CN1543344A - 治疗尿失禁的芳基(或杂芳基)氮杂茂甲醇衍生物 - Google Patents
治疗尿失禁的芳基(或杂芳基)氮杂茂甲醇衍生物 Download PDFInfo
- Publication number
- CN1543344A CN1543344A CNA028161009A CN02816100A CN1543344A CN 1543344 A CN1543344 A CN 1543344A CN A028161009 A CNA028161009 A CN A028161009A CN 02816100 A CN02816100 A CN 02816100A CN 1543344 A CN1543344 A CN 1543344A
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- Prior art keywords
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- ethyoxyl
- dimethylamine
- isophthalic acid
- pyrazoles
- 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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
通式(I)芳基(或杂芳基)氮杂茂甲醇衍生物和它们的生理学上可接受的盐在人和/或兽医治疗学中可用作药物，治疗哺乳动物、包括人类的尿失禁，其中Ar代表可选被取代的苯基基团或噻吩基基团，R1代表氢原子或低级烷基，R2代表二烷基氨基烷基或氮杂环基烷基，Het代表氮杂茂，它是未取代的或者可选地被一个或两个取代基取代。
Description
发明领域
本发明涉及通式(I)芳基(或杂芳基)氮杂茂甲醇衍生物和它们的生理学上可接受的盐作为人和/或动物治疗剂用于治疗尿失禁的用途。
发明背景
排尿是下部泌尿道的功能，它被定义为尿液通过尿道的排出。成人排尿被视为正常的是它是随意的、连续的、完全的、满意的、可中断的、隔开一定时间的(按社会上可接受的间隔)、不导致腹部压力的、不急迫的和在夜间仅是偶然的。
尿失禁是一种泌尿障碍，被定义为尿液的不随意排出，这可以得到客观的证明。膀胱的这种功能障碍就患有它的人口而言是社会与卫生意义日益增加的健康问题。根据我们的数据，尿失禁在15与64岁之间的人口中的发生率，男性大约1.5至5％，女性大约10至30％。不过，如果我们选择60岁以上的非住院人口部分，那么这部分人的发病率为15％至35％。另一方面，在研究60岁以上的住院患者时，发病率更高。尿失禁影响到大约两百万西班牙人。
尿失禁可以被视为一种症状、迹象或病理条件。下面是这种功能障碍的可能的分类之一。
强迫性排尿或急性失禁。此时，尿液的不随意排出伴有强烈的排尿欲望(尿急)。这可以分为运动原性尿急失禁或敏感性尿急失禁。运动原性尿急失禁与逼尿肌活动过强和/或逼尿肌膨胀性减少有关。活动过强是以逼尿肌在充盈期间的不随意收缩为特征的，该收缩是自发性的或被激发的，患者不能完全地抑制。逼尿肌的活动过强可以发生于排出尿流阻塞、炎症和膀胱受刺激的情形，或者它的病原学也可能是未知的(特发性的)。
反射过强，被描述为这样一种条件，它呈现逼尿肌收缩失控，与神经病学障碍有关，例如多发性硬化或斑块硬化、骨髓创伤后遗症或帕金森氏病。
泌尿应激性失禁，由尿道闭合不全机理引起，当膀胱内压力超过尿道中的压力时，即使逼尿肌没有收缩也存在尿液的不随意排出。不随意排出发生于进行一定体力活动的情形，例如跳跃、咳嗽、下楼等。另外一种因素可能是由绝经后雌激素过少引起的尿道结构改变。
混合型失禁，该术语表示尿急性失禁和应激性失禁的共同存在。
尿失禁的治疗选择依赖于失禁的类型。在尿急性失禁中，第一与最有效的治疗方案是药物治疗伴以一系列卫生调节和患者教育，第二方案包括其他疗法，例如最大电刺激或手术治疗。为应激性失禁保留了保守性措施，例如骨盆底锻炼和手术治疗，作为第一选择。
尿急性失禁和反射过强的药物治疗致力于减少逼尿肌的活动和增加膀胱的容量。在应激性失禁的情况下，治疗致力于增加对尿排出的抗性。
用于治疗尿失禁的药物包括具有不同作用机理的来自不同药理学分组的多种治疗药物(Hattori T.，Drug treatment of urinaryincontinence.Drugs of Today，1998，34(2)：125-138)，不过存在大量的混乱，并且它们的临床功效尚未得到完全证明。
第一组药物具有抗胆碱能作用，其中丙胺太林可以被视为纯粹的抗胆碱能剂。还有一种新的药物托特罗定，它具有选择性抗胆碱能作用，但是就毒蕈碱受体的不同亚型而言不是选择性的，尽管它似乎在围绕膀胱(逼尿肌)、唾液腺和人肠道的作用上具有选择性。一种具有抗胆碱能作用的药物oxybutin是具有混合作用的药物，它是中等的抗胆碱能剂和强效的直接的肌肉松弛剂。oxybutin现在是这种障碍的首选药物，尽管它的可耐受性不严重，但是副作用明显，例如口干、便秘和嗜睡，在有些情况下可能导致患者放弃治疗。
若干三环抗抑郁剂对逼尿肌活动过强患者具有有益效果。已用于临床的药物米帕明已经显示是儿童夜间遗尿和——例如——老人膀胱活动过强的有效治疗剂。由于这组药物的不同副作用已有报道，有时还很强烈(例如心血管作用)，必须在某些人口中研究这种治疗对排尿障碍的风险-益处，尤其是老年人。
有些αβ-肾上腺素能拮抗剂，例如哌唑嗪、特拉唑嗪或多沙唑嗪，能够改善逼尿肌活动过强和良性前列腺增生患者与逼尿肌机能障碍有关的症状，不过对活动过强膀胱的这种作用的证据目前仍处于讨论之中，尚无证据支持它在尿失禁中的用途。
另一组治疗剂相当于α-肾上腺素能剂，不过关于它们的功效，可用的信息仍然很少。已知α-肾上腺素能刺激作用能够松弛处于正常条件的人膀胱。逼尿肌无论处于正常条件还是在不稳定的膀胱的情况下，都对α-激动剂显示相似程度的响应，即松弛。α2-肾上腺素能受体激动剂、例如特布他林或沙丁胺醇，已经显示能够增加膀胱的容量。相反，这种药物仅在非常有限的临床研究和少量患者中显示在逼尿肌活动过强治疗中的功效。
在我们的专利EP 289380和WO 99/52525中，我们已经描述了具有止痛活性的通式(I)甲醇衍生物。
在这些通式(I)化合物中，Ar代表带有或者没有取代基的苯环或噻吩环，R1代表氢原子或C1至C4低级烷基，R2代表二烷基氨基烷基或氮杂环基烷基，Het代表带有或者没有取代基的氮杂茂，和它们的生理学上可接受的盐。
在我们的专利WO 97/20817、WO 99/02500、WO 99/07684和WO99/52525中，我们还描述了制备对映异构纯的通式(I)化合物的若干方法。
我们现已发现，通式(I)化合物和它们的生理学上可接受的盐尤其可用于制备用在人或兽医治疗学中的药物，以治疗或减轻尿失禁。
发明的详细说明
本发明涉及通式(I)芳基(或杂芳基)氮杂茂甲醇衍生物或其生理学上可接受的盐之一在药物制备中的用途，
其中
Ar代表苯基基团或噻吩基基团，没有取代或者可选地带有1、2或3个相同或不同的取代基，选自由氟、氯、溴、甲基、三氟甲基和甲氧基组成的组；
R1代表氢原子或C1至C4低级烷基；
R2代表二烷基(C1-C4)氨基烷基(C2-C3)基团或氮杂环基烷基(C2-C3)；和
Het代表氮杂茂，即五元含氮芳族杂环，它含有一至三个氮原子，没有取代或者可选地被1或2个相同或不同的取代基取代，取代基选自由氟、氯、溴和甲基组成的组；
该药物用于治疗哺乳动物、包括人的尿失禁，尤其是呈现尿急性或反射过强性失禁的患者。
术语“C1至C4低级烷基”代表从1至4个碳原子的饱和烃衍生的直链或支链基团，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
术语“二烷基(C1-C4)氨基烷基(C2-C3)或氮杂环基烷基(C2-C3)”代表其中具有两个或三个碳原子的烷基与二烷基(C1-C4)胺或环状胺连接基团，例如二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、哌啶基乙基、吗啉基丙基、吡咯烷基烷基等。
包括在本发明中的化合物的实例包括：
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑，
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐，
(+)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑，
(-)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑，
(+)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐，
(-)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐，
(±)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑，
(±)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑枸橼酸盐，
(+)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑，
(-)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑，
(+)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑枸橼酸盐，
(-)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑枸橼酸盐。
通式(I)化合物可以按照专利EP 289380或WO 99/52525所述方法加以合成。通式(I)化合物具有立体中心，本发明既涉及纯对映体的用途，也涉及对映体混合物的用途。对映体可以借助我们的专利WO97/20817、WO 99/02500、WO 99/07684或WO 99/52525所述任意方法加以制备。
本发明中，通式(I)化合物的活性已经在膀胱活动过强的过程中得到证明，它们因此可用于由反射过强性逼尿肌活性和尿急性失禁引起的尿失禁。
下面说明下式(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐(实施例1)的一些性质，它们构成本发明的目的：
下列药理试验中的实例仅供说明，本发明决不能被视为仅限于这些应用。
已经研究了实施例1对抗环磷酰胺-诱发的大鼠膀胱炎症的活性。环磷酰胺是若干疾病、包括癌症的有效治疗方式。这种产品的一种可能的副作用是膀胱的急性炎症。它的活性是基于活性代谢产物在肝内的转化作用的。
用环磷酰胺治疗可以引起若干副作用并发症，包括膀胱炎，它主要是由另一种环磷酰胺代谢产物、即丙烯醛引起的。
已知环磷酰胺-诱发的膀胱炎是由丙烯醛与泌尿道上皮的直接接触引起的，不过这种炎性反应的确切机理多半是未知的。炎性反应的表现之一是膀胱内的血浆外渗。为此，已经研究了实施例1对抗由环磷酰胺诱发的大鼠膀胱炎的活性，测定了它对膀胱内的血浆蛋白外渗的效果。
血浆蛋白的外渗是借助渗透性技术测量的，使用伊文思蓝(Evan’sblue)染剂，如A.saria和J.M.Lundberg所述(J.Neurosci.Methods 8：41-49，1983)。首先，向大鼠给以实施例1(80mg/kg，ip)或载体。五分钟后，向它们给以环磷酰胺(150mg/kg，ip)。三个半小时后，将大鼠用尿烷麻醉(1.2gr/kg，ip)，向颈静脉插套管，给以伊文思蓝染剂的H2O溶液(50mg/2.5ml)，剂量为50mg/kg，iv。注射染剂后十五分钟，通过输注37℃的50ml盐水溶液(0.9％)，借助心脏穿刺使大鼠放血。然后，取出膀胱，称重，用60℃的已知体积甲酰胺提取24小时之后，借助分光光度法(620mm)测定伊文思蓝染剂的含量。血浆蛋白的外渗以伊文思蓝染剂的含量表示，以每克组织的微克计。
所得结果显示，实施例1显著抑制血浆蛋白的外渗，超过75％。因此，实施例1在膀胱炎性条件中的保护效果是明显的，全部过程与环磷酰胺诱发的膀胱炎相似。
组别 大鼠数量 血浆蛋白的外渗
μg伊文思蓝/g组织
对照 10 25
环磷酰胺(150mg/kg，ip) 10 437
环磷酰胺+实施例1 10 125
(150mg/kg+80mg/kg，ip) (抑制率75.7％)
鉴于良好的药动学性质，根据本发明的芳基(或杂芳基)氮杂茂甲醇衍生物可以在人类与动物治疗学中令人满意地用于治疗和减轻尿失禁。
在人类治疗学中，本发明化合物的给药剂量依赖于所治疗的感染的严重性。剂量通常在50与400mg/天之间。本发明化合物例如是以胶囊或片剂的形式给药的。
作为实例，下面说明本发明化合物的具体药物剂型。
注射剂(im/iv)配方的实例
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H- 50mg
吡唑枸橼酸盐
0.1N氢氧化钠 c.s.pH 6
注射用水c.s.p. 1ml
片剂配方的实例
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基- 400mg
1H-吡唑枸橼酸盐
交联羧甲基纤维素钠(Ac-Di-Sol) 32mg
胶体二氧化硅(Aerosyl 200) 8mg
硬脂酸镁NF 16mg
聚维酮K-30 40mg
微晶纤维素(Avicel PH-102) 146mg
乳糖一水合物(Farmatose 200M) 158mg
总计 800mg
每粒胶囊配方的实例
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基- 200.0mg
1H-吡唑枸橼酸盐
胶体二氧化硅 0.8mg
硬脂酸镁 2.4mg
乳糖 276.8mg
总计 480mg
Claims (5)
1、通式(I)芳基(或杂芳基)氮杂茂甲醇衍生物或其生理学上可接受的盐之一在药物制备中的实例，
其中
Ar代表苯基基团或噻吩基基团，没有取代或者可选地带有1、2或3个相同或不同的取代基，选自由氟、氯、溴、甲基、三氟甲基和甲氧基组成的组；
R1代表氢原子或C1至C4低级烷基；
R2代表二烷基(C1-C4)氨基烷基(C2-C3)基团或氮杂环基烷基(C2-C3)；和
Het代表五元含氮芳族杂环，它含有一至三个氮原子，没有取代或者可选地被1或2个相同或不同的取代基取代，取代基选自由氟、氯、溴和甲基组成的组；
该药物用于治疗哺乳动物、包括人的尿失禁。
2、根据权利要求1的通式(I)化合物在药物制备中的实例，其中R1选自氢原子或由甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基组成的组，该药物用于治疗哺乳动物、包括人的尿失禁。
3、根据权利要求1的通式(I)化合物在药物制备中的实例，其中R2选自由二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、哌啶基乙基、吗啉基丙基和吡咯烷基乙基组成的组，该药物用于治疗哺乳动物、包括人的尿失禁。
4、根据权利要求1的通式(I)化合物在药物制备中的用途，该化合物选自：
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑，
(±)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐，
(+)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑，
(-)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑，
(+)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐，
(-)-5-{α-[2-(二甲胺)乙氧基]苄基}-1-甲基-1H-吡唑枸橼酸盐，
(±)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑，
(±)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑枸橼酸盐，
(+)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑，
(-)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑，
(+)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑枸橼酸盐，
(-)-5-{α-[2-(二甲胺)乙氧基]-2-噻吩基甲基}-1-甲基-1H-吡唑枸橼酸盐，
该药物用于治疗哺乳动物、包括人的尿失禁。
5、治疗哺乳动物、包括人的尿失禁的药物组合物，其特征在于它至少含有一种根据任意权利要求1至4的通式(I)化合物或其生理学上可接受的盐之一和药学上可接受的赋形剂。
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| ES200101587A ES2180449B1 (es) | 2001-07-06 | 2001-07-06 | Derivados de aril (o heteroaril) azolilcarbinoles para el tratamiento de la incontinencia urinaria. |
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| JP (1) | JP2004521150A (zh) |
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| CN (1) | CN1543344A (zh) |
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| AT (1) | ATE327752T1 (zh) |
| BR (1) | BR0211237A (zh) |
| CA (1) | CA2452646A1 (zh) |
| CY (1) | CY1105113T1 (zh) |
| DE (1) | DE60211913T2 (zh) |
| DK (1) | DK1413305T3 (zh) |
| ES (2) | ES2180449B1 (zh) |
| MA (1) | MA27056A1 (zh) |
| MX (1) | MXPA04000065A (zh) |
| NO (1) | NO20040031L (zh) |
| NZ (1) | NZ530817A (zh) |
| PL (1) | PL369062A1 (zh) |
| PT (1) | PT1413305E (zh) |
| RU (1) | RU2308268C2 (zh) |
| UA (1) | UA79238C2 (zh) |
| WO (1) | WO2003004022A1 (zh) |
| ZA (1) | ZA200400780B (zh) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040142929A1 (en) * | 2001-07-06 | 2004-07-22 | Ramon Merce-Vidal | Derivatives of aryl (or heteroaryl) azolylcarbinoles for the treatment of urinary incontinence |
| DE10335566A1 (de) * | 2003-07-31 | 2005-02-24 | Grünenthal GmbH | Arzneimittel enthaltend Derivate von Aryl( oder Heteroaryl)azolylcarbinolen |
| TW200533657A (en) * | 2004-02-17 | 2005-10-16 | Esteve Labor Dr | Substituted pyrazoline compounds, their preparation and use as medicaments |
| EP1584335A3 (en) * | 2004-04-05 | 2006-02-22 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising a carbinol composition and an opioid |
| ES2244326B1 (es) * | 2004-04-05 | 2007-02-16 | Laboratorios Del Dr. Esteve, S.A. | Combinacion de substancias activas. |
| US20060040924A1 (en) * | 2004-06-22 | 2006-02-23 | Laboratorios Dr. Esteve S.A. | Derivatives of aryl (or heteroaryl) azolylcarbinols for the treatment of renal colic |
| WO2006010627A1 (en) * | 2004-07-30 | 2006-02-02 | Laboratorios Del Dr. Esteve, S.A. | Aryl (or heteroaryl) azolylcarbinols |
| EP1743892A1 (en) * | 2005-07-15 | 2007-01-17 | Laboratorios del Dr. Esteve S.A. | Substituted pyrazoline compounds, their preparation and use as medicaments |
| EP1743890A1 (en) * | 2005-07-15 | 2007-01-17 | Laboratorios Del Dr. Esteve, S.A. | 4,5-Dihydro-1H-pyrazole derivatives, their preparation and use as medicaments |
| US7897589B2 (en) * | 2005-07-15 | 2011-03-01 | Laboratorios Del Dr. Esteve, S.A. | Substituted pyrazoline compounds, their preparation and use as medicaments |
| EP1757587A1 (en) * | 2005-07-15 | 2007-02-28 | Laboratorios Del Dr. Esteve, S.A. | Substituted pyrazoline compounds, their preparation and use as medicaments |
| US20070021485A1 (en) * | 2005-07-22 | 2007-01-25 | Gomis Antonio F | Aryl (or heteroaryl) azolylcarbinols |
| ES2334548B1 (es) * | 2005-07-29 | 2010-10-27 | Laboratorios Del Dr. Esteve, S.A | Forma de dosificacion de liberacion controlada de compuestos de pirazol para el tratamiento de la incontinencia urinaria. |
| US8722079B2 (en) | 2008-04-18 | 2014-05-13 | Warsaw Orthopedic, Inc. | Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine |
| EP2151234A1 (en) * | 2008-07-28 | 2010-02-10 | Laboratorios Del. Dr. Esteve, S.A. | Pharmaceutical formulation comprising a CB1-receptor compound in a solid solution and/or solid dispersion |
| US20100291151A1 (en) * | 2009-04-21 | 2010-11-18 | Auspex Pharmaceuticals, Inc. | 1-methylpyrazole modulators of substance p, calcitonin gene-related peptide, adrenergic receptor, and/or 5-ht receptor |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE891865A (fr) * | 1981-01-30 | 1982-07-22 | Sandoz Sa | Nouveaux medicaments a base de derives condenses de l'imidazole pour le traitement des troubles urinaires |
| ES2150353B1 (es) * | 1998-04-15 | 2001-07-01 | Esteve Labor Dr | Tienilazolilalcoxietanaminas, su preparacion y su aplicacion como medicamentos. |
| ES2137136B1 (es) * | 1998-05-18 | 2000-07-01 | Esteve Labor Dr | Empleo de derivados de aril (o heteroaril) azolilcarbinoles en la elaboracion de un medicamento para el tratamiento de la inflamacion neurogenica. |
| ES2150378B1 (es) * | 1998-08-07 | 2001-07-01 | Esteve Labor Dr | Empleo de derivados de aril(o heteroaril)azolilcarbinoles en la elaboracion de un medicamento para el tratamiento de los trastornos mediados por un exceso de substancia p. |
-
2001
- 2001-07-06 ES ES200101587A patent/ES2180449B1/es not_active Expired - Fee Related
-
2002
- 2002-01-07 UA UA2004020880A patent/UA79238C2/uk unknown
- 2002-07-01 DE DE60211913T patent/DE60211913T2/de not_active Expired - Fee Related
- 2002-07-01 ES ES02745440T patent/ES2263792T3/es not_active Expired - Lifetime
- 2002-07-01 JP JP2003510033A patent/JP2004521150A/ja active Pending
- 2002-07-01 RU RU2004103475/15A patent/RU2308268C2/ru not_active IP Right Cessation
- 2002-07-01 KR KR10-2004-7000056A patent/KR20040030788A/ko not_active Application Discontinuation
- 2002-07-01 EP EP02745440A patent/EP1413305B1/en not_active Expired - Lifetime
- 2002-07-01 MX MXPA04000065A patent/MXPA04000065A/es unknown
- 2002-07-01 DK DK02745440T patent/DK1413305T3/da active
- 2002-07-01 AR ARP020102482A patent/AR034679A1/es not_active Application Discontinuation
- 2002-07-01 BR BR0211237-0A patent/BR0211237A/pt not_active IP Right Cessation
- 2002-07-01 WO PCT/ES2002/000326 patent/WO2003004022A1/es active IP Right Grant
- 2002-07-01 CN CNA028161009A patent/CN1543344A/zh active Pending
- 2002-07-01 PT PT02745440T patent/PT1413305E/pt unknown
- 2002-07-01 AT AT02745440T patent/ATE327752T1/de not_active IP Right Cessation
- 2002-07-01 NZ NZ530817A patent/NZ530817A/en unknown
- 2002-07-01 CA CA002452646A patent/CA2452646A1/en not_active Abandoned
- 2002-07-01 PL PL02369062A patent/PL369062A1/xx not_active Application Discontinuation
- 2002-07-03 US US10/189,915 patent/US20030022925A1/en not_active Abandoned
-
2004
- 2004-01-05 NO NO20040031A patent/NO20040031L/no not_active Application Discontinuation
- 2004-01-30 ZA ZA200400780A patent/ZA200400780B/en unknown
- 2004-02-04 MA MA27514A patent/MA27056A1/fr unknown
-
2005
- 2005-01-28 US US11/045,708 patent/US20050131049A1/en not_active Abandoned
-
2006
- 2006-07-28 CY CY20061101049T patent/CY1105113T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1413305B1 (en) | 2006-05-31 |
| US20050131049A1 (en) | 2005-06-16 |
| BR0211237A (pt) | 2004-08-10 |
| US20030022925A1 (en) | 2003-01-30 |
| DK1413305T3 (da) | 2006-09-18 |
| NO20040031L (no) | 2004-03-02 |
| PT1413305E (pt) | 2006-09-29 |
| NZ530817A (en) | 2005-07-29 |
| JP2004521150A (ja) | 2004-07-15 |
| PL369062A1 (en) | 2005-04-18 |
| DE60211913D1 (de) | 2006-07-06 |
| ES2180449A1 (es) | 2003-02-01 |
| ATE327752T1 (de) | 2006-06-15 |
| UA79238C2 (en) | 2007-06-11 |
| ES2180449B1 (es) | 2004-01-16 |
| CA2452646A1 (en) | 2003-01-16 |
| CY1105113T1 (el) | 2010-03-03 |
| DE60211913T2 (de) | 2007-05-24 |
| KR20040030788A (ko) | 2004-04-09 |
| ES2263792T3 (es) | 2006-12-16 |
| EP1413305A1 (en) | 2004-04-28 |
| RU2004103475A (ru) | 2005-06-10 |
| RU2308268C2 (ru) | 2007-10-20 |
| MXPA04000065A (es) | 2004-05-21 |
| WO2003004022A1 (es) | 2003-01-16 |
| ZA200400780B (en) | 2005-01-31 |
| MA27056A1 (fr) | 2004-12-20 |
| AR034679A1 (es) | 2004-03-03 |
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