出，N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺单独给药对PaO2没有影响。这是与未治疗的对照组比较得出的结论。用肺表面活性剂给药(25或100mg/kg)使PaO2增加(使用的肺表面活性剂相当于实施例1中未使用N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺的组合物)。与各自的肺表面活性剂剂量相比，向各自的肺表面活性剂剂量中加入600μg/kg或6.0mg/kg N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺改善了PaO2值。这可从将N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺与肺表面活性剂联合给药产生了意料不到的超叠加效果看出。因此可以节省一部分非常昂贵的肺表面活性剂，或获得每一单个组分的增加了的疗效。表1：
*化合物A＝N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺表2：
*化合物A＝N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺
| 对照组 | 化合物A*600μg/kg | 肺表面活性剂25mg/kg | 肺表面活性剂25mg/kg+化合物A*600μg/kg | 肺表面活性剂100mg/kg | 肺表面活性剂100mg/kg+化合物A*600μg/kg | |
| A | 67±17 | 59±12 | 305±96 | 341±105 | 427±78 | 473±31 |
| B | 75±24 | 311±111 | 359±74 | 457±58 | 478±43 |
| 肺表面活性剂25mg/kg | 肺表面活性剂25mg/kg+化合物A*6.0mg/kg | 肺表面活性剂100mg/kg | 肺表面活性剂100mg/kg+化合物A*6.0mg/kg | |
| A | 305±96 | 407±65 | 427±78 | 502±32 |
| B | 311±111 | 369±147 | 457±58 | 511±28 |
与本实验结合起来进行的对实验大鼠的肺所做的组织学检查表明，其中形成了严重的透明膜(HM)，发生了炎症细胞的严重汇集[例如多形核白细胞浸润(PMNL)]，这表示形成了急性呼吸窘迫综合征。
对含有N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和肺表面活性剂(磷脂混合物)以及含有或不含有表面活性蛋白的本发明制剂在此模型中进行的研究发现，与肺表面活性剂或N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺单独给药相比，本发明制剂使充氧和组织学改变(抑制HM的形成和抑制PMNL的汇集)有了超叠加程度的改善。作为此意料不到的协同作用的结果，治疗IRDS和ARDS所需的时间可缩短，伴随这类综合征的高死亡率可以降低。
Claims (7)
1.含有N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和/或其可药用盐以及肺表面活性剂的治疗IRDS和ARDS的组合物。
2.根据权利要求1的组合物，其中含有磷脂混合物作为肺表面活性剂。
3.根据权利要求2的组合物，其中含有得自天然肺表面活性剂的磷脂。
4.根据权利要求2或3的组合物，其中还含有肺表面活性蛋白。
5.根据权利要求4的组合物，其中还含有SP-B和/或SP-C和/或其修饰衍生物。
6.根据权利要求1的组合物，其中含有得自肺灌洗物的肺表面活性剂。
7.N-(3，5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺和/或其可药用盐以及肺表面活性剂在制备用于治疗IRDS和ARDS的药物中的应用。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19705924.4 | 1997-02-17 | ||
| DE19705924A DE19705924A1 (de) | 1997-02-17 | 1997-02-17 | Neue Zusammensetzungen |
| EP97102639.8 | 1997-02-19 | ||
| EP97102639 | 1997-02-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1248169A CN1248169A (zh) | 2000-03-22 |
| CN1123345C true CN1123345C (zh) | 2003-10-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN98802597A Expired - Lifetime CN1123345C (zh) | 1997-02-17 | 1998-02-14 | 治疗ards或irds的组合物 |
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| US (2) | US6436970B1 (zh) |
| EP (1) | EP0977577B1 (zh) |
| JP (1) | JP4763104B2 (zh) |
| KR (1) | KR100640025B1 (zh) |
| CN (1) | CN1123345C (zh) |
| AT (1) | ATE336254T1 (zh) |
| AU (1) | AU734122B2 (zh) |
| BR (1) | BR9807399B1 (zh) |
| CA (1) | CA2276429C (zh) |
| CZ (1) | CZ293871B6 (zh) |
| DE (1) | DE69835594T2 (zh) |
| DK (1) | DK0977577T3 (zh) |
| EA (1) | EA001758B1 (zh) |
| EE (1) | EE04094B1 (zh) |
| ES (1) | ES2271990T3 (zh) |
| HK (1) | HK1026145A1 (zh) |
| HU (1) | HU227520B1 (zh) |
| IL (1) | IL130658A (zh) |
| NO (1) | NO323594B1 (zh) |
| NZ (1) | NZ336569A (zh) |
| PL (1) | PL190775B1 (zh) |
| PT (1) | PT977577E (zh) |
| SI (1) | SI0977577T1 (zh) |
| TR (1) | TR199901772T2 (zh) |
| UA (1) | UA50808C2 (zh) |
| WO (1) | WO1998035683A1 (zh) |
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| HU227520B1 (hu) * | 1997-02-17 | 2011-07-28 | Nycomed Gmbh | ARDS és IRDS kezelésére szolgáló, 3-(ciklopropil-metoxi)-N-(3,5-diklór-4-piridinil)-4-(difluor-metoxi)-benzamidot és tüdõfelületaktív anyagot tartalmazó kompozíció |
| WO2001019392A1 (en) * | 1999-09-16 | 2001-03-22 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Combination of c1-inh and lung surfactant for the treatment of respiratory disorders |
| DE19957898A1 (de) * | 1999-12-01 | 2001-06-07 | Byk Gulden Lomberg Chem Fab | Neue Verwendung von Lungensurfactant |
| AU2001261962B2 (en) | 2000-05-25 | 2005-04-21 | Merck Frosst Canada Ltd | Fluoroalkoxy-substituted benzamide dichloropyridinyl n-oxide pde4 inhibitor |
| DE60205899T2 (de) | 2001-05-24 | 2006-06-29 | Merck Frosst Canada & Co, Kirkland | 1-biaryl-1,8-naphthyridin-4-one als phosphodieseterase-inhibitoren |
| US20030099601A1 (en) * | 2001-11-27 | 2003-05-29 | Gordon Marc S. | Inhalation lung surfactant therapy |
| WO2003053455A1 (en) * | 2001-12-12 | 2003-07-03 | Penn State Research Foundation | Surfactant prevention of lung complications from cancer chemotherapy |
| US20030170223A1 (en) * | 2002-02-01 | 2003-09-11 | Board Of Trustees Of Michigan State University | Pulmonary vasodilator surfactant compositions and method of use |
| MY140561A (en) * | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| US6822114B1 (en) | 2002-10-08 | 2004-11-23 | Albemarle Corporation | Process for production of fluoroalkoxy-substituted benzamides and their intermediates |
| ATE399544T1 (de) * | 2002-11-27 | 2008-07-15 | Nycomed Gmbh | Synergistische zusammensetzung enthaltend roflumilast und (r,r)-formoterol |
| ATE399543T1 (de) * | 2002-11-27 | 2008-07-15 | Nycomed Gmbh | Neue synergistische zusammensetzung enthaltend roflumilast und formoterol |
| MXPA04008070A (es) | 2003-03-10 | 2004-11-26 | Altana Pharma Ag | Novedoso proceso para la preparacion de roflumilasto. |
| JP2006527737A (ja) * | 2003-06-16 | 2006-12-07 | アルタナ ファルマ アクチエンゲゼルシャフト | 肺サーファクタントとｐｄｅ５阻害剤とを含有する肺疾病の治療用の組成物 |
| AU2005268755B2 (en) | 2004-08-06 | 2011-04-07 | Takeda Gmbh | Composition comprising a pulmonary surfactant and a TNF-derived peptide |
| EP1861074B1 (en) * | 2005-03-16 | 2013-04-24 | Takeda GmbH | Taste masked dosage form containing roflumilast |
| WO2008076265A1 (en) * | 2006-12-13 | 2008-06-26 | Gilead Sciences, Inc. | MONOPHOSPHATES AS MUTUAL PRODRUGS OF ANTI-INFLAMMATORY SIGNAL TRANSDUCTION MODULATORS (AISTM'S) AND β-AGONISTS FOR THE TREATMENT OF PULMONARY INFLAMMATION AND BRONCHOCONSTRICTION |
| WO2009055788A1 (en) * | 2007-10-26 | 2009-04-30 | Aeris Therapeutics, Inc. | Pneumoreductive therapy and compositions useful therein |
| ES2909752T3 (es) * | 2013-08-01 | 2022-05-10 | Swedish Stromabio Ab | MSC en el tratamiento de enfermedades pulmonares inflamatorias |
| CN104800214A (zh) * | 2014-01-27 | 2015-07-29 | 成都英诺新科技有限公司 | 一种罗氟司特吸入气雾剂复方及制备方法 |
| RU2728821C1 (ru) * | 2020-05-13 | 2020-07-31 | Федеральное государственное бюджетное учреждение науки "Научный центр биомедицинских технологий Федерального медико-биологического агентства" (ФГБУН НЦБМТ ФМБА России) | Способ лечения острого респираторного дистресс-синдрома даларгином и легочным сурфактантом |
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