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    Piperazine oxime dervatives having NK-1 receptor antagonistic activity
    3.
    发明授权
    Piperazine oxime dervatives having NK-1 receptor antagonistic activity 有权
    具有NK-1受体拮抗活性的哌嗪肟衍生物

    公开(公告)号：US07094779B2

    公开(公告)日：2006-08-22

    申请号：US10480542

    申请日：2002-07-03

    申请人： Wouter I. Iwema Bakker ,  Jan H. van Maarseveen ,  Hein K. A. C. Coolen ,  Martinus Th. M. Tulp ,  Arnoldus H. J. Herremans ,  Andrew C. Mccreary ,  Gustaaf J. M. van Scharrenburg ,  Adrianus van den Hoogenband

    发明人： Wouter I. Iwema Bakker ,  Jan H. van Maarseveen ,  Hein K. A. C. Coolen ,  Martinus Th. M. Tulp ,  Arnoldus H. J. Herremans ,  Andrew C. Mccreary ,  Gustaaf J. M. van Scharrenburg ,  Adrianus van den Hoogenband

    IPC分类号： A61K31/496 ,  C07D403/06 ,  C07D413/14 ,  C07D471/04

    CPC分类号： C07D401/14 ,  C07D241/04 ,  C07D403/06 ,  C07D403/14 ,  C07D405/06 ,  C07D405/14 ,  C07D409/06 ,  C07D471/04

    摘要： The present invention relates to a group of novel piperazine oxime derivatives having interesting NK-1 antagonistic activity. The invention relates to compounds of the general formula (1) wherein: X represents phenyl or pyridyl substituted with 1 or 2 substituents from the group CH3, CF3, OCH3, halogen, cyano and 5-CF3-tetrazol-1-yl; Y represents 2- or 3-indolyl, phenyl, 7-aza-indol-3-yl or 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl, 2-benzofuranyl, which groups may be substituted with one or more halogen or alkyl (1–3C); n has the value 0–3; m has the value 0–2; R1 represents NH2, NH-alkyl (1–3C), dialkyl (1–3C)N, morpholino or morpholino substituted with one or two methyl and/or methoxymethyl groups, thiomorpholino, 1,1-dioxothiomorpholino, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl; R2 is hydrogen, alkyl (1–4C) or phenyl, or R2 together with (CH2)m wherein m is 1, and the intermediate carbon, nitrogen and oxygen atoms forms an isoxazolyl or a 4,5-dihydroisoxazolyl group; R3 and R4 independently represent hydrogen or methyl, or R3 and R4 together are oxygen. The invention also relates to a method for the preparation of the novel compounds, and to pharmaceutical compositions comprising compounds with formula (1) as an active ingredient and the use of these compounds for the treatment of disorders in which neurokinin-1 receptors are involved

    摘要翻译： 本发明涉及一组具有有趣的NK-1拮抗活性的新型哌嗪肟衍生物。 本发明涉及通式（1）的化合物，其中：X表示苯基或被1或2个取代基取代的吡啶基，其中CH 3，CF 3，OCH 3， N 3，卤素，氰基和5-CF 3 - 四唑-1-基; Y代表2-或3-吲哚基，苯基，7-氮杂 - 吲哚-3-基或3-吲唑基，2-萘基，3-苯并[b]噻吩基，2-苯并呋喃基，它们可以被一个或多个 卤素或烷基（1-3C）; n的值为0-3; m的值为0-2; R 1表示NH 2，NH-烷基（1-3C），（1-3C）二烷基，吗啉代或吗啉基，被一或两个甲基和/或甲氧基甲基 基团，硫代吗啉代，1,1-二氧代硫代吗啉代，2-，3-或4-吡啶基或4- CH 3 - 哌嗪基; R 2是氢，烷基（1-4C）或苯基，或R 2和（CH 2 CH 2）m， 其中m为1，中间碳，氮和氧原子形成异恶唑基或4,5-二氢异恶唑基; R 3和R 4独立地代表氢或甲基，或R 3和R 4一起是氧。 本发明还涉及一种制备新化合物的方法，以及包含式（1）化合物作为活性成分的药物组合物，以及这些化合物用于治疗涉及神经激肽-1受体的疾病的用途

    Bisaryl (thio)morpholine derivatives as S1P modulators
    6.
    发明授权
    Bisaryl (thio)morpholine derivatives as S1P modulators 有权
    二芳基（硫代）吗啉衍生物作为S1P调节剂

    公开(公告)号：US09029371B2

    公开(公告)日：2015-05-12

    申请号：US13808900

    申请日：2011-07-08

    申请人： Wouter I. Iwema Bakker ,  Raymond Bronger

    发明人： Wouter I. Iwema Bakker ,  Raymond Bronger

    IPC分类号： C07D295/15 ,  C07D265/30 ,  C07D413/10 ,  A61K31/5377 ,  A61K31/5375

    CPC分类号： A61K31/5375 ,  A61K31/5377 ,  A61K31/54 ,  C07D265/30 ,  C07D295/15 ,  C07D413/10

    摘要： The present invention relates to bisaryl (thio)morpholine derivatives of the formula (I) or a pharmaceutically acceptable salt, a solvate or hydrate thereof, with the proviso that the derivative of formula (I) is not 2-[4-(4-chlorophenoxy)-2-chlorophenyl]-4 -morpholineethanol. The compounds of the invention have affinity to S1 Preceptors and may be used in the treatment, alleviation or prevention of S1 Preceptor mediated diseases and conditions.

    摘要翻译： 本发明涉及式（I）的二芳基（硫代）吗啉衍生物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-（4- 氯苯氧基）-2-氯苯基] -4-吗啉乙醇。 本发明的化合物对S1受体具有亲和力，可用于治疗，缓解或预防S1受体介导的疾病和病症。

    BISARYL (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS
    8.
    发明申请
    BISARYL (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS 有权

    公开(公告)号：US20130203745A1

    公开(公告)日：2013-08-08

    申请号：US13808900

    申请日：2011-07-08

    申请人： Wouter I. Iwema Bakker ,  Raymond Bronger

    发明人： Wouter I. Iwema Bakker ,  Raymond Bronger

    IPC分类号： C07D295/15

    CPC分类号： A61K31/5375 ,  A61K31/5377 ,  A61K31/54 ,  C07D265/30 ,  C07D295/15 ,  C07D413/10

    摘要： The present invention relates to bisaryl(thio)morpholine derivatives of the formula (I) wherein R1 is an aryl substitutent selected from phenyl, pyridyl, pyrimidinyl, biphenyl and naphthyl, each optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl optionally substituted with one or more fluoro atoms, (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 and —NH—CO-(1-4C)alkyl, or substituted with phenoxy, benzyl, benzyloxy, phenylethyl or morpholinyl, each optionally substituted with (1-4C)alkyl, and (8-10C)bicyclic group, bicyclic heterocycle, each optionally substituted with (1-4C)alkyl optionally substituted with one or more fluoro atoms or oxo; A is selected from —CO—, —NH—, —O—, —S—, —SO— or —SO2—; 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-R6 wherein the alkylene group may be substituted with (CH2)2 to form a cyclopropyl moiety or with one or more halogen atoms, or R3 is (3-6C)cycloalkylene-R5 or —CO—CH2—R6, wherein R6 is —OH, —PO3H2, —OPO3H2, —COOH, —COO(1-4C)alkyl or tetrazol-5-yl; R4 is H or (1-4C)alkyl; R5 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-(4-chlorophenoxy)-2-chloro-phenyl]-4-morpholineethanol. 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.

    FUSED HETEROCYCLIC DERIVATIVES AS S1P MODULATORS
    9.
    发明申请
    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.

    (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS
    10.
    发明申请
    (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.