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1. 发明申请

US20070078132A1 Pyrido-and pyrimidopyrimidine derivatives as anti-profilerative agents 有权
公开(公告)号：US20070078132A1
公开(公告)日：2007-04-05
申请号：US10596512
申请日：2004-12-15
申请人： Eddy Freyne , Marc Willems , Pierre Storck , Virginie Poncelet , Kristof Van Emelen , Peter Jacobus Johnnes Buijnsters , Werner Embrechts , Timothy Perera
发明人： Eddy Freyne , Marc Willems , Pierre Storck , Virginie Poncelet , Kristof Van Emelen , Peter Jacobus Johnnes Buijnsters , Werner Embrechts , Timothy Perera
IPC分类号： A61K31/5377 , A61K31/535 , A61K31/525 , C07D491/22
CPC分类号： C07D498/16 , C07D471/04 , C07D487/04 , C07D487/16 , C07D487/22
摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O— or —NR11—; X2 represents —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

2. 发明申请

US20060183747A1 Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors 有权
公开(公告)号：US20060183747A1
公开(公告)日：2006-08-17
申请号：US10565065
申请日：2004-07-12
申请人： Eddy Freyne , Christopher Love , Ludwig Cooymans , Nele Vandermaesen , Peter Jacobus Buijnsters , Marc Willems , Werner Embrechts
发明人： Eddy Freyne , Christopher Love , Ludwig Cooymans , Nele Vandermaesen , Peter Jacobus Buijnsters , Marc Willems , Werner Embrechts
IPC分类号： A61K31/519 , C07D487/02
CPC分类号： C07D487/04
摘要： This invention concerns compounds of formula a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein ring A represents phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl; R1 represents hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy; or optionally substituted C1-6alkyloxyC1-6alkylcarbonyl; X1 represents a direct bond; —(CH2)n3— or —(CH2)n4—X1a—X1b—; R2 represents optionally substituted C3-7cycloalkyl; phenyl; a 4, 5, 6- or 7-membered monocyclic heterocycle containing at least one hetetoatom selected from O, S or N; benzoxazolyl or a radical of formula X2 represents a direct bond; —NR1—; —NR1—(CH2)n3—; —O—; —O—(CH2)n3—; —C(═O)—; —C(═O)—(CH2)n3—; —C(═O)—NR5—(CH2)n3—; —C(═S)—; —S—; —S(═O)n1—; —(CH2)n3—; —(CH2)n4—X1a—X1b—; —X1a—X1b—(CH2)n4—; —S(═O)n1—NR5—(CH2)n3—NR5— or —S(═O)n1—NR5—(CH2)n3—; R3 represents an optionally substituted 5- or 6-membered monocyclic heterocycle containing at least one heteroatom selected from O, S or N, or a 9- or 10-membered bicyclic heterocycle containing at least one heteroatom selected from O, S or N; R4 represents hydrogen; halo; hydroxy; optionally substituted C1-4alkyl; optionally substituted C2-4alkenyl or C2-4alkynyl; polyhaloC1-3alkyl; optionally substituted C1-4alkyloxy; polyhaloC1-3alkyloxy; C1-4alkylthio; polyhaloC1-3alkylthio; C1-4alkyloxycarbonyl; C1-4alkylcarbonyloxy; C1-4alkylcarbonyl; polyhaloC1-4alkylcarbonyl; nitro; cyano; carboxyl; NR9R10; C(═O)NR9R10; —NR5—C(═O)—NR9R10; —NR5—C(═O)—R11; —S(═O)n1—R11; —NR5—S(═O)n1—R11; —S—CN; —NR5—CN; their use, pharmaceutical compositions comprising them and processes for their preparation.

3. 发明申请

US20060247237A1 Macrocyclic quinazoline derivatives as antiproliferative agents 有权
公开(公告)号：US20060247237A1
公开(公告)日：2006-11-02
申请号：US10558007
申请日：2004-05-25
申请人： Eddy Jean Freyne , Timothy Perera , Peter Jacobus Buijnsters , Marc Willems , Gaston Diels , Werner Embrechts
发明人： Eddy Jean Freyne , Timothy Perera , Peter Jacobus Buijnsters , Marc Willems , Gaston Diels , Werner Embrechts
IPC分类号： A61K31/5377 , A61K31/519 , C07D487/22
CPC分类号： C07D498/06 , C07C229/16 , C07C229/40 , C07D239/88 , C07D239/93 , C07D239/94
摘要： The present invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents O, CH2, NH or S; in particular Z represents NH; Y represents —C3-9alkyl-, —C3-9alkenyl-, —C3-9alkynyl-, —C3-7alkyl-CO—NH— optionally substituted with amino, mono- or di(C1-4alkyl)amino or C1-4 alkyloxycarbonylamino-, —C3-7alkenyl-CO—NH— optionally substituted with amino, mono- or di(C1-4alkyl)amino- or C1-4alkyloxycarbonylamino-, C1-5alkyl-oxy-C1-5alkyl-, —C1-5alkyl NR13—, —C1-5alkyl-, —C1-5alkyl-NR14—CO—C1-5alkyl-, —C1-5alkyl-CO NR15—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—, —C1-3alkyl-NH—CS-Het20-, —C1-3alkyl-NH—CO-Het20, —C1-2alkyl-CO-Het21-CO—, -Het22-CH2—CO—NH—C1-3alkyl-, —CO—NH—C1-6alkyl-, —NH—CO—C1-6alkyl-, —CO—C1-7alkyl-, —C1-7alkyl-CO—, —C1-6alkyl-CO—C1-6alkyl-, —C1-2alkyl-NH—CO—CR16R17—NH—, —C1-2alkyl-CO—NH—CR18R19—CO—, —C1-2alkyl-CO—NR20—C1-3alkyl-CO—, C1-2alkyl-NR21—CH2—CO—NH—C1-3alkyl-, or NR22—CO—C1-3alkyl-NH—, X1 represents a direct bond, O or —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR11, —NR11—C1-2alkyl-, —CH2—, —O—N═CH— or —C1-2alkyl-; X2 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR12, —NR12—C1-2alkyl-, —CH2—, —O—N═CH— or —C1-2alkyl-. The growth inhibitory effect anti-tumour activity of the present compounds has been demonstrated in vitro, in enzymatic on the receptor tyrosine kinase EGFR.

4. 发明授权

US08772272B2 Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents 有权
标题翻译：吡啶并嘧啶并嘧啶衍生物作为抗增殖剂
公开(公告)号：US08772272B2
公开(公告)日：2014-07-08
申请号：US12724203
申请日：2010-03-15
申请人： Eddy Jean Edgard Freyne , Marc Willems , Pierre Henri Storck , Virginie Sophie Poncelet , Kristof Van Emelen , Peter Jacobus Johnnes Antonius Buijnsters , Werner Constant Johan Embrechts , Timothy Pietro Suren Perera
发明人： Eddy Jean Edgard Freyne , Marc Willems , Pierre Henri Storck , Virginie Sophie Poncelet , Kristof Van Emelen , Peter Jacobus Johnnes Antonius Buijnsters , Werner Constant Johan Embrechts , Timothy Pietro Suren Perera
IPC分类号： A61K31/33 , A61K31/519 , C07D487/00 , C07D487/18
CPC分类号： C07D498/16 , C07D471/04 , C07D487/04 , C07D487/16 , C07D487/22
摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O— or —NR11—; X2 represents —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.
摘要翻译：本发明涉及N-氧化物形式的化合物，其药学上可接受的加成盐和立体化学异构体，其中a1-a2 = a3-a4表示选自N-CH = CH-CH，N- CH = N-CH或CH-CH = N-CH; Z表示NH; Y表示-C3-9烷基 - ，-C1-5烷基-NR13-C1-5烷基 - ，C1-6烷基-NH-CO-或-CO-NH-C1-6烷基 - ; X1表示-O-或-NR11-; X2表示-C1-2烷基 - ， - O-C1-2烷基，-O-或-O-CH2-; R1表示氢或卤素; R 2表示氢，氰基，卤素，羟基羰基 - ，C 1-4烷氧基羰基 - ，Het 16 - 羰基 - 或Ar 5; R3表示氢; R 4表示羟基，C 1-4烷氧基 - ，Ar 4 -C 1-4烷氧基或R 4表示被一个或多个可能的两个或多个选自C 1-4烷氧基或Het 2-的取代基取代的C 1-4烷氧基; R11表示氢; R 12表示氢，C 1-4烷基 - 或C 1-4烷基 - 氧基 - 羰基 - ; R13表示Het14-C1-4烷基，特别是吗啉基-C 1-4烷基; Het2表示选自任选被C 1-4烷基，优选甲基取代的吗啉基或哌啶基的杂环; Het14代表吗啉基; Het16表示选自吗啉基或吡咯烷基的杂环; Ar4表示苯基; Ar 5表示任选被氰基取代的苯基。

5. 发明授权

US08148388B2 2,4 (4,6) pyrimidine derivatives 有权
标题翻译： 2,4（4,6）嘧啶衍生物
公开(公告)号：US08148388B2
公开(公告)日：2012-04-03
申请号：US11720681
申请日：2005-12-08
申请人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
发明人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
IPC分类号： A01N43/54 , A61K31/505 , C07D471/00 , C07D487/00 , C07D491/00 , C07D239/02
CPC分类号： C07D487/18 , C07D487/08 , C07D487/22 , C07D498/08 , C07D498/18
摘要： The present invention is drawn to 2,4 (4,6) pyrimidine derived macrocyclcs, pharmaceutical compositions thereof, and methods of making said compounds. The compounds disclosed herein are inhibitors of EGF receptor tyrosine kinases and are useful for treating cell proliferative disorders, including atherosclerosis, restenosis, and cancer.
摘要翻译：本发明涉及2,4（4,6）个嘧啶衍生的大环内酯，其药物组合物，以及制备所述化合物的方法。本文公开的化合物是EGF受体酪氨酸激酶的抑制剂，并且可用于治疗细胞增殖性疾病，包括动脉粥样硬化，再狭窄和癌症。

6. 发明申请

US20100160310A1 2,4 (4,6) PYRIMIDINE DERIVATIVES 有权
公开(公告)号：US20100160310A1
公开(公告)日：2010-06-24
申请号：US11720681
申请日：2005-12-08
申请人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
发明人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
IPC分类号： A61K31/5377 , C07D471/22 , C07D498/22 , C07D413/14 , A61K31/4985 , A61K31/519 , A61K31/33 , A61P3/10
CPC分类号： C07D487/18 , C07D487/08 , C07D487/22 , C07D498/08 , C07D498/18
摘要： The present invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z1 and Z2 represent NH; Y represents —C3-9alkyl-, —C3-9alkenyl-, —C1-5alkyl-NR6—C1-5alkyl-, —C1-5alkyl-NR7—CO—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—, —C1-2alkyl-CO-Het10-CO—, —C1-3alkyl-NH—CO-Het3-, -Het4-C1-3alkyl-CO—NH—C1-3alkyl-, —C1-2alkyl-NH—CO-L1-NH—, —NH—CO-L2-NH—, —C1-2alkyl-CO—NH-L3-CO—, —C1-2alkyl-NH—CO-L1-NH—CO—C1-3alkyl-, —C1-2alkyl-CO—NH-L3-CO—NH—C1-3alkyl-, —C1-2alkyl-NR11—CH2—CO—NH—C1-3alkyl-, Het5-CO—C1-2alkyl-, (C1-5alkyl-CO—NH—C1-3alkyl-CO—NH, —C1-5alkyl-NR13—CO—C1-3alkyl-NH—, —C1-3alkyl-NH—CO-Het27-CO—, or —C1-3alkyl-CO-Het28-CO—NH—; X1 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR16—C1-2alkyl-, —CO—NR17—, Het23-C1-2alkyl- or C1-2alkyl; X2 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR18—C1-2alkyl-, —CO—NR19—, Het24—C1-2alkyl- or C1-2alkyl; R1 and R5 each independently represent hydrogen, halo, C1-6alkyloxy- or C1-6alkyloxy- substituted with Het1 or C1-4alkyloxy-; R2 and R4 each independently represent hydrogen or halo; R3 represents hydrogen or cyano; R6, R7, R13, R17 and R19 represent hydrogen; R11 represents hydrogen or C1-4alkyl; R16 and R18 represent hydrogen, C1-4alkyl or Het17-C1-4alkyl-; L1, L2 and L3 each independently represents C1-8alkyl optionally substituted with one or where possible two or more substituents selected from phenyl, methylsulfide, cyano, polyhaloC1-4alkyl-phenyl-, C1-4alkyloxy, pyridinyl, mono- or di(C1-4alkyl)-amino- or C3-6cycloalkyl; Het1, Het2, Het17 each independently represent morpholinyl, oxazolyl, isoxazolyl, or piperazinyl; Het3, Het4, Het5 each independently represent morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl; Het10 represents piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl; Het22 represents morpholinyl, oxazolyl, isoxazolyl or piperazinyl wherein said Het22 is optionally substituted with C1-4alkyl; Het23 and Het24 each independently represent a heterocycle selected from pyrrolidinyl, piperazinyl or piperidinyl wherein said Het23 or Het24 are optionally substituted with Het22-carbonyl; Het27 and Het28 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl.

7. 发明授权

US08394955B2 2,4 (4,6) pyrimidine derivatives 有权
标题翻译： 2,4（4,6）嘧啶衍生物
公开(公告)号：US08394955B2
公开(公告)日：2013-03-12
申请号：US13277651
申请日：2011-10-20
申请人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
发明人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
IPC分类号： C07D239/02
CPC分类号： C07D487/18 , C07D487/08 , C07D487/22 , C07D498/08 , C07D498/18
摘要： The present invention is drawn to intermediates relating to 2,4 (4,6) pyrimidine derived macrocycles, pharmaceutical compositions thereof, and methods of making said compounds. The compounds disclosed herein are inhibitors of EGF receptor tyrosine kinases and are useful for treating cell proliferative disorders, including atherosclerosis, restenosis, and cancer.
摘要翻译：本发明涉及涉及2,4（4,6）个嘧啶衍生的大环化合物的中间体，其药物组合物，以及制备所述化合物的方法。本文公开的化合物是EGF受体酪氨酸激酶的抑制剂，并且可用于治疗细胞增殖性疾病，包括动脉粥样硬化，再狭窄和癌症。

8. 发明申请

US20120065395A1 2,4 (4,6) PYRIMIDINE DERIVATIVES 有权
公开(公告)号：US20120065395A1
公开(公告)日：2012-03-15
申请号：US13277651
申请日：2011-10-20
申请人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
发明人： Eddy Jean Edgard Freyne , Marc Willems , Werner Constant Johan Embrechts , Kristof Van Emelen , Sven Franciscus Anna Van Brandt , Frederik Jan Rita Rombouts
IPC分类号： C07D239/48 , C07D405/12 , C07D403/12
CPC分类号： C07D487/18 , C07D487/08 , C07D487/22 , C07D498/08 , C07D498/18
摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z1 and Z2 represent NH; Y represents —C3-9alkyl-, —C3-9 alkenyl-, —C1-5alkyl-NR6—C1-5alkyl-, —C1-5alkyl-NR7—CO—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—, —C1-2alkyl-CO-Het10-CO—, —C1-3alkyl-NH—CO-Het3-, -Het4-C1-3alkyl-CO—NH—C1-3alkyl-, —C1-2alkyl-NH—CO-L1-NH—, —NH—CO-L2-NH—, —C1-2alkyl-CO—NH-L3-CO—, —C1-2alkyl-NH—CO-L1-NH—CO—C1-3 alkyl-, —C1-2alkyl-CO—NH-L3-CO—NH—C1-3alkyl-, —C1-2alkyl-NR11—CH2—CO—NH—C1-3alkyl-, Het5-CO—C1-2alkyl-, —C1-5alkyl-CO—NH—C1-3alkyl-CO—NH—, —C1-5alkyl-NR13—CO—C1-3alkyl-NH—, —C1-3alkyl-NH—CO-Het27-CO—, or —C1-3alkyl-CO-Het28-CO—NH—; X1 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR16—C1-2alkyl-, —CO—NR17—, Het23-C1-2alkyl- or C1-2alkyl; X2 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR18—C1-2alkyl-, —CO—NR19—, Het24-C1-2alkyl- or C1-2alkyl; R1 and R5 each independently represent hydrogen, halo, C1-6alkyloxy- or C1-6alkyloxy- substituted with Het1 or C1-4alkyloxy-; R2 and R4 each independently represent hydrogen or halo; R3 represents hydrogen or cyano; R6, R7, R13, R17 and R19 represent hydrogen; R11 represents hydrogen or C1-4alkyl; R16 and R18 represent hydrogen, C1-4alkyl or Het17-C1-4alkyl-; L1, L2 and L3 each independently represents C1-8alkyl optionally substituted with one or where possible two or more substituents selected from phenyl, methylsulfide, cyano, polyhaloC1-4alkyl-phenyl-, C1-4alkyloxy, pyridinyl, mono- or di(C1-4alkyl)-amino- or C3-6cycloalkyl; Het1, Het2, Het17 each independently represent morpholinyl, oxazolyl, isoxazolyl, or piperazinyl; Het3, Het4, Het5 each independently represent morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl; Het10 represents piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl; Het22 represents morpholinyl, oxazolyl, isoxazolyl or piperazinyl wherein said Het22 is optionally substituted with C1-4alkyl; Het23 and Het24 each independently represent a heterocycle selected from pyrrolidinyl, piperazinyl or piperidinyl wherein said Het23 or Het24 are optionally substituted with Het22-carbonyl; Het27 and Het28 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl.

9. 发明申请

US20100173913A1 PYRIDO-AND PYRIMIDOPYRIMIDINE DERIVATIVES AS ANTI-PROLIFERATIVE AGENTS 有权
标题翻译：作为抗增生剂的吡咯并吡啶并吡啶衍生物
公开(公告)号：US20100173913A1
公开(公告)日：2010-07-08
申请号：US12724203
申请日：2010-03-15
申请人： Eddy Jean Edgard Freyne , Marc Willems , Pierre Henri Storck , Virginie Sophie Poncelet , Kristof Van Emelen , Peter Jacobus Johannes Antonius Buijnsters , Werner Constant Johan Embrechts , Timothy Pietro Suren Perera
发明人： Eddy Jean Edgard Freyne , Marc Willems , Pierre Henri Storck , Virginie Sophie Poncelet , Kristof Van Emelen , Peter Jacobus Johannes Antonius Buijnsters , Werner Constant Johan Embrechts , Timothy Pietro Suren Perera
IPC分类号： A61K31/529 , C07D498/18 , A61P35/00 , C07D487/18
CPC分类号： C07D498/16 , C07D471/04 , C07D487/04 , C07D487/16 , C07D487/22
摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O— or —NR11—; X2 represents —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.
摘要翻译：本发明涉及N-氧化物形式的化合物，其药学上可接受的加成盐和立体化学异构体，其中a1-a2 = a3-a4表示选自N-CH = CH-CH，N- CH = N-CH或CH-CH = N-CH; Z表示NH; Y表示-C3-9烷基 - ，-C1-5烷基-NR13-C1-5烷基 - ，C1-6烷基-NH-CO-或-CO-NH-C1-6烷基 - ; X1表示-O-或-NR11-; X2表示-C1-2烷基 - ， - O-C1-2烷基，-O-或-O-CH2-; R1表示氢或卤素; R 2表示氢，氰基，卤素，羟基羰基 - ，C 1-4烷氧基羰基 - ，Het 16 - 羰基 - 或Ar 5; R3表示氢; R 4表示羟基，C 1-4烷氧基 - ，Ar 4 -C 1-4烷氧基或R 4表示被一个或多个可能的两个或多个选自C 1-4烷氧基或Het 2-的取代基取代的C 1-4烷氧基; R11表示氢; R 12表示氢，C 1-4烷基 - 或C 1-4烷基 - 氧基 - 羰基 - ; R13表示Het14-C1-4烷基，特别是吗啉基-C 1-4烷基; Het2表示选自任选被C 1-4烷基，优选甲基取代的吗啉基或哌啶基的杂环; Het14代表吗啉基; Het16表示选自吗啉基或吡咯烷基的杂环; Ar4表示苯基; Ar 5表示任选被氰基取代的苯基。

10. 发明申请

US20050004125A1 Heteroaryl amines as glycogen synthase kinase 3beta inhibitors (gsk3 inhibitors) 有权
标题翻译：杂芳基胺作为糖原合酶激酶3β抑制剂（gsk3抑制剂）
公开(公告)号：US20050004125A1
公开(公告)日：2005-01-06
申请号：US10493452
申请日：2002-10-29
申请人： Eddy Jean Edgard Freyne , Peter Jacobus Buijnsters , Marc Willems , Werner Embrechts , Christopher Love , Paul Janssen , Paulus Lewi , Jan Heeres , Marc de Jonge , Lucien Koymans , Hendrik Vinkers , Koen Van Aken , Gaston Diels
发明人： Eddy Jean Edgard Freyne , Peter Jacobus Buijnsters , Marc Willems , Werner Embrechts , Christopher Love , Paul Janssen , Paulus Lewi , Jan Heeres , Marc de Jonge , Lucien Koymans , Hendrik Vinkers , Koen Van Aken , Gaston Diels
IPC分类号： A61K31/435 , A61K31/4406 , A61K31/50 , A61K31/501 , A61K31/505 , A61K31/506 , A61K31/5377 , A61P3/10 , A61P17/00 , A61P21/04 , A61P25/00 , A61P25/04 , A61P25/16 , A61P25/18 , A61P25/24 , A61P25/28 , A61P29/00 , A61P31/18 , A61P35/00 , A61P35/02 , C07D213/53 , C07D213/74 , C07D239/42 , C07D239/48 , C07D401/04 , C07D401/12 , C07D403/04 , C07D403/12 , C07D405/12 , C07D409/12 , C07D417/12 , A61K31/4965
CPC分类号： C07D213/74 , C07D239/42 , C07D239/48 , C07D401/04 , C07D401/12 , C07D403/04 , C07D403/12 , C07D405/12 , C07D409/12 , C07D417/12
摘要： This invention concerns a compound of formula a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein ring A is a 6-membered heterocycle; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl; optionally substituted C1-6alkyloxyC1-6alkylcarbonyl; X is a direct bond or a linker atom or group; Z is a direct bond or a linker atom or group; R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, a carbocycle or a heterocycle, each of said groups may optionally be substituted; R3 is hydrogen; hydroxy; halo; optionally substituted C1-6alkyl or C2-6alkenyl or C2-6alkynyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(C1-6alkyl)amino; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; polyhaloC1-6alkylthio; R21; R21—C1-6alkyl; R21—O—; R21—S—; R21—C(═O)—; R21—S(═O)p—; R7—S(═O)p—; R7—S(═O)p—NH—; R21—S(═O)p—NH—; R7—C(═O)—; —NHC(═O)H; —C(═O)NHNH2; R7—C(═O)—NH—; R21—C(═O)—NH—; —C(═NH)R7—C(═NH)R21; R4 is an optionally substituted heterocycle provided that —X—R2 and/or R3 is other than hydrogen; their use, pharmaceutical compositions comprising them and processes for their preparation.
摘要翻译：本发明涉及式的化合物N-氧化物，药学上可接受的加成盐，季胺及其立体化学异构形式，其中环A是6-元杂环; R 1是氢; 芳基; 甲酰基 C 1-6烷基羰基; 任选取代的C 1-6烷基; C 1-6烷氧基羰基; 任选取代的C 1-6烷氧基C 1-6烷基羰基; X是直接键或连接原子或基团; Z是直接键或连接原子或基团; R 2是氢，C 1-10烷基，C 2-10烯基，C 2-10炔基，碳环或杂环，所述基团中的每一个可任选被取代; R 3是氢; 羟基; 光环; 任选取代的C 1-6烷基或C 2-6烯基或C 2-6炔基; C 1-6烷氧基; C 1-6烷硫基; C 1-6烷氧基羰基; C 1-6烷基羰基氧基; 羧基; 氰基; 硝基氨基; 单或二（C 1-6烷基）氨基; 多卤代C 1-6烷基; 多卤代C 1-6烷氧基; 多卤代C 1-6烷硫基; R 21; R 21 -C 1-6烷基; R 21 -O- R 21 -S-; R 21 -C（= O） - ; R 21 -S（= O）p - ; R 7 -S（= O）p-; R 7 -S（= O）p-NH-; R 21 -S（= O）p -NH-; R 7 -C（= O） - ; -NHC（= O）H; -C（= O）NHNH 2; R 7 -C（= O）-NH-; R 21 -C（= O）-NH-; -C（= NH）R 7 -C（= NH）R 21; R 4是任选取代的杂环，条件是-X-R 2和/或R 3不是氢; 其用途，包含它们的药物组合物及其制备方法。

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