公开(公告)号：US06376707B1

公开(公告)日：2002-04-23

申请号：US09889857

申请日：2001-07-23

申请人： Michio Toda ,  Tetsuro Tamai ,  Nobuyuki Tanaka ,  Kiyoshi Kasai ,  Junichi Sonehara ,  Eiji Tsuru

发明人： Michio Toda ,  Tetsuro Tamai ,  Nobuyuki Tanaka ,  Kiyoshi Kasai ,  Junichi Sonehara ,  Eiji Tsuru

IPC分类号： C07C22900

CPC分类号： C07C217/60 ,  C07C213/10

摘要： The present invention relates to a crystalline polymorph of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid having strong diffraction peaks (diffraction angle: 2&thgr;±0.1°) at 10.8, 19.1, 19.3, 19.8, 20.6 and 27.0° in powder X-ray diffraction pattern, which has potent &bgr;2- and &bgr;3-adrenoceptor stimulating effects and is useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis, and the like. For example, the crystalline polymorph can be prepared by hydrolyzing ethyl 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-amino]ethyl]phenoxy]acetate phosphate by sodium hydroxide, adding an aqueous phosphoric acid solution at 40° C. and over, adding a mixed solvent of water and methanol or methanol to the resulting compound, and stirring the suspension at 40° C. to reflux temperature for 30 minutes to several hours.

摘要翻译： 本发明涉及2- [4- [2 - [[（1S，2R）-2-羟基-2-（4-羟基 - 苯基）-1-甲基乙基]氨基]乙基]苯氧基]乙酸的结晶多晶型物 在其粉末X射线衍射图中，在10.8,19.1,19.3,19.8,20.6和27.0°处具有强衍射峰（衍射角：2θ±0.1°）的酸，其具有有效的β2-和β3-肾上腺素受体刺激作用，并且是有用的 作为缓解疼痛并促进尿石结石中的结石的去除的药剂等。 例如，结晶多晶型物可以通过水解2- [4- [2 - [[（1S，2R）-2-羟基-2-（4-羟基苯基）-1-甲基乙基] - 氨基]乙基]苯氧基 ]乙酸磷酸盐与氢氧化钠反应，在40℃加入磷酸水溶液，过滤，向所得化合物中加入水和甲醇或甲醇的混合溶剂，并在40℃下将悬浮液在回流温度下搅拌30 几分钟到几个小时。

公开(公告)号：US20060142374A1

公开(公告)日：2006-06-29

申请号：US10526898

申请日：2003-09-05

申请人： Eiji Tsuru ,  Michio Toda ,  Kazuma Hirata

发明人： Eiji Tsuru ,  Michio Toda ,  Kazuma Hirata

IPC分类号： A61K31/404 ,  A61K9/48 ,  A61K9/20 ,  C07D209/14

CPC分类号： A61K31/404 ,  C07D209/08

摘要： A crystal for oral solid medicament comprised of indoline compound (KMD-3213) which exerts α1-adrenaline receptor blocking effect, is useful as a therapeutic agent for dysuria and is represented by the formula: (I) wherein in the powder X-ray diffraction pattern, the compound is characterized by main peaks of 5.5°±0.2°, 6.1°±0.2°, 9.8°±0.2°, 11.1°±0.2°, 12.2°±0.2°, 16.4°±0.2°, 19.7°±0.2° and 20.0°±0.2° as 2θ. There is further provided an oral solid medicament for dysuria treatment containing the crystal as an active ingredient.

摘要翻译： 用于口服固体药物的晶体，其由发挥α1-肾上腺素受体阻断作用的二氢吲哚化合物（KMD-3213）组成，可用作排尿困难的治疗剂，并由下式表示：（I）其中在粉末X射线衍射 该化合物的特征是主峰为5.5°±0.2°，6.1°±0.2°，9.8°±0.2°，11.1°±0.2°，12.2°±0.2°，16.4°±0.2°，19.7°±0.2 °和20.0°±0.2°为2θ。 还提供了含有晶体作为活性成分的排尿困难的口服固体药物。

公开(公告)号：US07763654B2

公开(公告)日：2010-07-27

申请号：US11912407

申请日：2006-04-24

申请人： Kiyoshi Kasai ,  Michio Toda

发明人： Kiyoshi Kasai ,  Michio Toda

IPC分类号： A61K31/24 ,  C07C229/00

CPC分类号： C07C217/60

摘要： The present invention provides a novel crystal polymorph of ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate hydrochloride which can be determined by characteristic diffraction peaks of the powder X-ray diffraction or the like, and obtained from ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate by a specific method.

摘要翻译： 本发明提供了（ - ） - 2- [4- [2 - [[1S，2R] -2-羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] 可以通过粉末X射线衍射等的特征衍射峰确定，并由（ - ） - 2- [4- [2 - [[1S，2R] -2- 羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] -2,5-二甲基苯氧基乙酸酯。

公开(公告)号：US20090069421A1

公开(公告)日：2009-03-12

申请号：US11912407

申请日：2006-04-24

申请人： Kiyoshi Kasai ,  Michio Toda

发明人： Kiyoshi Kasai ,  Michio Toda

IPC分类号： A61K31/216 ,  C07C229/34 ,  A61P13/00

CPC分类号： C07C217/60

摘要： The present invention provides a novel crystal polymorph of ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate hydrochloride which can be determined by characteristic diffraction peaks of the powder X-ray diffraction or the like, and obtained from ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate by a specific method.

摘要翻译： 本发明提供了（ - ） - 2- [4- [2 - [[1S，2R] -2-羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] 可以通过粉末X射线衍射等的特征衍射峰确定，并由（ - ） - 2- [4- [2 - [[1S，2R] -2- 羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] -2,5-二甲基苯氧基乙酸酯。

公开(公告)号：US08003694B2

公开(公告)日：2011-08-23

申请号：US11912420

申请日：2006-04-24

申请人： Hidetoshi Isawa ,  Michio Toda

发明人： Hidetoshi Isawa ,  Michio Toda

IPC分类号： A61K31/24 ,  C07C229/38

CPC分类号： C07C217/60

摘要： The present invention provides ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate hydrochloride ¼ hydrate or a crystal thereof which can be determined by characteristic diffraction peaks of the powder X-ray diffraction, thermogravimetry-differential thermal analysis or the like, and obtained by manufacturing ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]-2,5-dimethylphenoxyacetate by a specific method.

摘要翻译： 本发明提供（ - ） - 2- [4- [2 - [[1S，2R] -2-羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] -2,5-二甲基苯氧基乙酸乙酯 可以通过粉末X射线衍射，热重分析 - 差示热分析等的特征衍射峰确定，并通过制备（ - ） - 2- [4- [2- [ [1S，2R] -2-羟基-2-（4-羟基苯基）-1-甲基 - 乙基]氨基]乙基] -2,5-二甲基苯氧基乙酸乙酯。

公开(公告)号：US20090036526A1

公开(公告)日：2009-02-05

申请号：US11912420

申请日：2006-04-24

申请人： Hidetoshi Isawa ,  Michio Toda

发明人： Hidetoshi Isawa ,  Michio Toda

IPC分类号： A61K31/24 ,  C07C229/38 ,  A61P13/02

CPC分类号： C07C217/60

摘要： The present invention provides ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate hydrochloride ¼ hydrate or a crystal thereof which can be determined by characteristic diffraction peaks of the powder X-ray diffraction, thermogravimetry-differential thermal analysis or the like, and obtained by manufacturing ethyl (−)-2-[4-[2-[[1S,2R]-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxyacetate by a specific method.

摘要翻译： 本发明提供（ - ） - 2- [4- [2 - [[1S，2R] -2-羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] -2,5-二甲基苯氧基乙酸乙酯 可以通过粉末X射线衍射，热重分析 - 差示热分析等的特征衍射峰确定，并通过制备（ - ） - 2- [4- [2- [ [1S，2R] -2-羟基-2-（4-羟基苯基）-1-甲基乙基]氨基]乙基] -2,5-二甲基苯氧基乙酸酯。

公开(公告)号：US4026896A

公开(公告)日：1977-05-31

申请号：US568423

申请日：1975-04-16

申请人： Kozaburo Harita ,  Yukiyoshi Ajisawa ,  Kinji Iizuka ,  Michio Toda ,  Yukihiko Kinoshita ,  Tetsuhide Kamijo ,  Michihiro Kobayashi

发明人： Kozaburo Harita ,  Yukiyoshi Ajisawa ,  Kinji Iizuka ,  Michio Toda ,  Yukihiko Kinoshita ,  Tetsuhide Kamijo ,  Michihiro Kobayashi

IPC分类号： C07D317/60 ,  C07C103/84

CPC分类号： C07D317/60

摘要： New aromatic amidocarboxylic acid derivatives of the general formula: ##STR1## wherein R.sub.1 and R.sub.2 each represent a hydrogen atom or an alkyl gp with 1-4 carbon atoms; R.sub.3 and R.sub.4 each represent a hydrogen atom or may be combined together to form an additional chemical bond; X represents a hydroxyl group, a halogen atom, a straight or branched chain saturated or unsaturated alkyl group with 1-4 carbon atoms, a straight or branched chain saturated or unsaturated alkoxy group with 1-4 carbon atoms, an acyloxy group with 1-4 carbon atoms, or a cycloalkyl group with up to 6 carbon atoms; n is zero or an integer of 1-3 with the proviso that when n is 2 or 3, X's may be the same or different and that when two X's are commonly the alkyl or alkoxy group, both X's may be combined together to form a ring; and Y represents a straight or branched chain alkylene group or a straight or branched chain oxyalkylene group connected to the benzene nucleus through an oxygen atom, as well as physiologically acceptable salts thereof.The new compounds possess a strong antiallergic effect and are thus useful for the treatment of asthma, hay fever, urticaria and atopic dermatitis.The above-mentioned aromatic amidocarboxylic acid and a salt thereof are prepared, for example, by reacting a reactive functional derivative of the general formula: ##STR2## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, X and n have the same meanings as given above, with an aminophenylalkylcarboxylic acid derivative or an aminophenoxyalkylcarboxylic acid dervative of the general formula: ##STR3## wherein Y has the same meaning as given above, and if desired, converting the resulting amidocarboxylic acid into a corresponding salt thereof or vice versa.

摘要翻译： 新的芳族酰胺基羧酸衍生物，其通式如下：其中R 1和R 2各自表示氢原子或具有1-4个碳原子的烷基; R 3和R 4各自表示氢原子，或者可以组合在一起形成附加的化学键; X表示羟基，卤素原子，具有1-4个碳原子的直链或支链饱和或不饱和烷基，具有1-4个碳原子的直链或支链饱和或不饱和烷氧基，具有1- 4个碳原子或具有至多6个碳原子的环烷基; n为0或1-3的整数，条件是当n为2或3时，X可以相同或不同，并且当两个X通常为烷基或烷氧基时，两个X可以组合在一起形成 环; Y表示通过氧原子与苯环连接的直链或支链亚烷基或直链或支链氧化烯基，以及其生理上可接受的盐。