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1. 发明申请

WO2012004373A1 FUSED HETEROCYCLIC DERIVATIVES AS S1P MODULATORS 审中-公开
标题翻译：作为S1P调节剂的熔融杂环衍生物
公开(公告)号：WO2012004373A1
公开(公告)日：2012-01-12
申请号：PCT/EP2011/061586
申请日：2011-07-08
申请人： ABBOTT HEALTHCARE PRODUCTS B.V. , SMID, Pieter , IWEMA BAKKER, Wouter, I. , COOLEN, Hein, K.A.C. , SLIEDREGT, Leonardus, A.J.M. , VAN DONGEN, Maria, J.P. , DEN HARTOG, Jacobus, A.J.
发明人： SMID, Pieter , IWEMA BAKKER, Wouter, I. , COOLEN, Hein, K.A.C. , SLIEDREGT, Leonardus, A.J.M. , VAN DONGEN, Maria, J.P. , DEN HARTOG, Jacobus, A.J.
IPC分类号： C07D487/04 , C07D491/04 , C07D498/04 , C07D513/04 , A61P25/28 , A61K31/429 , A61K31/4355 , A61K31/4365 , A61K31/437 , A61K31/55
CPC分类号： C07D491/048 , C07D471/04 , C07D487/04 , C07D491/04 , C07D495/04 , C07D498/04 , C07D513/04
摘要： The present invention relates to a fused heterocyclic derivative of the formula (I) The variables R1-R4, z, A, Q, X and Y are as defined in the claims. The following heterocycles are exemplified substructures of formula (I): The compounds of formula (I) are modulators of the S1P receptor (Sphingosine-1-phosphate receptor), More specifically, they are agonists of S1P5. The compounds have therapeutic use in treatment of cognitive disorders, age-relate cognitive decline and dementia.
摘要翻译：本发明涉及式（I）的稠合杂环衍生物。变量R1-R4，z，A，Q，X和Y如权利要求中所定义。以下杂环是式（I）的亚结构：式（I）化合物是S1P受体（鞘氨醇-1-磷酸受体）的调节剂，更具体地说，它们是S1P5的激动剂。该化合物在治疗认知障碍，与年龄有关的认知衰退和痴呆方面具有治疗用途。

2. 发明申请

WO2008129054A2 HETEROCYCLIC COMPOUNDS WITH AFFINITY TO MUSCARINIC RECEPTORS 审中-公开
标题翻译：具有对肌肉受体的亲和性的杂环化合物
公开(公告)号：WO2008129054A2
公开(公告)日：2008-10-30
申请号：PCT/EP2008/054897
申请日：2008-04-23
申请人： SOLVAY PHARMACEUTICALS B.V. , STOIT, Axel , COOLEN, Hein K.A.C. , KRUSE, Cornelis G. , TERWEL, Louise, heir of REINDERS, Jan H. (deceased)
发明人： STOIT, Axel , COOLEN, Hein K.A.C. , KRUSE, Cornelis G. , TERWEL, Louise, heir of REINDERS, Jan H. (deceased)
IPC分类号： C07D401/04 , C07D401/14 , C07D413/04 , C07D471/08 , A61K31/4439 , A61K31/4427 , A61K31/439 , A61P25/28 , C07D453/02
CPC分类号： C07D401/04 , C07D401/14 , C07D413/04 , C07D453/02 , C07D471/08
摘要： The present invention relates to heterocyclic compounds of the formula (I) wherein - the heterocycle comprises two double bonds which may be present at several positions, represented by the dashed lines ( -- ); - the heterocycle contains two heteroatoms, - W being N or NH; - Y being CH, O or NH, wherein if Y is O, X 1 is CH and X 2 is the residue C-Z-R2 or C-R3, wherein Z is NH, O, or S; and if Y is CH or NH, one of X 1 and X 2 is CH or N, the other being the residue C-Z-R2 or C-R3, wherein Z is NH or S; - R1 is selected from the structures (a), (b) and (c): - R2 is selected from (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents selected from halogen, hydroxy, cyano, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; or - R2 is an unbranched (C 2 -C 8 )alkyl substituted at the Za-symbol of a group with the formula (Ia) wherein if X 1 is CH or N 1 X 1 is CH or N and X 2 a is C-Za-, or if X 1 is C-Z-R2, X 1 a is C-Za- and X 2 a is CH or N; and the symbols Wa, Ya and Za and the substituent R1a have the same meanings as defined previously for the symbols W, Y and Z and the substituent R1, and are not independently selected, each of the symbols Wa, Ya and Za and the substituent R1 a representing identical symbols and substituents, respectively, as the symbols W, Y and Z and the substituent R1 in the other part of the structure of formula (I); - R3 is selected from (C 4 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl and (C 2 -C 10 ) alkynyl, optionally independently substituted with one or more substituents selected from halogen, hydroxy, cyano, (C 1 C 6 ) alkoxy, (C 1 C 6 ) alkylthio, (C 1 C 6 )alkenyloxy, (C 1 C 6 ) alkenylthio, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkoxy, (C 5 -C 7 ) cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; or a pharmaceutically acceptable salt, a solvate or hydrate thereof. The compounds of the invention have affinity to muscarinic receptors and may be used in the treatment, alleviation or prevention of muscarinic receptor mediated diseases and conditions.
摘要翻译：本发明涉及式（I）的杂环化合物，其中 - 杂环包含两个双键，其可以存在于由虚线（ - ）表示的几个位置。 - 杂环含有两个杂原子，-W为N或NH; - Y是CH，O或NH，其中如果Y是O，则X 1是CH且X 2是残基CZ-R2或C-R3，其中Z是 NH，O或S; 并且如果Y是CH或NH，则X 1和X 2中的一个是CH或N，另一个是残基CZ-R2或C-R3，其中Z是 NH或S; - R 1选自结构（a），（b）和（c）：-R 2选自（C 1 -C 10）烷基，（C 1 -C 10）（C 2 -C 10 -C 10）链烯基和（C 2 -C 10 -C 10）炔基，任选地独立地被一个或多个取代基选自卤素，羟基，氰基，氧代，（C 1 -C 6 - ）烷氧基，（C 1 -C 6 - （C 1 -C 6 -C 6）烷氧基，（C 1 -C 6）烷硫基，（C 1 -C 6 -C 6）烷氧基，（C 1 -C 6 - ）链烯硫基，（C 1 -C 4 -C 4）烷氧基（C 1 -C 4）烷氧基，（C 5元不饱和杂环（任选被卤素取代），苯基，苯氧基和苯硫基，其中苯基任选被卤素取代; 或 - R 2是在具有式（Ia）的基团的Za符号处被取代的未支化的（C 2 -C 8 -C 8）烷基，其中如果X 1 CH或N 1 X 1是CH或N，X 2是C-Z a，或者如果X < A 1是CZ-R 2，X 1 a是C 1 -C 8，X 2是CH或N; 并且符号Wa，Ya和Za以及取代基R 1a具有与前面对符号W，Y和Z以及取代基R所定义的相同的含义，并且不是独立地选择，每个符号Wa，Ya和Za以及取代基 R1a分别表示与式（I）结构的另一部分中的符号W，Y和Z以及取代基R 1相同的符号和取代基; R 3选自（C 1 -C 10 -C 10）烷基，（C 2 -C 10 -C 10）链烯基（C 1 -C 10）炔基，任选独立地被一个或多个选自卤素，羟基，氰基，（C 1 -C 10）（C 1 -C 6）烷硫基，（C 1 -C 6）烷氧基，（C 1 -C 6）烷硫基，（C 1 -C 6）（C 1 -C 6）链烯硫基，（C 1 -C 4 -C 4）烷氧基，（C 1 -C 6）烷硫基，（C 1 -C 6）（C 1 -C 4 - ）烷氧基，（C 5 -C 7 -C 7）环烷基，5元环任选被卤素，苯基，苯氧基和苯硫基取代的不饱和杂环，其中苯基任选被卤素取代; 或其药学上可接受的盐，溶剂合物或水合物。本发明的化合物对毒蕈碱受体具有亲和力，可用于治疗，缓解或预防毒蕈碱受体介导的疾病和病症。

3. 发明申请

WO2003084955A1 DIAZABICYCLO ALKANE DERIVATIVES WITH NK1 ANTAGONISTIC ACTIVITY 审中-公开
标题翻译：具有NK1拮抗活性的DIAZABICYCLO ALKANE衍生物
公开(公告)号：WO2003084955A1
公开(公告)日：2003-10-16
申请号：PCT/EP2003/050086
申请日：2003-04-02
申请人： SOLVAY PHARMACEUTICALS B.V. , DE BOER, Dirk , COOLEN, Hein, K.A.C. , HESSELINK, Mayke, B. , IWEMA BAKKER, Wouter, I. , KUIL, Gijsbert, D. , VAN MAARSEVEEN, Jan, H. , MCCREARY, Andrew, C. , VAN SCHARRENBURG, Gustaaf, J.M.
发明人： DE BOER, Dirk , COOLEN, Hein, K.A.C. , HESSELINK, Mayke, B. , IWEMA BAKKER, Wouter, I. , KUIL, Gijsbert, D. , VAN MAARSEVEEN, Jan, H. , MCCREARY, Andrew, C. , VAN SCHARRENBURG, Gustaaf, J.M.
IPC分类号： C07D471/04
CPC分类号： C07D471/04 , C07D487/04
摘要： The present invention relates to a group of unique diazabicyclo alkane derivatives having interesting neurokinin-NK 1 receptor antagonistic activity represented by the general formula (1) wherein: R 1 represents phenyl, 2-indolyl, 3-indolyl, 3-indazolyl or benzo[b]thiophen-3-yl, which groups may be substituted with halogen or alkyl (1-3C), R 2 and R 3 independently represent halogen, H, OCH 3, CH 3 and CF 3 , R 4 , R 5 and R 6 independently represent H, OH, O-alkyl(1-4C), CH 2 OH, NH 2 , dialkyl(1-3C)N, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl or morpholin-4-yl substituted with one or two methyl or methoxymethyl groups, morpholin-4-ylamino, morpholin-4-ylmethyl, imidazol-1-yl, thiomorpholin-4-yl, 1, 1-dioxothiomorpholin-4-yl or 3-oxa-8-azabicyclo[3.2.1]oct-8-yl; R 4 and R 5 together may represent a keto, a 1,3-dioxan-2-yl or a 1,3-dioxolan-2-yl group, X represents either O or S, n has the value of 1, 2 or 3, a is the asymmetrical carbon atom 8a, 9a or 10a when n equals 1, 2 or 3 respectively The invention also relates to a method for the preparation of the novel compounds, and to pharmaceutical compositions containing at least one of these compounds as an active ingredient.
摘要翻译：本发明涉及具有由通式（1）表示的感兴趣的神经激肽-N NK受体拮抗作用的独特的二氮杂双环烷烃衍生物，其中：R 1表示苯基，2-吲哚基，3-吲哚基，3-吲唑基或苯并 [b]噻吩-3-基，该基团可以被卤素或烷基（1-3C）取代，R 2和R 3独立地表示卤素，H，OCH 3，CH 3和CF 3，R 4， R 5和R 6独立地表示H，OH，O-烷基（1-4C），CH 2 OH，NH 2，二烷基（1-3C）N，吡咯烷-1-基，哌啶-1-基，吗啉 - 被一个或两个甲基或甲氧基甲基取代的吗啉-4-基或吗啉-4-基氨基，吗啉-4-基甲基，咪唑-1-基，硫代吗啉-4-基，1,1-二氧代硫代吗啉-4 - 基或3-氧杂-8-氮杂双环[3.2.1]辛-8-基; R 4和R 5一起可以表示酮，1,3-二氧杂环戊烷-2-基或1,3-二氧戊环-2-基，X表示O或S，n的值为 1,2或3中，a是当n等于1,2或3时不对称碳原子8a，9a或10a。本发明还涉及制备新化合物的方法，以及含有至少一种这些化合物作为活性成分。

4. 发明申请

WO2012004378A1 SPIRO-CYCLIC AMINE DERIVATIVES AS S1P MODULATORS 审中-公开
标题翻译：作为S1P调节剂的螺旋环胺衍生物
公开(公告)号：WO2012004378A1
公开(公告)日：2012-01-12
申请号：PCT/EP2011/061599
申请日：2011-07-08
申请人： ABBOTT HEALTHCARE PRODUCTS B.V. , STOIT, Axel , IWEMA BAKKER, Wouter, I. , COOLEN, Hein K.A.C. , VAN DONGEN, Maria J.P. , LEFLEMME, Nicolas J.-L.D.
发明人： STOIT, Axel , IWEMA BAKKER, Wouter, I. , COOLEN, Hein K.A.C. , VAN DONGEN, Maria J.P. , LEFLEMME, Nicolas J.-L.D.
IPC分类号： C07D265/36 , C07D491/107 , C07D491/20 , A61K31/407 , A61K31/4355 , A61K31/5386 , A61P25/00
CPC分类号： C07D491/107 , C07D265/34 , C07D265/36 , C07D491/20 , C07F9/6561
摘要： The present invention relates spiro- cyclic amine derivatives of the formula (I) wherein R1; R2; R3; Q; -W-T-; R5; Z; and A have the definitions provided in the claims; or a pharmaceutically acceptable salt, a solvate or hydrate thereof or one or more N-oxides thereof. The compounds of the invention have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of diseases and conditions in which (a) S1P receptor (s) is (are) involved.
摘要翻译：本发明涉及式（I）的螺环胺衍生物，其中R1; R2; R3; Q; -W-T-; R5; Z者除外; 和A具有权利要求中提供的定义; 或其药学上可接受的盐，溶剂合物或水合物或其一种或多种N-氧化物。本发明的化合物对S1P受体具有亲和力，可用于治疗，缓解或预防（a）S1P受体涉及的疾病和病症。

5. 发明申请

WO2011023795A1 (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS 审中-公开
标题翻译：（THIO）吗啉衍生物作为S1P调节剂
公开(公告)号：WO2011023795A1
公开(公告)日：2011-03-03
申请号：PCT/EP2010/062552
申请日：2010-08-27
申请人： ABBOTT HEALTHCARE PRODUCTS B.V. , IWEMA BAKKER, Wouter, I. , COOLEN, Hein K.A.C. , MONS, Harmen , STOIT, Axel , RONKEN, Eric , KAM, VAN DER, Elizabeth , FRANKENA, Jurjen
发明人： IWEMA BAKKER, Wouter, I. , COOLEN, Hein K.A.C. , MONS, Harmen , STOIT, Axel , RONKEN, Eric , KAM, VAN DER, Elizabeth , FRANKENA, Jurjen
IPC分类号： C07D265/30 , C07D265/32 , C07D413/12 , C07D419/12 , C07D471/04 , A61K31/5377 , A61P25/04 , A61P25/06 , A61P25/16 , A61P25/18 , A61P25/24 , A61P25/28 , C07D279/12 , C07D417/12 , C07D487/04
CPC分类号： C07D295/15 , C07D265/30 , C07D265/32 , C07D279/12 , C07D413/04 , C07D413/06 , C07D413/12 , C07D417/12 , C07D471/04 , C07F9/6533
摘要： The present invention relates to (thio)morpholine derivatives of the formula (I), wherein R1 is selected from cyano, (2-4C)alkynyl, (1-4C)alkyl, (3-6C)cycloalkyl, (4-6C)cycloalkenyl, (6-8C)bicycloalkyl, (8-10C)bicyclic group, each optionally substituted with (1-4C)alkyl, phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyloptionally substituted with one or more fluoro atoms, (2-4C)alkynyl, (1-4C)alkoxy optionally substituted with one or more fluoro atoms,amino, di(1-4C)alkylamino, -SO 2 -(1-4C)alkyl, -CO-(1-4C)alkyl, -CO-O-(1-4C)alkyl, -NH-CO-(1-4C)alkyl and (3-6C)cycloalkyl, phenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl, monocyclic heterocycle optionally substituted with halogen, (1-4C)alkyl or with phenyl optionally substituted with (1-4C)alkyl, and bicyclic heterocycle optionally substituted with (1-4C)alkyl; A is selected from -CO-O-, -O-CO-, -NH-CO-, -CO-NH, -C=C-, -CCH 3 -O- and the linking group –Y-(CH 2 ) n -X- wherein Y is attached to R1 and selected from a bond, -O-, -S-, -SO-, -SO 2 -, -CH 2 -O-, -CO-, -O-CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C-and -C≡C-; n is an integer from 1 to 10; and X is attached to the phenylene / pyridyl group and selected from a bond, -O-, -S-, -SO-, -SO 2 -, -NH, -CO-, -C=C-and -C≡C-; ring structure B optionally contains one nitrogen atom; R2 is H, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, or halogen; and R3 is (1-4C)alkylene-R5 wherein the alkylene group may be substituted with (CH 2 ) 2 to form a cyclopropyl moiety or one or two halogen atoms, or R3 is is (3-6C)cycloalkylene-R5 or -CO-CH 2 -R5, wherein R5 is -OH, -PO 3 H 2 , -OPO 3 H 2 , -COOH, -COO(1-4C)alkyl or tetrazol-5-yl; R4 is H or (1-4C)alkyl; R6 is one or more substituents independently selected from H, (1-4C)alkyl or oxo; W is -O-, -S-, -SO- or -SO 2 -; or a pharmaceutically acceptable salt, a solvate or hydrate thereof; with the proviso that the derivative of formula (I) is not 2-(4-ethylphenyl)-4-morpholinoethanol or 4-[4-(2-hydroxyethyl)-2-morpholinyl]benzeneacetonitrile or a pharmaceutically acceptable salt, a solvate or hydrate thereof. The compounds of the invention have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of S1P receptor mediated diseases and conditions.
摘要翻译：本发明涉及式（I）的（硫代）吗啉衍生物，其中R 1选自氰基，（2-4C）炔基，（1-4C）烷基，（3-6C）环烷基，（4-6C）环烷基，（6-8C）双环烷基，（8-10C）双环基团，各自任选被（1-4C）烷基，苯基，联苯基，萘基取代，各自任选被一个或多个独立地选自卤素，（1- 氨基，二（1-4C）烷基氨基，-SO 2 - （1-4C）烷氧基，被一个或多个氟原子烷基取代的（2-4C）炔基，任选被一个或多个氟原子取代的（1-4C）） - （1-4C）烷基，-CO-O-（1-4C）烷基，-NH-CO-（1-4C）烷基和（3-6C）环烷基，被苯氧基取代的苯基（1-4C）烷基或任选被（1-4C）烷基任意取代的苯基的单环杂环，和任选被取代的（1-4C）烷基的双环杂环，与（1-4C）烷基; A选自-CO-O-，-O-CO-，-NH-CO-，-CO-NH，-C = C-，-CCH 3 -O-和连接基-Y-（CH 2）n X- 其中Y连接到R 1并且选自-O - ， - S - ， - SO - ， - SO 2 - ， - CH 2 -O-，-CO-，-O-CO-，-CO-O-， -CO-NH-，-NH-CO-，-C≡C-和-C = C-; n为1〜10的整数，并且X连接到亚苯基/吡啶基上，并且选自-O - ， - S - ， - SO - ， - SO 2 - ， - NH，-CO - ， - C = C - 和-C = C- ; 环结构B任选地含有一个氮原子; R2是H，任选被一个或多个氟原子取代的（1-4C）烷基，（1-4C）任选被一个或多个氟原子取代的烷氧基或卤素; 并且R 3是（1-4C）亚烷基-R 5，其中亚烷基可以被（CH 2）2取代以形成环丙基部分或一个或两个卤素原子，或者R 3是（3-6C）亚环烷基-R 5或-CO -CH 2 -R 5，其中R 5是-OH，-PO 3 H 2，-OPO 3 H 2，-COOH，-COO（1-4C）烷基或四唑-5-基; R4是H或（1-4C）烷基; R6是一个或多个独立地选自H，（1-4C）烷基或氧代的取代基; W是-O - ， - S - ， - SO-或-SO 2 - ; 或其药学上可接受的盐，溶剂合物或水合物; 条件是式（I）的衍生物不是2-（4-乙基苯基）-4-吗啉代乙醇或4- [4-（2-羟乙基）-2-吗啉基]苯乙腈或其药学上可接受的盐，溶剂合物或水合物。本发明的化合物对S1P受体具有亲和力，可用于治疗，缓解或预防S1P受体介导的疾病和病症。

6. 发明申请

WO2008003736A1 AZAINDOLE DERIVATIVES WITH A COMBINATION OF PARTIAL NICOTINIC ACETYLCHOLINE RECEPTOR AGONISM AND DOPAMINE REUPTAKE INHIBITION 审中-公开
标题翻译：具有部分NICOTINIC乙酰胆碱受体激动剂和多巴胺反复抑制组合的联合衍生物
公开(公告)号：WO2008003736A1
公开(公告)日：2008-01-10
申请号：PCT/EP2007/056792
申请日：2007-07-05
申请人： SOLVAY PHARMACEUTICALS B.V. , STOIT, Axel , COOLEN, Hein K.A.C. , VAN DER NEUT, Martina A.W. , KRUSE, Cornelis G.
发明人： STOIT, Axel , COOLEN, Hein K.A.C. , VAN DER NEUT, Martina A.W. , KRUSE, Cornelis G.
IPC分类号： C07D471/04 , C07D487/04 , C07D519/00 , A61P25/16 , A61P25/28 , A61P25/30 , A61K31/445 , A61K31/40
CPC分类号： C07D471/04 , C07D487/04 , C07D519/00
摘要： The invention concerns azaindole derivatives having the general formula (I) wherein the symbols have the meanings given in the specification. These compounds have a combination of partial nicotinic acetylcholine receptor agonism and dopamine reuptake inhibition. The invention also relates to pharmaceutical compositions containing these compounds, to methods for preparing them, methods for preparing novel intermediates useful for their synthesis, methods for preparing compositions, and uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in disorders in which nicotinic receptors and/or dopamine transporters are involved, or that can be treated via manipulation of those receptors.
摘要翻译：本发明涉及具有通式（I）的氮杂吲哚衍生物，其中符号具有说明书中给出的含义。这些化合物具有部分烟碱乙酰胆碱受体激动和多巴胺再摄取抑制的组合。本发明还涉及含有这些化合物的药物组合物，其制备方法，制备用于其合成的新中间体的方法，制备组合物的方法，以及这些化合物和组合物的用途，特别是其用于给患者施用在其中涉及烟碱受体和/或多巴胺转运蛋白的病症中的治疗效果，或者可以通过这些受体的操纵来治疗。

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