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1. 发明申请

US20130196998A1 SPIRO-CYCLIC AMINE DERIVATIVES AS S1P MODULATORS 审中-公开
公开(公告)号：US20130196998A1
公开(公告)日：2013-08-01
申请号：US13808903
申请日：2011-07-08
申请人： Axel Stoit , Wouter I. Iwema Bakker , Hein K.A.C. Coolen , Maria J.P. van Dongen , Nicolas J.-L.D. Leflemme
发明人： Axel Stoit , Wouter I. Iwema Bakker , Hein K.A.C. Coolen , Maria J.P. van Dongen , Nicolas J.-L.D. Leflemme
IPC分类号： C07D491/107 , C07D265/34 , C07D491/20
CPC分类号： C07D491/107 , A61K31/44 , C07D265/34 , C07D265/36 , C07D401/00 , C07D491/20 , C07F9/6561
摘要： The present invention relates to spiro-cyclic amine derivatives of the formula (I) wherein R1 is selected from cyano, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkyl each optionally substituted with CN or one or more fluoro atoms, (3-6C)cycloalkyl, (4-6C)cycloalkenyl or a (8-10C)bicyclic group, each optionally substituted with halogen or (1-4C)alkyl, phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, cyano, (1-6C)alkyl optionally substituted with one or more fluoro atoms, (1-6C)alkoxy optionally substituted with one or more fluoro atoms, amino, di(1-4C)alkylamino and (3-6C)cycloalkyl optionally substituted with phenyl which may be substituted with (1-4C)alkyl or halogen, phenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl optionally substituted with one or more fluoro atoms, monocyclic heterocycle optionally independently substituted with halogen, (1-6C)alkyl optionally substituted with one or more fluoro atoms, (3-6C)cycloalkyl, or phenyl optionally substituted with (1-4C)alkyl or halogen, and bicyclic heterocycle optionally substituted with halogen or (1-4C)alkyl optionally substituted with one or more fluoro atoms; —Y—(Cn-alkylene)-X— is a linking group wherein Y is attached to R1 and selected from a bond, —O—, —CO—, —S—, —SO—, —SO2—, —NH—, —CH═CH—, —C(CF3)═CH—, —C≡C—, —CH2—O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO—, and trans-cyclopropylene; n is an integer from 0 to 10; and X is attached to the phenylene/pyridyl moiety and selected from a bond, —O—, —S—, —SO—, —SO2—, —NH—, —CO—, —CH═CH—, and trans-cyclopropylene; R2 is H or independently selected from one or more substituents selected from halogen, (1-4C)alkoxy and (1-4C)alkyl optionally substituted with one or more fluor atoms; and R3 is (1-4C)alkylene-R4 wherein the alkylene group may be substituted with one or more halogen atoms or with (CH2)2 to form a cyclopropyl moiety, or R3 is (3-6C)cycloalkylene-R4, —CH2-(3-6C)cycloalkylene-R4, (3-6C)cycloalkylene-CH2—R4 or —CO—CH2—R4, wherein R4 is —OH, —PO3H2, —OPO3H2, —COON, —COO(1-4C)alkyl or tetrazol-5-yl; Q is a bond or —O—; —W—T— is selected from —CH═CH—, —CH2—CH2—, —CH2—O—, —O—CH2—, —O—CH2—CH2—, and —CO—O—; R5 is H or independently selected from one or more halogens; Z is CH, CR2 or N; and A represents a morpholine ring structure or a 5-, 6- or 7-membered cyclic amine; 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.

2. 发明申请

US20080009514A1 AZAINDOLE DERIVATIVES WITH A COMBINATION OF PARTIAL NICOTINIC ACETYL-CHOLINE RECEPTOR AGONISM AND DOPAMINE REUPTAKE INHIBITION 有权
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：US20080009514A1
公开(公告)日：2008-01-10
申请号：US11773111
申请日：2007-07-03
申请人： Axel STOIT , Hein K.A.C. Coolen , Martina A. W. Van Der Neut , Cornelis G. Kruse
发明人： Axel STOIT , Hein K.A.C. Coolen , Martina A. W. Van Der Neut , Cornelis G. Kruse
IPC分类号： C07D471/04 , A61K31/437 , A61P1/00 , A61P25/00 , A61P37/00
CPC分类号： C07D471/04 , C07D519/00
摘要： Azaindole derivatives of formula (I): wherein the symbols have the meanings given in the specification, are described. 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, for example, 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：描述了式（I）的Azaindole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型中间体的方法，制备组合物的方法，以及这些化合物和组合物的用途，例如其用于给予患者的用途以在涉及烟碱受体和/或多巴胺转运蛋白的病症中获得治疗效果，或者可以通过操纵那些受体来治疗

3. 发明申请

US20110053962A1 AZAINDOLE DERIVATIVES WITH A COMBINATION OF PARTIAL NICOTINIC ACETYL-CHOLINE RECEPTOR AGONISM AND DOPAMINE REUPTAKE INHIBITION 有权
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：US20110053962A1
公开(公告)日：2011-03-03
申请号：US12940271
申请日：2010-11-05
申请人： Axel Stoit , Hein K.A.C. Coolen , Martina A.W. Van Der Neut , Cornelis G. Kruse
发明人： Axel Stoit , Hein K.A.C. Coolen , Martina A.W. Van Der Neut , Cornelis G. Kruse
IPC分类号： A61K31/519 , A61K31/437 , A61P25/00 , A61P29/00 , A61P27/02 , A61P9/00 , A61P3/00 , A61P1/04
CPC分类号： C07D471/04 , C07D519/00
摘要： Azaindole derivatives of formula (I): wherein the symbols have the meanings given in the specification, are described. 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, for example, 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：描述了式（I）的Azaindole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型中间体的方法，制备组合物的方法，以及这些化合物和组合物的用途，例如其用于给予患者的用途以在涉及烟碱受体和/或多巴胺转运蛋白的病症中获得治疗效果，或者可以通过这些受体的操纵来治疗。

4. 发明申请

US20090018160A1 Heterocyclic Compounds with Affinity to Muscarinic Receptors 有权
公开(公告)号：US20090018160A1
公开(公告)日：2009-01-15
申请号：US12108275
申请日：2008-04-23
申请人： Axel Stoit , Hein K.A.C. Coolen , Cornelis G. Kruse , Jan H. Reinders , Louise Terwel
发明人： Axel Stoit , Hein K.A.C. Coolen , Cornelis G. Kruse , Jan H. Reinders , Louise Terwel
IPC分类号： C07D401/04 , A61K31/4439 , C07D413/04 , C07D451/02 , C07D453/02 , A61K31/439 , A61K31/46 , A61P25/00 , C07F7/02
CPC分类号： C07D471/08 , A61K31/439 , A61K45/06 , C07D401/04 , C07D403/04 , C07D413/04 , C07F7/1804
摘要： The present invention relates to heterocyclic compounds of the formula (I) or a pharmaceutically acceptable salt, a solvate or hydrate thereof wherein the heterocycle comprises two double bonds which may be present at several positions, and which are represented by the dashed lines (---); the heterocycle contains two heteroatoms, W is N or NH; Y is CH, O or NH, wherein if Y is O, X1 is CH and X2 is C-Z-R2 or C—R3, wherein Z is NH, O, or S; and if Y is CH or NH, one of X1 and X2 is CH or N, wherein if X1 is CH or N, X2 is C-Z-R2 or C—R3, and if X2 is CH or N, X1 is C-Z-R2 or C—R3, wherein Z is NH or S; R1 is chosen from structures (a), (b) and (c): R2 is chosen from (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, oxo, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenyloxy, (C1-C6)alkenylthio, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, a 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; and R3 is chosen from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenyloxy, (C1-C6)alkenylthio, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; and optionally, when R2 is an unbranched (C2-C8)alkyl, R2 links to formula (Ia) or a pharmaceutically acceptable salt, a solvate or hydrate thereof, through the X1a or X2a of formula (Ia), wherein if X1 is CH or N, X1a is CH or N and X2a is C-Za-, or if X1 is C-Z-R2, X1a is C-Za- and X2a is CH or N, wherein X1a or X2a having Za links to R2; 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 R1a 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). 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.

5. 发明申请

US20130203737A1 FUSED HETEROCYCLIC DERIVATIVES AS S1P MODULATORS 有权
公开(公告)号：US20130203737A1
公开(公告)日：2013-08-08
申请号：US13808908
申请日：2011-07-08
申请人： Pieter Smid , Wouter I. Iwema Bakker , Hein K.A.C. Coolen , Leonardus A.J.M. Sliedregt , Maria J.P. van Dongen , Jacobus A.J. den Hartog
发明人： Pieter Smid , Wouter I. Iwema Bakker , Hein K.A.C. Coolen , Leonardus A.J.M. Sliedregt , Maria J.P. van Dongen , Jacobus A.J. den Hartog
IPC分类号： C07D513/04 , C07D495/04 , C07D487/04 , C07D471/04 , C07D491/048 , C07D498/04
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) wherein R1 is selected from cyano, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkyl, each optionally substituted with CN or one or more fluoro atoms, (3-6C)cycloalkyl, (4-6C)cycloalkenyl or a (8-10C)bicyclic group, each optionally substituted with halogen or (1-4C)alkyl optionally substituted with one or more fluoro atoms, phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, cyano, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with phenyl which may be substituted with (1-4C)alkyl or halogen, and phenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl, Z is a linking group —W—(Cn-alkylene)-T- wherein W is attached to R1 and selected from a bond, —O—, —CO—, —S—, —SO—, —SO2—, —NH—, —CH═CH—, —C(CF3)═CH—, —C≡C—, —CH2—O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO— and trans-cyclopropylene; n is an integer from 0 to 10; and T is attached to the phenylene/pyridyl moiety and selected from a bond, —O—, —S—, —SO—, —SO2—, —NH—, —CO—, —C═C—, —C≡C—, and trans-cyclopropylene; R2 is H or one or more substituents independently selected from cyano, halogen, (1-4C)alkyl optionally substituted with one or more halogen atoms, or (1-4C)alkoxy optionally substituted with one or more halogen atoms; ring structure A may contain one nitrogen atom; X is selected from C or N; if X is C, R3 is selected from H and (1-4C)alkyl, otherwise R3 is not present; Y is selected from NH, O and S; structure Q is a 5-, 6- or 7-membered cyclic amine; and R4 is (1-4C)alkylene-R5 wherein one or more carbon atoms in the alkylene group may independently be substituted with one or more halogen atoms or with (CH2)2 to form a cyclopropyl moiety, or R4 is (3-6C)cycloalkylene-R5, —CH2-(3-6C)cycloalkylene-R5, (3-6C)cycloalkylene-CH2-R5 or —CO—CH2-R5, wherein R5 is —OH, —PO3H2, —OPO3H2, —COOH, —COO(1-4C)alkyl or tetrazol-5-yl; 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 (any) S1P receptor(s) is (are) involved or in which modulation of the endogenous S1P signaling system via any S1P receptor is involved.

6. 发明申请

US20120220552A1 (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS 有权
公开(公告)号：US20120220552A1
公开(公告)日：2012-08-30
申请号：US13393497
申请日：2010-08-27
申请人： Wouter I. Iwema Bakker , Hein K.A.C. Coolen , Axel Stoit , Harmen Mons , Eric Ronken , Elizabeth Van Der Kam , Jurjen Frankena
发明人： Wouter I. Iwema Bakker , Hein K.A.C. Coolen , Axel Stoit , Harmen Mons , Eric Ronken , Elizabeth Van Der Kam , Jurjen Frankena
IPC分类号： A61K31/5375 , C07D413/10 , A61K31/5377 , C07F9/6533 , A61P25/24 , C07D279/12 , A61K31/54 , A61P25/00 , A61P25/28 , C07D265/30 , A61K31/675
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 disclosure 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)alkyl optionally 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, —SO2-(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—, —CCH3—O— and the linking group —Y—(CH2)n—X— wherein Y is attached to R1 and selected from a bond, —O—, —S—, —SO—, —SO2—, —CH2—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—, —SO2—, —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 (CH2)2 to form a cyclopropyl moiety or one or two halogen atoms, or R3 is (3-6C)cycloalkylene-R5 or —CO—CH2—R5, wherein R5 is —OH, —PO3H2, —OPO3H2, —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 —SO2—; 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 disclosure have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of S1P receptor mediated diseases and conditions.

7. 发明申请

US20120095039A1 HETEROCYCLIC COMPOUNDS WITH AFFINITY TO MUSCARINIC RECEPTORS 有权
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：US20120095039A1
公开(公告)日：2012-04-19
申请号：US13300800
申请日：2011-11-21
申请人： Axel Stoit , Hein K.A.C. Coolen , Cornelis G. Kruse , Jan H. Reinders , Louise Terwel
发明人： Axel Stoit , Hein K.A.C. Coolen , Cornelis G. Kruse , Jan H. Reinders , Louise Terwel
IPC分类号： A61K31/439 , A61K31/46 , C07D413/04 , A61P25/18 , C07D401/04 , C07F7/02 , C07D487/08 , A61P25/00
CPC分类号： C07D471/08 , A61K31/439 , A61K45/06 , C07D401/04 , C07D403/04 , C07D413/04 , C07F7/1804
摘要： The present invention relates to heterocyclic compounds of formula (I) having affinity to muscarinic receptors, a pharmaceutical composition containing the compounds, as well as the use of the compounds for the preparation of a medicament for treating, alleviating or preventing muscarinic receptor mediated diseases and conditions.
摘要翻译：本发明涉及对毒蕈碱受体具有亲和力的式（I）的杂环化合物，含有这些化合物的药物组合物，以及该化合物用于制备治疗，减轻或预防毒蕈碱受体介导的疾病的药物的用途，条件。

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