公开(公告)号：WO1997000251A1

公开(公告)日：1997-01-03

申请号：PCT/HU1996000033

申请日：1996-06-14

申请人： BIOREX KUTATO ES FEJLESZTO RT. ,  ÜROGDI, László ,  MARVANYOS, Ede ,  BARABAS, Mihály ,  JASZLITS, László ,  BIRO, Katalin ,  JEDNAKOVITS, Andrea ,  RADVANYNÉ HEGEDÜS, Erzsébet ,  KÜRTHY, Mária ,  UDVARDY NAGY, Istvánné

发明人： BIOREX KUTATO ES FEJLESZTO RT.

IPC分类号： C07D295/092

CPC分类号： C07D213/75 ,  C07C275/64 ,  C07D295/088

摘要： The invention relates to novel hydroxylamine derivatives represented by general formula (I), the pharmaceutically acceptable acid addition salts thereof as well as the pharmaceutical compositions containing the same as active ingredient. Another object of the invention is the preparation of the hydroxylamine derivatives and salts thereof. The compounds according to the invention possess anti-ischaemic effect. In the above formula (I) X is O, -NH or a group of the formula -NR'-, wherein R and R', independently from each other, are alkyl, cycloalkyl, phenylalkyl; a phenyl group optionally substituted with halo, haloalkyl, alkyl, alkoxy or nitro; or an N-containing hetero ring; R is H or alkanoyl; R is H or hydroxy optionally acylated with alkanoyl; and R is a group of the formula -N(R )R wherein R and R , independently from each other, may be H, alkyl or a group of the formula -C(O)-NH-R wherein R is as defined above, or R and R , when taken together with the adjacent nitrogen attached thereto, form a 5 to 7-membered hetero ring which may contain one additional hetero atom selected from nitrogen, oxygen and sulfur and which is optionally substituted with alkyl of phenylalkyl.

摘要翻译： 本发明涉及由通式（I）表示的新型羟胺衍生物，其药学上可接受的酸加成盐以及含有与活性成分相同的药物组合物。 本发明的另一个目的是制备羟胺衍生物及其盐。 根据本发明的化合物具有抗缺血作用。 在上式（I）中，X是O，-NH或式-NR'-的基团，其中R和R'彼此独立地是烷基，环烷基，苯基烷基; 任选被卤素，卤代烷基，烷基，烷氧基或硝基取代的苯基; 或含N的杂环; R 1是H或烷酰基; R 2是任选用烷酰基进行酰化的H或羟基; 并且R 3是式-N（R 4）R 5的基团，其中R 4和R 5彼此独立地可以是H，烷基或式 -C（O）-NH-R，其中R如上定义，或R 4和R 5与连接在其上的相邻氮原子一起形成5至7元杂环，其可以含有一个 选自氮，氧和硫的另外的杂原子，其任选被苯基烷基的烷基取代。

公开(公告)号：WO1998006400A3

公开(公告)日：1998-02-19

申请号：PCT/HU1997000044

申请日：1997-08-06

申请人： BIOREX KUTATO ÉS FEJLESZTO"e; RT. ,  JEDNAKOVITS, Andrea ,  ÜRÖGDI, László ,  MARVANYOS, Ede ,  BARABAS, Mihály ,  KURUCZ, István ,  BACSY, Erno"e; ,  KORANYI, László ,  ERDO"e;, Sándor ,  DORMAN, György ,  VITAI, Márta ,  SCHMIDT, György ,  SINKA, Márta ,  TÖRÖK, Magdolna

发明人： BIOREX KUTATO ÉS FEJLESZTO"e; RT.

IPC分类号： A61K31/445

公开(公告)号：WO1997016439A1

公开(公告)日：1997-05-09

申请号：PCT/HU1996000064

申请日：1996-11-01

申请人： BIOREX KUTATO ÉS FEJLESZTO RT. ,  VIGH, László ,  LITERATI NAGY, Péter ,  SZILBEREKY, Jeno"e; ,  ÜRÖGDI, László ,  JEDNAKOVITS, Andrea ,  JASZLITS, László ,  BIRO, Katalin ,  MARVANYOS, Ede ,  BARABAS, Mihály ,  HEGEDÜS, Erzsébet ,  KORANYI, László ,  KÜRTHY, Mária ,  BALOGH, Gábor ,  HORVATH, Ibolya ,  TÖRÖK, Zsolt ,  UDVARDY, Éva ,  DORMAN, György ,  MEDZIHRADSZKY, Dénes ,  MÉZES, Bea ,  KOVACS, Eszter ,  DUDA, Erno"e; ,  FARKAS, Beatrix ,  GLATZ, Attila

发明人： BIOREX KUTATO ÉS FEJLESZTO RT.

IPC分类号： C07D333/38

CPC分类号： C07D213/78 ,  C07C259/02 ,  C07C259/18 ,  C07C275/64 ,  C07C279/18 ,  C07C2601/14 ,  C07D213/89 ,  C07D215/54 ,  C07D217/26 ,  C07D295/088 ,  C07D307/68 ,  C07D333/38 ,  C07D409/12 ,  C07D413/04

摘要： A method of increasing expression of a molecular chaperon by a cell and/or enhancing the activity of a molecular chaperon in cells is provided. The method comprises treating a cell that is exposed to a physiological stress which induces expression of a molecular chaperon by the cell with an effective amount of a certain hydroxylamine derivative to increase the stress. Alternatively, a hydroxylamine derivative can be administrated to a cell before it is exposed to a physiological stress which induces expression of a molecular chaperon by the cell. Preferably, the cell to which a hydroxylamine derivative is administered is a eukaryotic cell. The hydroxylamine derivative corresponds to the formulae (I) or (II). The invention also provides novel hydroxylamine derivatives falling within the scope of the formulae (I) and (II) as well as pharmaceutical and/or cosmetical compositions comprising the said compounds.

摘要翻译： 提供了增加细胞分子伴侣表达和/或提高细胞中分子伴侣活性的方法。 所述方法包括用有效量的某种羟胺衍生物处理暴露于生理应激的细胞，所述生理应激诱导细胞表达分子伴侣以增加应激。 或者，可以在细胞暴露于诱导细胞分子伴侣表达的生理应激之前向细胞施用羟胺衍生物。 优选地，施用羟胺衍生物的细胞是真核细胞。 羟胺衍生物对应于式（I）或（II）。 本发明还提供了落入式（I）和（II）范围内的新型羟胺衍生物以及包含所述化合物的药物和/或化妆品组合物。

公开(公告)号：WO1995030649A1

公开(公告)日：1995-11-16

申请号：PCT/HU1995000014

申请日：1995-05-04

申请人： BIOREX KUTATO ÉS FEJLESZTO"e; RT. ,  BARABAS, Mihály ,  MARVANYOS, Ede ,  ÜRÖGDI, László ,  VERECZKEY, László ,  JASZLITS, László ,  BIRO, Katalin ,  JEDNAKOVITS, Andrea ,  RADVANYI, Erzsébet ,  UDVARDY-NAGY, Istvánné

发明人： BIOREX KUTATO ÉS FEJLESZTO"e; RT.

IPC分类号： C07C259/02

CPC分类号： C07D295/088 ,  C07C259/02 ,  C07C259/18 ,  C07D213/78

摘要： The invention relates to novel compounds of formula (I), wherein X means halogen; Z stands for an aromatic group, pyridinyl group or the like; and R represents an alkyl or phenylalkyl group or an -A-N(R1)R2 group, and in the latter R1 and R2 stand, independently from each other, for hydrogen or alkyl group; or R1 and R2, together with the adjacent nitrogen atom, form a 5- to 7-membered, saturated heterocyclic group optionally containing an additional nitrogen, oxygen or sulfur atom, said heterocyclic group optionally being substituted by at least one alkyl group; and A stands for a straight or branched chain alkylene group, as well as the pharmaceutically acceptable acid addition salts thereof; furthermore, to processes for the preparation of the above novel compounds, and pharmaceutical compositions containing these compounds or their pharmaceutically acceptable acid addition salts as active ingredients. Further, the invention relates to certain novel intermediates of formula (II). The compounds of formula (I) possess anti-ischaemic effect and therefore, they are useful for treating ischaemic states and diseases, e.g. myocardial ischaemia (induced e.g. by occlusion of the coronary arteries).

摘要翻译： 本发明涉及新的式（I）化合物，其中X表示卤素; Z表示芳基，吡啶基等; 并且R表示烷基或苯基烷基或-A-N（R 1）R 2基团，并且在后面的R 1和R 2彼此独立地表示氢或烷基; 或R 1和R 2与相邻的氮原子一起形成任选地含有另外的氮，氧或硫原子的5至7元饱和杂环基，所述杂环基任选被至少一个烷基取代; A表示直链或支链亚烷基，以及其药学上可接受的酸加成盐; 此外，涉及制备上述新化合物的方法，以及含有这些化合物或其药学上可接受的酸加成盐作为活性成分的药物组合物。 此外，本发明涉及式（II）的某些新型中间体。 式（I）化合物具有抗缺血作用，因此它们可用于治疗缺血状态和疾病，例如， 心肌缺血（例如通过冠状动脉闭塞诱发）。

公开(公告)号：WO1998043948A1

公开(公告)日：1998-10-08

申请号：PCT/HU1997000082

申请日：1997-12-05

申请人： BIOREX KUTATO ÉS FEJLESZTO"e; RT. ,  ÜRÖGDI, László ,  BARABAS, Mihály ,  MARVANYOS, Ede ,  TÖRÖK, Magdolna ,  CSAKAI, Zita

发明人： BIOREX KUTATO ÉS FEJLESZTO"e; RT.

IPC分类号： C07C249/12

CPC分类号： C07C259/02

摘要： The present invention relates to a novel process for preparing O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of formula (I) by reacting a carboxamide oxime of formula (II) wherein R is as specified above with reactive 3-amino-2-hydroxy-propane derivative, diazotizing the O-substituted carboxamide oxime thus obtained with sodium nitrite in the presence of hydrogen halide, decomposing the diazonium salt and if desired, separating the optically active enantiomers and/or reacting the resulting base with an organic or mineral acid, wherein the carboxamide oxime of formula (II) is reacted with a 3-hydroxy azetidinium salt of formula (III) wherein R and R are as defined above and Y is a salt forming anion, in a lower alcoholic, preferably ethanolic medium optionally containing water and made alkaline with an alkali hydroxide, and before diazotizing the O-substituted carboxamide oxime intermediate obtained, the reaction mixture is neutralised and the organic solvent is removed. The process according to the invention provides the compounds of formula (I) with a higher yield compared to the prior art processes.

摘要翻译： 本发明涉及式（I）的O-（3-氨基-2-羟基 - 丙基） - 羟基酰卤的制备方法，其中R 1为其中R 1为指定的式（II）的酰胺肟 用反应性3-氨基-2-羟基 - 丙烷衍生物，在卤化氢存在下，用亚硝酸钠进行重氮化O-取代的甲酰胺肟，分解重氮盐，如果需要，分离光学活性对映体和/或反应 所得到的碱与有机或无机酸反应，其中式（II）的甲酰胺肟与式（III）的3-羟基氮杂环丁烷鎓盐反应，其中R 2和R 3如上定义， - >是形成阴离子的盐，在低级醇，优选乙醇介质中，任选地含有水并用碱金属氢氧化物碱化，然后在得到的O-取代的甲酰胺肟中间体重氮化之前，将反应混合物中和，除去有机溶剂 编辑。 根据本发明的方法提供了与现有技术方法相比具有更高产率的式（I）化合物。