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2. 发明专利

DE10006453A1 New piperidylcarboxylic acid derivatives, are integrin antagonists useful for treating inflammatory, autoimmune or immunological diseases, e.g. atherosclerosis, asthma, diabetes, rheumatoid arthritis or transplant rejection 未知
公开(公告)号：DE10006453A1
公开(公告)日：2001-08-16
申请号：DE10006453
申请日：2000-02-14
申请人： BAYER AG
发明人： FISCHER RUEDIGER , LEHMANN THOMAS , MUELLER GERHARD , HESLER GERHARD , TAJIMI MASAOMI , ZIEGELBAUER KARL , OKIGAMI HIROMI , HASEGAWA HARUKI , KOMURA HIROSHI , MIZOGUCHI MANAMI
IPC分类号： A61P37/08 , C07D207/16 , C07D211/34 , C07D211/60 , C07D211/62 , C07D263/58 , C07D403/04 , C07D413/12 , C07D487/04 , C07D211/32 , A61K31/5355 , C07K14/78
摘要： Piperidylcarboxylic acid derivatives and analogs (I) are new. Piperidylcarboxylic acid derivatives and analogs of formula (I) and their salts are new: [Image] R1 + R2group completing a 4-8 membered (un)saturated ring (optionally containing 1 N and/or 1 or 2 of O and S as heteratom(s)), optionally fused with a 4-8 membered (un)saturated or aromatic ring (also optionally containing 1 N and/or 1 or 2 of O and S as heteratom(s)), both rings being optionally substituted (os) by 1 or 2 -R11-R12-R13-Z groups and/or by 1 or 2 of R18, halo, NO2, NH2, CN or oxo; R11irect bond, O, S, NR14, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or Het1 (all os by 1 or 2 R14); R14H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or Het1 (all os by 1-3 of T, OT, Ph, Cy, halo, NO2, CN or oxo); Het14-9 membered (un)saturated heterocycle containing 1-3 of O, S and N as heteroatom(s); T : 1-4C alkyl; Cy : 3-6C cycloalkyl; R12direct bond, O, S, NR14, alkyl, alkenyl or alkynyl (all os by alkyl, alkenyl, alkynyl or R14); R13direct bond, alkyl, alkenyl or alkynyl (all os by 1 or 2 R14); Z : H, COORz1, CONRz2Rz3, SO2NRz2Rz3, S(O)ORz1, SO2ORz1, P(O)Rz1(ORz3), P(O)(ORz1)(ORz3) or 5-tetrazolyl; Rz2C(O)Rz4, SO2Rz4, T, 2-6C alkenyl, 2-6C alkynyl, Cy or aryl (all os by 1-3 of halo, NO2, CN or oxo); Rz4T, 2-6C alkenyl, 2-6C alkynyl, Cy or aryl (all os by 1-3 of halo, NO2, CN or oxo); Rz1, Rz3H, T, 2-6C alkenyl, 2-6C alkynyl, Cy or aryl (all os by 1-3 of T, OT, halo, NO2 or CN); R18T, OT, Ph or Cy (all os by 1-5 halo); R3 -R5H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or Het2 (all os by 1-3 R31 and/or by one of cycloalkyl, aryl, 4-9C heteroaryl or Het2 (itself os by 1-3 R31)); or R3 + R4 or R4 + R5group completing a 4-7 membered (un)saturated ring (optionally containing 1-3 of N, O and S as heteratom(s)), os by 1 or 2 of T, Ph, CH2Ph, cycloalkyl, halo, NO2, CN or oxo and optionally fused with a 3-7 membered carbocyclic or heterocyclic, (un)saturated or aromatic ring; Het24-9 membered (un)saturated heterocycle containing 1 or 2 of O, S and N as heteroatom(s); R31T, CF3, OCF3, OR32, SR32, NR33, R34, C(O)R32, S(O)R32, SO2R32, COOR32, OC(O)R32, CONR33R34, NR32COR32, SO2NR33R34, NR32SO2R32, NR32CONR33R34, NR32COOR32, OCONR33R34, halo, CN, NO2 or oxo; R32H, T, Cy or aryl (all os by one of T, OT, Ph, Cy, halo); R33, R34H, T, Cy or aryl; or NR33R344-7 membered ring (optionally containing 1 or 2 additional O, S or N heteroatom(s) and/or 1 or 2 double bonds); R6phenyl or 5- or 6-membered heteroaryl (containing 1-3 of O, N and S as heteroatom(s)), both optionally fused with a 5-8 membered (un)saturated ring (optionally containing 1-3 of O, N and S as heteroatom(s)) and os by 1 or 2 of alkyl, alkenyl, alkynyl, aryl or cycloalkyl (themselves os by 1-3 R61); and X : bond, CRx1Rx2, O or NRx3; or X + R6group completing a 4-7 membered ring (optionally containing 1 or 2 additional O, S or N heteroatom(s) and/or 1 or 2 double bonds), os by 1 or 2 of T, Ph, CH2Ph, cycloalkyl, OT, NH2, halo, NO2, CN or oxo; R61T, CF3, OCF3, OR62, SR62, NR62R63, C(O)R62, S(O)R62, SO2R62, COOR62, OC(O)R62, CONR62R63, NR63COR62, SO2NR62R63, NR63SO2R62, NR63CONR62R64, NR63COOR62, OCONR62R63, halo, CN, NO2 or oxo; R62H, T, Cy, aryl or Het1 (all os by 1-3 R65); R65T, CF3, OCF3, OR66, SR66 or NR67R68; R66H, T, Cy or aryl (all os by 1-3 of T, OT, Ph, CH2Ph, Cy, OH, NH2, halo, NO2, CN, CF3 or OCF3); R67, R68H, T, Cy, aryl or Het2 (all os as for R66); or NR67R684-7 membered ring (optionally containing 1 or 2 additional O, S or N heteroatom(s) and/or 1 or 2 double bonds), os by 1 or 2 of T, OT, Ph, CH2Ph, Cy, OH, NH2, halo, NO2, CN, CF3, OCF3 or oxo; R63, R64H, bond, T, Cy, aryl or Het2 (all os by 1-3 of T, CF3, OCF3, OR66, SR66 or NR67R68); or NR62R63 or NR63R644-7 membered ring (optionally containing 1 or 2 additional O, S or N heteroatom(s) and/or 1 or 2 double bonds), os by 1 or 2 of T, OT, Ph, CH2Ph, Cy, OH, NH2, halo, NO2, CN, CF3, OCF3 or oxo and/or os by 1-3 R65; A : C(O), C(O)-C(O), SO, SO2, P(O)Ra1, 2- or 4-pyrimidinyl, 2-pyridyl, 2- or 4-imidazolyl, 2-benzimidazolyl or phenylene; or 2-thiazolyl, 2-oxazolyl, 3-pyrazolyl, 3-isothiazolyl, 3-isoxazolyl, 4H-1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-oxadiazol-3-yl, 4,5-dihydro-thiazol-2-yl, 4,5-dihydro-imidazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, pyrazin-2-yl or pyridazin-3-yl (where the bonding position indicated is the bond to N(R5), X being bonded to another ring C); rings systems in A being os by T, OT, halo, NO2, NH2, CN or CN; Ra1T or OT; Rx1 - Rx3bond, H, T, 2-4C alkenyl or 2-4 C alkynyl; Y' : bond, C(O), S(O), SO2, O, S, CRy1Ry2 or NRy3; Ry1 - Ry3bond, H, T, 2-4C alkenyl or 2-4 C alkynyl (all os by 1 or 2 of T, Ph, CH2Ph, cycloalkyl, OT, NH2, halo, NO2, CN or oxo; D : N or CRd1; Rd1as Ry1; With the following provisos: (1) if R13 is a bond then R12 cannot be a heteroatoms; (2) R11 and R12 cannot both be heteroatoms; and (3) Y' and D cannot both be heteroatoms; unless specified otherwise alkyl moieties have 1-10C, alkenyl or alkynyl moieties 2-10C, cycloalkyl moieties 3-7C and aryl moieties 6C or 10C. An INDEPENDENT CLAIM is included for the preparation of (I). - ACTIVITY : Antiinflammatory; immunosuppressive; antiarteriosclerotic; antiasthmatic; antiallergic; antidiabetic; neuroprotective; cardiant; antirheumatic; antiarthritic. - MECHANISM OF ACTION : Integrin antagonist. (I) are especially alpha 4beta 1 integrin antagonists, but may also show alpha 4beta 7 and/or alpha 4beta 9 antagonist activity. 2-(1-(2-(2-(4-((2-Toluidinocarbonyl)-amino)-phen yl)-acetyl)-L-leucine)-2-piperidinyl)-acetic acid (Ia) had IC50 0.5 mu M or less in a Jurkat-VCAM-1 in vitro assay.

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