CN1317490A - 新的-6-氨磺酰-3-喹啉基膦酸化合物,其制备方法及含有它们的药物组合物 - Google Patents
新的-6-氨磺酰-3-喹啉基膦酸化合物,其制备方法及含有它们的药物组合物 Download PDFInfo
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- 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)]
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- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
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Abstract
式(Ⅰ)的化合物,其中:X代表氯原子或氟原子或三氟甲基,R代表氢原子或基团以及药物。
Description
本发明涉及新的6-氨磺酰-3-喹啉基膦酸化合物,其制备方法及含有它们的药物组合物。
本发明构成与专利EP0640612相关的选择发明。专利说明书EP0640612描述了一类通过阻碍AMPA(α-氨基-3-羟基-5-甲基-4-异噁唑-丙酸)/红藻氨酸酯受体的初始激活而具有阻碍兴奋性氨基酸(FAA)的兴奋性和毒性作用的能力的化合物。它们的用途通过抑制病理学现象特别是与兴奋性氨基酸的神经传导途径的超活化相关的神经中毒现象而得到认识。然而,申请人发现使用这些化合物可同时伴随严重的肾毒性问题,例如,(6,7-二氯-2-氧代-1,2-二氢-3-喹啉基)膦酸有此问题,而且对于参考文献(Journal of Cerebral Blood Flow andMetabolism,1994,14,251-261)中的其它非NMDA(N-甲基-D-天冬氨酸酯)拮抗剂,例如6-硝基-7-氨磺酰-苯并[f]喹喔啉-2,3-二酮(NBQX)也存在相同问题。
申请人令人惊奇地发现,专利说明书EP0640612中所没有描述的一小组化合物不但具有强的非-NMDA拮抗剂的特性,而且完全没有伴随的肾毒性。因此这些化合物是新的,是用于急性和慢性治疗与那些氨基酸有关的神经性和心理性疾病的强有力的潜在治疗试剂,例如,诸如脑血管意外的变性疾病,大脑或脊椎创伤,癫痫,诸如阿尔茨海默氏病的慢性神经变性疾病,精神分裂症,肌萎缩性脊髓侧索硬化或亨廷顿舞蹈病。
更明确地,本发明涉及式(Ⅰ)的化合物,其异构体和其与药学上可接受的碱的加成盐:
其中,X代表氯原子或氟原子,或三氟甲基,
直链或支链(C1-C6)烷基,或苯基。
药学上可接受的碱中可能会提及,但不限于,氢氧化钠,氢氧化钾,三乙胺,叔丁胺等。
本发明优选的化合物为式(Ⅰ)的化合物,其中R代表氢原子。
更特别地,本发明涉及的式(Ⅰ)的化合物是:
★(7-氯-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸,
★(7-三氟甲基-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸,
★(7-氟-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸。
优选化合物的异构体及其与药学上可接受的碱的加成盐构成了本发明的完整部分。
其中,X与式(Ⅰ)中的定义相同,
得到式(Ⅳ)的化合物:
其中X的定义与前面相同,
式(Ⅳ)化合物在催化量的哌啶存在下环化得到式(Ⅴ)的化合物:
其中X的定义与此前相同,
其中X的定义与此前相同,
其中X的定义与此前相同,
其中X的定义与此前相同,
其中X的定义与此前相同,
其中X的定义与此前相同,
其中,R’如式(Ⅰ)中所定义,
其中X和R’的定义与此前相同,
式(Ⅰ/a)和(Ⅰ/b)的化合物构成了全部式(Ⅰ)的化合物,可以通过常规的分离技术得到纯化,并在需要时转化为其与一药学上可接受的碱的加成盐,并如果需要,可使用常规的分离技术分离得到它们的异构体。
本发明的化合物具有非常有价值的药理学性质,因为它们是强的AMPA受体抑制剂,此外,它们还具有选择性,因为它们不影响NMDA受体,因此,它们没有任何NMDA拮抗剂所述的副作用。总之,本发明化合物没有与许多AMPA/非-NMDA拮抗剂相伴随的肾毒性。使用这些化合物作为与兴奋性氨基酸的神经传导途径的超活化相关的病理学现象的抑制剂是适宜的,尤其适用于急性和特别是慢性治疗与那些氨基酸有关的神经性和心理性疾病,例如,诸如脑血管意外的变性疾病,大脑或脊椎创伤,癫痫,诸如阿尔茨海默氏病的慢性神经变性疾病,精神分裂症,肌萎缩性脊髓侧索硬化或亨廷顿舞蹈病。
本发明还涉及包含至少一种作为活性成分的式(Ⅰ)化合物本身或与一种或多种药学上可接受的赋形剂结合的药物组合物。
本发明药用组合物中,可特别提及那些适用于口服,肠胃外,经鼻,经皮或透皮,直肠,经舌,经眼或呼吸给药的组合物,特别是片剂,或糖衣片,舌下片,sachets,paquets,明胶胶囊剂,glossettes,锭剂,栓剂,霜剂,油膏剂,皮肤凝胶,及可饮用或可注射安瓿。
剂量根据患者的性别,年龄或体重,给药途径,治疗适应症的性质,或协同的治疗而不同,为每24小时50mg-1g,一次或多次给药。
下面的实施例将用于解释本发明,但本发明不限制于此。
实施例1:(7-氯-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸
步骤A:[(5-氯-2-甲酰基-苯基氨基甲酰基)甲基]膦酸二乙酯
向2-氨基-4-氯-苯甲醛(6.18g,39.7mmol)在170ml无水甲苯中的溶液中,加入吡啶(3.7ml,45.7mmol),而后向其中滴加氯甲酰基甲基膦酸二乙酯(9.8g,45.7mmol)在15ml无水甲苯中的溶液,期间保持反应混合物的温度低于30℃。滴加完毕后,混合物在室温下搅拌1小时。反应混合物用水洗而后用1N HCl溶液洗数次,而后再用水洗。混合物最后用饱和NaCl水溶液洗涤。有机相用MgSO4干燥,过滤,蒸出溶剂,得到所要的粗产品的橙色油状物。粗产品用于下面步骤。
步骤B:(7-氯-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
将步骤A中所得到的全部化合物溶于300ml甲苯和0.3ml哌啶中,在瓶口装有Dean-Stark装置的园底烧瓶中在强力搅拌下回流4小时。室温下结晶,过滤得到淡黄色固体。
熔点:210-213℃
元素微分析:C% H% N% Cl%
计算值: 49.46 4.79 4.44 11.23
测定值: 49.77 4.78 4.46 11.63
步骤C:(7-氯-6-硝基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
向用冰浴冷却的55ml 96%的硫酸中加入55ml硝酸,而后向其中分批加入(7-氯-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯(14.7g,46.6mmol),期间保持温度小于或等于5℃。加料完毕后,继续搅拌15分钟,撤去冰浴,在约一小时30分钟内使反应混合物的温度升至常温。将溶液倒入冰中,搅拌沉淀得到可过滤的固体。过滤,水洗至中性,真空干燥。固体悬浮于210ml乙醇中,回流,冷却,干燥,过滤得到目标化合物。
熔点:258-262℃
元素微分析:C% H% N% Cl%
计算值: 43.29 3.91 7.77 9.83
测定值: 43.33 4.06 7.60 9.70
步骤D:(6-氨基-7-氯-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
将步骤C中得到的化合物(7.0g,19.4mmol),铁粉(10.8g,194mmol)和氯化铵(10.4g,194mmol)在270ml甲醇和90ml水中的悬浮物在回流下搅拌反应1小时。悬浮物用Celite热过滤,固体用甲醇淋洗几次。滤液蒸干,残余物用水悬浮,固体过滤,用水淋洗,干燥得到目标产物的橙色结晶。
熔点:255-260℃
元素微分析:C% H% N%
计算值: 47.22 4.88 8.47
测定值: 47.06 4.99 8.08
步骤E:(7-氯-6-氯磺酰基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
向13.4ml乙酸和2.25ml水中吹入SO2气体15分钟,使其被SO2饱和。同时,于5℃下准备在步骤D中得到的化合物(3.34g,10.1mmol)在10ml冰乙酸和17ml浓盐酸的混合物中的溶液。向得到的溶液中滴加亚硝酸钠(767mg,11.11mmol)预先溶于5ml水中的溶液,反应混合物在5℃下搅拌30分钟。向SO2饱和的溶液中加入CuCl2·2H2O(689mg,4.04mmol),得到的悬浮液冷却至5℃。向得到的悬浮液中滴加上述所制备的重氮氯化物溶液。混合物在5℃下搅拌1小时,而后继续搅拌3小时同时使其回到常温。将反应混合物倒入冰中,过滤沉淀,沉淀用水淋洗。干燥得到目标产物的淡黄色粉末。
熔点:190-200℃
元素微分析:C% H% N% S% Cl%
计算值: 37.70 3.41 3.38 7.74 17.12
测定值: 38.04 3.47 3.40 7.74 17.16
步骤F:(7-氯-2-氧代-6-氨磺酰基-1,2-二氢-3-喹啉基)膦酸二乙酯
搅拌在步骤E中所获得的化合物(1.26g,3.0mmol)在18ml 28%的氢氧化铵中的悬浮液,几分钟后,发现溶解现象发生。继续搅拌30分钟,将反应混合物用4N盐酸酸化。在搅拌下加入几毫升乙酸乙酯,生成沉淀。将沉淀过滤,真空干燥,得到目标产物,为乳酪色粉末。
熔点:288-290℃
步骤G:(7-氯-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸
向步骤F中所获得的化合物(1.0g,2.53mmol)在30ml无水乙腈中的悬浮液中加入3.33ml(25.3mmol)三甲基溴硅烷。混合物在回流下搅拌1小时,蒸发至干。残余物用真空干燥,加入甲醇。得到的悬浮液搅拌30分钟,变得越来越稠。将得到的白色沉淀过滤,用少量甲醇淋洗,而后用乙醚洗,得到目标产物。
熔点:>300℃
元素微分析:C% H% N% S%
计算值: 31.92 2.38 8.27 9.47
测定值: 31.76 2.52 7.92 9.18实施例2:(7-三氟甲基-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸
根据实施例1的方法将步骤A中的2-氨基-4-氯苯甲醛换成2-氨基-4-三氟甲基苯甲醛,按照步骤D中的方法用Pd-C/甲酸铵代替Fe/NH4Cl在稀醇介质中进行还原。
步骤A:[(5-三氟甲基-2-甲酰基-苯基氨基甲酰基)甲基]膦酸二乙酯
熔点:62-64℃
元素微分析:C% H% N%
计算值: 45.79 4.67 3.81
测定值: 45.89 4.66 3.76
步骤B:(7-三氟甲基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:151℃
元素微分析:C% H% N%
计算值: 48.15 4.33 4.01
测定值: 48.19 4.32 3.92
步骤C:(7-三氟甲基-6-硝基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:209-215℃
元素微分析: C% H% N%
计算值: 42.65 3.58 7.11
测定值: 42.86 3.58 6.78
步骤D:(6-氨基-7-三氟甲基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
将步骤C中得到的化合物490mg(1.24mmol),甲酸铵650mg(12.4mmol)和120mg的10%Pd/C在50ml甲醇中的混合物在回流下搅拌反应1小时。用一种膜过滤除去催化剂,滤液蒸干,残余物用水处理,将悬浮物过滤,用水淋洗。吸滤,真空干燥得目标产物的黄色固体。
熔点:240-244℃
元素微分析:C% H% N%
计算值: 46.16 4.43 7.69
测定值: 46.26 4.37 7.62
步骤E:(7-三氟甲基-6-氯磺酰基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:165-171℃
元素微分析:C% H% N% S% Cl%
计算值: 37.56 3.15 3.13 7.16 7.92
测定值 37.54 3.20 3.18 7.05 7.97
步骤F:(7-三氟甲基-2-氧代-6-氨磺酰基-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:258-259℃
元素微分析:C% H% N% S%
计算值: 39.26 3.76 6.54 7.49
测定值: 39.54 3.65 6.46 7.35
步骤G:(7-三氟甲基-2-氧代-6-氨磺酰基-1,2-二氢-3-喹啉基)膦酸
熔点:>260℃
元素微分析:C% H% N% S%
计算值: 32.27 2.17 7.53 8.61
测定值: 32.45 2.01 7.64 8.96
实施例3:(7-氟-2-氧代-6-氨磺酰基-1,2-二氢-3-喹啉基)膦酸
按照实施例1的步骤,用2-氨基-4-氟苯甲醛代替步骤A中的2-氨基-4-氯苯甲醛。
步骤A:[(5-氟-2-甲酰基-苯基氨基甲酰基)甲基]膦酸二乙酯
产物未经分离以油状物直接用于步骤B。
步骤B:(7-氟-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:230-233℃
步骤C:(7-氟-6-硝基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:259-262℃
元素微分析:C% H% N%
计算值: 45.36 4.10 8.14
测定值: 45.40 4.28 8.06
步骤D:(6-氨基-7-氟-2-氧-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:253-257℃
元素微分析:C% H% N%
计算值: 49.69 5.13 8.91
测定值: 49.52 5.28 8.70
步骤E:(7-氟-6-氯磺酰基-2-氧代-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:159-160℃
元素微分析:C% H% N% S% Cl%
计算值: 39.26 3.55 3.52 8.06 8.91
测定值: 39.74 3.73 3.74 7.85 8.59
步骤F:(7-氟-2-氧代-氨磺酰基-1,2-二氢-3-喹啉基)膦酸二乙酯
熔点:266-268℃
元素微分析:C% H% N% S%
计算值: 41.27 4.26 7.40 8.48
测定值: 41.17 4.48 7.17 8.34
步骤G:(7-氟-2-氧代-6-氨磺酰基-1,2-二氢-3-喹啉基)膦酸
熔点:>300℃
元素微分析:C% H% N% S%
计算值: 33.55 2.50 8.69 9.95
测定值: 33.51 2.73 8.48 9.56
药理研究
实施例A:对注射了大鼠皮层mRNAs的非洲蟾蜍卵母细胞给予(R,S)-AMPA(10μM)所诱导的电流的抑制
向非洲蟾蜍卵母细胞中注射50ng从大鼠的大脑皮层中分离出的多(A+)mRNAs(poly(A+)mRNAs),并在18℃下孵化2-3天以使蛋白质表达。给予(R,S)-AMPA(10μM)所诱导的流入电流用2电极电压夹的方法(电势=-60mV)在具有下面组分的介质中测定:NaCl(82.5mM),KCl(2.5mM),CaCl2(1mM),MgCl2(1mM),NaH2PO4(1mM),HEPES(5mM),pH7.4。本发明的产物以浓度依赖的方式在给予激动剂(R,S)-AMPA之前30秒和期中给予。
它们对(R,S)-AMPA所诱导的电流的抑制能力通过IC50值(μM)进行测定,IC50值代表抑制给予(R,S)-AMPA(10μM)所诱导的电流50%的浓度。
本发明的化合物显示出色的抑制性,IC50值(μM)为0.1数量级。
实施例B:DBA/2小鼠的音源性惊厥试验
对于未成熟的DBA/2小鼠,可通过将其置于高强度高频率的声音刺激下引发惊厥。AMPA型谷氨酸盐受体拮抗剂对这种惊厥以剂量依赖的方式产生拮抗作用(Chapman等人,Epilepsy Res.,1991,9,92-96)。本试验用于研究本发明化合物的抗惊厥作用。简单来说,将未成熟的DBA/2小鼠(21-28天)暴露在105dB和18kHz的噪音下60秒。这将导致阵挛性惊厥的出现。用于研究的产物和溶剂在试验开始前30分钟以i.p.途径按0.1ml/10g的量给药。对每个化合物的ED50值(抑制50%的惊厥发生的剂量)按照Litchfield和Wicoxon(J.Pharmacol.Exp.Ther.,1949,96,99-113)的方法进行测定。
本发明化合物显示出色的惊厥抑制能力,EC50值在3mg/kg i.p.数量级。
实施例C: Fischer大鼠的肾毒性试验
对体重200-250g的成熟的雄性Fischer大鼠进行本发明化合物的肾影响评定。用戊巴比妥(Nembutal_,60mg/kg i.p.)对Fischer大鼠进行麻醉。麻醉进行90分钟后,以3,10,15mg/kg的剂量将测试化合物从静脉内给药。给药24小时后,处死动物,除去原生质,测定肌酸血和尿毒症(uraemia)。用单因子方差分析法进行统计分析,而后进行Newman-Keuls试验,对进行治疗的动物和仅接受载体的动物进行比较。
本发明化合物显示出色的肾耐受力,在剂量小于或等于15mg/kg i.v.下没有受到毒性。
实施例D:药物细合物
1000片5mg剂量片中(7-氯-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸(实施例1)……5g小麦淀粉………………………………………………………………20g玉米淀粉………………………………………………………………20g乳糖……………………………………………………………………30g硬脂酸镁………………………………………………………………2g硅石……………………………………………………………………1g羟丙基纤维素…………………………………………………………2g
Claims (8)
2.根据权利要求1的式(Ⅰ)的化合物,其中R代表氢原子,它们的异构体和与药学上可接受的碱的加成盐。
3.根据权利要求1的式(Ⅰ)的化合物,为(7-氯-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸,其异构体和与药学上可接受的碱的加成盐。
4.根据权利要求1的式(Ⅰ)的化合物,为(7-三氟甲基-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸,其异构体和与药学上可接受的碱的加成盐。
5.根据权利要求1的式(Ⅰ)的化合物,为(7-氟-2-氧代-6-氨磺酰-1,2-二氢-3-喹啉基)膦酸,其异构体和与药学上可接受的碱的加成盐。
6.制备根据权利要求1的式(Ⅰ)的化合物的方法,其特征在于使用式(Ⅱ)的化合物为起始原料:
其中,X与式(Ⅰ)中的定义相同,
式(Ⅱ)化合物在诸如吡啶的碱存在下与式(Ⅲ)的化合物缩合:
得到式(Ⅳ)的化合物:
其中X的定义与前面相同,
式(Ⅳ)化合物在催化量的哌啶存在下环化得到式(Ⅴ)的化合物:
其中X的定义与此前相同,
其中X的定义与此前相同,
式(Ⅵ)化合物用钯/碳在氢气存在下或在稀的醇介质中用铁还原得到式(Ⅶ)的化合物:
其中X的定义与此前相同,
其中X的定义与此前相同,
其中Ⅹ的定义与此前相同,
其中X的定义与此前相同,
式(Ⅰ/a)化合物可在碱性介质中与式(Ⅹ)的化合物反应:
其中,R’如式(Ⅰ)中所定义,
得到式(Ⅰ)化合物的特例-式(Ⅰ/b)的化合物:
其中X和R’的定义与此前相同,
式(Ⅰ/a)和(Ⅰ/b)的化合物构成了全部式(Ⅰ)的化合物,可以通过常规的分离技术得到纯化,并在需要时转化为其与一药学上可接受的碱的加成盐,并如果需要,可使用常规的分离技术分离得到它们的异构体。
7.药物组合物,包含根据权利要求1-5中任意一项的至少一种式(Ⅰ)化合物或其与药学上可接受的碱的加成盐作为活性成分,单独或与一种或多种药学上可接受的赋形剂结合。
8.根据权利要求7的药物组合物,用于制造一种急性或慢性治疗与兴奋性氨基酸的神经传导途径的超活化相关的病理学现象,诸如脑血管意外,大脑或脊椎创伤,癫痫,诸如阿尔茨海默氏病的慢性神经变性疾病,精神分裂症,肌萎缩性脊髓侧索硬化或亨廷顿舞蹈病的药物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0002011A FR2805260A1 (fr) | 2000-02-18 | 2000-02-18 | Nouveaux derives d'acides 6-sulfamoyl-3-quinolinyl phosphoniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR0002011 | 2000-02-18 |
Publications (1)
Publication Number | Publication Date |
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CN1317490A true CN1317490A (zh) | 2001-10-17 |
Family
ID=8847122
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN01112384A Pending CN1317490A (zh) | 2000-02-18 | 2001-02-16 | 新的-6-氨磺酰-3-喹啉基膦酸化合物,其制备方法及含有它们的药物组合物 |
Country Status (20)
Country | Link |
---|---|
US (2) | US6518258B1 (zh) |
EP (1) | EP1125941B1 (zh) |
JP (1) | JP2001253892A (zh) |
KR (1) | KR20010082703A (zh) |
CN (1) | CN1317490A (zh) |
AR (1) | AR027429A1 (zh) |
AT (1) | ATE236911T1 (zh) |
AU (1) | AU2304001A (zh) |
BR (1) | BR0100604A (zh) |
CA (1) | CA2337786A1 (zh) |
DE (1) | DE60100165D1 (zh) |
EA (1) | EA200100156A3 (zh) |
FR (1) | FR2805260A1 (zh) |
HK (1) | HK1039619A1 (zh) |
HU (1) | HUP0100750A3 (zh) |
MX (1) | MXPA01001558A (zh) |
NO (1) | NO20010800L (zh) |
NZ (1) | NZ510001A (zh) |
PL (1) | PL345918A1 (zh) |
ZA (1) | ZA200101338B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1871369A4 (en) * | 2005-04-04 | 2009-11-11 | Eisai R&D Man Co Ltd | DIHYDROPYRIDINE COMPOUNDS AND COMPOSITIONS FOR HEADACHES |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2683818B1 (fr) * | 1991-11-14 | 1993-12-31 | Adir Cie | Nouveaux derives de 3-sulfonylamino-2-(1h)-quinoleinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
US5342946A (en) * | 1992-12-02 | 1994-08-30 | Guilford Pharmaceuticals Inc. | Phosphonoalkylquinolin-2-ones as novel antagonists of non-NMDA ionotropic excitatory amino acid receptors |
FR2709489B1 (fr) * | 1993-08-31 | 1995-10-20 | Adir | Nouveaux dérivés de 2-(1H)-quinoléinone, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
FR2750988B1 (fr) * | 1996-07-11 | 1998-09-18 | Adir | Nouveaux derives de 2-(1h)-quinoleinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2805261A1 (fr) * | 2000-02-18 | 2001-08-24 | Adir | Nouveaux derives d'acides 6-amino ou 6-hydrazinosulfonyl-3- quinolinyl phosphoniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2805262A1 (fr) * | 2000-02-18 | 2001-08-24 | Adir | Nouveaux derives d'acides aryle ou heteroaryle quinolinyl phosphoniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2000
- 2000-02-18 FR FR0002011A patent/FR2805260A1/fr active Pending
-
2001
- 2001-02-07 JP JP2001030597A patent/JP2001253892A/ja not_active Ceased
- 2001-02-12 MX MXPA01001558A patent/MXPA01001558A/es unknown
- 2001-02-14 US US09/783,650 patent/US6518258B1/en not_active Expired - Fee Related
- 2001-02-15 AR ARP010100676A patent/AR027429A1/es unknown
- 2001-02-16 NO NO20010800A patent/NO20010800L/no unknown
- 2001-02-16 BR BR0100604-5A patent/BR0100604A/pt not_active IP Right Cessation
- 2001-02-16 CN CN01112384A patent/CN1317490A/zh active Pending
- 2001-02-16 HU HU0100750A patent/HUP0100750A3/hu unknown
- 2001-02-16 DE DE60100165T patent/DE60100165D1/de not_active Expired - Lifetime
- 2001-02-16 KR KR1020010007743A patent/KR20010082703A/ko active IP Right Grant
- 2001-02-16 CA CA002337786A patent/CA2337786A1/fr not_active Abandoned
- 2001-02-16 ZA ZA200101338A patent/ZA200101338B/xx unknown
- 2001-02-16 AT AT01400408T patent/ATE236911T1/de not_active IP Right Cessation
- 2001-02-16 EP EP01400408A patent/EP1125941B1/fr not_active Expired - Lifetime
- 2001-02-16 AU AU23040/01A patent/AU2304001A/en not_active Abandoned
- 2001-02-16 NZ NZ510001A patent/NZ510001A/xx unknown
- 2001-02-16 PL PL01345918A patent/PL345918A1/xx not_active IP Right Cessation
- 2001-02-19 EA EA200100156A patent/EA200100156A3/ru unknown
-
2002
- 2002-02-22 HK HK02101314.5A patent/HK1039619A1/zh unknown
- 2002-12-09 US US10/314,509 patent/US6596709B1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP1125941B1 (fr) | 2003-04-09 |
BR0100604A (pt) | 2001-09-18 |
HK1039619A1 (zh) | 2002-05-03 |
NO20010800L (no) | 2001-08-20 |
HU0100750D0 (en) | 2001-04-28 |
FR2805260A1 (fr) | 2001-08-24 |
HUP0100750A3 (en) | 2002-09-30 |
CA2337786A1 (fr) | 2001-08-18 |
EP1125941A1 (fr) | 2001-08-22 |
EA200100156A2 (ru) | 2001-08-27 |
PL345918A1 (en) | 2001-08-27 |
ZA200101338B (en) | 2001-08-21 |
NO20010800D0 (no) | 2001-02-16 |
MXPA01001558A (es) | 2002-08-06 |
AU2304001A (en) | 2001-08-23 |
EA200100156A3 (ru) | 2001-10-22 |
JP2001253892A (ja) | 2001-09-18 |
NZ510001A (en) | 2002-11-26 |
DE60100165D1 (de) | 2003-05-15 |
KR20010082703A (ko) | 2001-08-30 |
ATE236911T1 (de) | 2003-04-15 |
HUP0100750A2 (hu) | 2002-01-28 |
US6596709B1 (en) | 2003-07-22 |
AR027429A1 (es) | 2003-03-26 |
US6518258B1 (en) | 2003-02-11 |
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