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    Hypoglycemic imidazoline compounds
    42.
    发明公开
    Hypoglycemic imidazoline compounds 有权
    低聚咪唑啉衍生物

    公开(公告)号：EP0924209A1

    公开(公告)日：1999-06-23

    申请号：EP98310461.3

    申请日：1998-12-18

    申请人： ELI LILLY AND COMPANY

    发明人： Jirousek, Michael Robert ,  Paal, Michael ,  Rühter, Gerd ,  Schotten, Theo ,  Stenzel, Wolfgang ,  Takeuchi, Kumiko

    IPC分类号： C07D403/06 ,  A61K31/415 ,  C07D233/10 ,  C07D233/20 ,  C07D233/22 ,  C07D401/04 ,  C07D401/14 ,  C07D403/04 ,  C07D405/04 ,  C07D405/10 ,  C07D405/14 ,  C07D409/04 ,  C07D409/10 ,  C07D409/14 ,  C07D413/04 ,  A61K31/42

    CPC分类号： C07D401/04 ,  C07D233/10 ,  C07D233/20 ,  C07D233/22 ,  C07D401/14 ,  C07D403/04 ,  C07D403/06 ,  C07D405/04 ,  C07D405/10 ,  C07D405/14 ,  C07D409/04 ,  C07D409/10 ,  C07D409/14 ,  C07D413/04 ,  Y02P20/55

    摘要： This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.
    The compounds have the following formula:
    wherein

    X is -O-, -S-, or -NR 5 -,
    R 5 is hydrogen, C 1-8 alkyl, or an amino protecting group;
    R 1 , R 1' , R 2 , and R 3 are independently hydrogen or C 1-8 alkyl;
    R 1 and R 2 optionally together form a bond and R 1' and R 3 are independently hydrogen or C 1-8 alkyl;
    R 1 and R 2 optionally combine together with the carbon atoms to which they are attached form a C 3-7 carbocyclic ring and R 1' and R 3 are independently hydrogen or C 1-8 alkyl;
    R 1 and R 1' together with the carbon atom to which they are attached optionally combine to form a C 3-7 spirocarbocyclic ring and R 2 and R 3 are independently hydrogen or C 1-8 alkyl;
    R 2 and R 3 together with the carbon atom to which they are attached optionally combine to form a C 3-7 spirocarbocyclic and R 1 and R 1' are independently hydrogen or C 1-8 alkyl;
    n is 0, 1, or 2;
    m is 0, 1 or 2;
    m' is 0, 1, or 2;
    q' is 0,1,2,3,4, or 5;
    R 4 is


    Y is -O-, -S-, or -NR 8 -;
    Y' is -O- or -S-;
    R 6 and R 7 are independently hydrogen, C 1-8 alkyl, C 3-7 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, halo C 1-8 alkylthio, C 1-8 alkylsulfinyl, C 1-8 alkylsulfonyl, C 3-7 cycloalkoxy, aryl-C 1-8 alkoxy, halo, halo-C 1-8 alkyl, halo- C 1-8 alkoxy, nitro, -NR 10 R 11 , -CONR 10 R 11 , aryl C 1-8 alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, COR 12 , halo C 1-8 alkylsulfinyl, or halo C 1-8 alkylsulfonyl, or alkoxyalkyl of the formula

            CH 3 (CH 2 ) p -O-(CH 2 ) q -O-;

    where
    p is 0, 1, 2, 3, or 4; and
    q is 1, 2, 3, 4, or 5;
    R 12 is C 1-8 alkyl or optionally substituted phenyl;
    R 8 is hydrogen, C 1-8 alkyl, halo-C 1 _ 8 alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO C 1-8 alkyl, optionally substituted COaryl, COC 1-8 alkyl, SO 2 C 1-8 alkyl, optionally substituted SO 2 aryl, optionally substituted phenyl-C 1-8 alkyl, CH 3 (CH 2 ) p -O-(CH 2 ) q -O-;
    R 9 is hydrogen, halo, C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkylthio, halo C 1-8 alkylthio, C 3-7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C 1-8 alkoxy, C 3-7 cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C 3-7 cycloalkyl, halo C 3-7 cycloalkyl, C 3-7 cycloalkenyl, cyano, COOR 10 ,CONR 10 R 11 or NR 10 R 11 , C 2-6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C 1-8 alkyl, optionally substituted heteroaryl C 1-8 alkyl in which the alkyl group can be substituted by hydroxy, or C 1-8 alkyl substituted by hydroxy,
    R 10 and R 11 are independently hydrogen, C 1-8 alkyl, optionally substituted aryl C 1-8 alkyl, optionally substituted phenyl, or R 10 and R 11 together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two C 1-8 alkyl groups or one carbon atom may be replaced by oxygen or sulfur;
    R 14 and R 16 are independently hydrogen, halo, C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkoxy, C 3-7 cycloalkylC 1-8 alkoxy, halo-C 1-8 alkyl, halo-C 1-8 alkoxy, C 1-8 alkoxy, carbo(C 1-8 )alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;
    R 15 and R 17 are independently hydrogen, halo, C 1-8 alkoxy, C 3-7 -cycloalkyl, C 3-7 cycloalkylC 1-8 alkoxy, C 1-8 alkyl, C 3-7 cycloalkoxy, hydroxy, halo C 1-8 alkoxy, carbo(C 1-8 )alkoxy, optionally substituted phenyl, optionally substituted phenyl-C 1-8 alkyl, optionally substituted phenyloxy, optionally substituted phenyl-C 1-8 alkoxy, (tetrahydropyran-2-yl)methoxy, C 1-8 alkyl-S(O) m -, optionally substituted aryl-C 1-8 alkyl-S(O) m' -, CH 3 (CH 2 ) p -Z 1 -(CH 2 ) q -Z 2 -, or Z 3 -(CH 2 )q'-Z 2 -;
    Z 1 and Z 2 are independently a bond, O, S, SO, SO 2 , sulphoximino, or NR 10 ; and
    Z 3 is hydroxy, protected hydroxy, NR 10 R 11 , protected amino, SH or protected SH;
    provided that when R 1 , R 1' , R 2 and R 3 are all hydrogen; n is 0; R 4 is naphthyl; and R 14 , R 15 and R 16 , or R 15 , R 16 and R 17 are all hydrogen, then R 17 or R 14 , respectively, is other than halo, methoxy, or C1-6 alkyl.
    or a pharmaceutically acceptable salt or ester thereof.

    摘要翻译： 本发明涉及某些新的咪唑啉化合物及其类似物，其用于治疗糖尿病，糖尿病并发症，代谢紊乱或其中存在葡萄糖处置受损的相关疾病，其包含它们的药物组合物及其制备方法。 该化合物具有下式：其中X是-O - ， - S-或-NR 5 - ，R 5是氢，C 1-8烷基或氨基保护基的 R 1，R 1，R 2和R 3独立地是氢或C 1-8烷基; R 1和R 2任选地一起形成键，R 1和R 3独立地是氢或C 1-8烷基; R 1和R 2任选地与它们所连接的碳原子一起形成C 3-7碳环，R 1和R 3独立地是氢或C 1-8烷基; R 1和R 1与它们所连接的碳原子一起任选地结合形成C 3-7螺环碳环，R 2和R 3独立地是氢或C 1-8烷基; R 2和R 3与它们所连接的碳原子一起任选地结合形成C 3-7螺环碳环，R 1和R 1独立地是氢或C 1-8烷基; n为0,1或2; m为0,1或2; m'为0,1或2; q'为0,1,2,3,4或5; R 4是 CHEM，Y是-O - ， - S-或-NR 8 - 。 Y'为-O-或-S-; R 6和R 7独立地是氢，C 1-8烷基，C 3-7环烷基，C 1-8烷氧基，C 1-8烷硫基，卤代C 1-8烷硫基，C 1-8烷基亚磺酰基，C 1-8烷基磺酰基，C 3 -7环烷氧基，芳基-C 1-8烷氧基，卤素，卤代-C 1-8烷基，卤代-C 1-8烷氧基，硝基，-NR 10 R 11，-CONR 10 R 11，芳基 C 1-8烷基，任选取代的杂环基，任选取代的苯基，任选取代的萘基，任选的卤素取代的酰基氨基，氰基，羟基，COR 12，卤代C 1-8烷基亚磺酰基或卤代C 1-8烷基磺酰基，或式CH 3的烷氧基烷基 （CH2）PO-（CH2）qO-; 其中p为0,1,2,3或4; q为1,2,3,4或5; R 12是C 1-8烷基或任选取代的苯基; R 8是氢，C 1-8烷基，卤代-C 1-8烷基，任选取代的苯基，任选取代的杂环基，COO C 1-8烷基，任选取代的芳基，COC 1-8烷基，SO 2 C 1-8烷基，任选取代的SO 2芳基， 任选取代的苯基-C 1-8烷基，CH 3（CH 2）p O-（CH 2）q O-; R 9是氢，卤素，C 1-8烷基，卤代C 1-8烷基，C 1-8烷硫基，卤代C 1-8烷硫基，C 3-7环烷硫基，任选取代的芳硫基或杂芳硫基，C 1-8烷氧基，C 3-7 环烷氧基，任选取代的芳氧基，任选取代的杂芳氧基或任选取代的芳基或杂芳基，C 3-7环烷基，卤素C 3-7环烷基，C 3-7环烯基，氰基，COOR 10，CONR 10 R 11或NR 任选取代的芳基C 1-8烷基，任选取代的杂芳基C 1-8烷基，其中烷基可以被羟基取代，或被C 1-8烷基取代的C 1-8烷基， 羟基，R 10和R 11独立地是氢，C 1-8烷基，任选取代的芳基C 1-8烷基，任选取代的苯基，或R 10和R 11与它们的氮原子一起 可以结合形成具有多达六个碳原子的环，其任选地可以被至多两个C 1-8烷基取代，或者一个碳原子可以是 由氧或硫置换; R 14和R 16独立地是氢，卤素，C 1-8烷基，C 3-7环烷基，C 3-7环烷氧基，C 3-7环烷基C 1-8烷氧基，卤代-C 1-8烷基，卤代-C 1-8 烷氧基，C 1-8烷氧基，碳（C 1-8）烷氧基，任选取代的芳基或任选取代的杂芳基; R 15和R 17独立地是氢，卤素，C 1-8烷氧基，C 3-7 - 环烷基，C 3-7环烷基C 1-8烷氧基，C 1-8烷基，C 3-7环烷氧基，羟基，卤代C 1-8 烷氧基，碳（C 1-8）烷氧基，任选取代的苯基，任选取代的苯基-C 1-8烷基，任选取代的苯氧基，任选取代的苯基-C 1-8烷氧基，（四氢吡喃-2-基）甲氧基，C 1-8烷基 - S（O）m - ，任选取代的芳基-C 1-8烷基-S（O）m'-，CH 3（CH 2）pZ 1 - （CH 2）q Z 2 - 或Z 3 - （CH 2 ）Q'-Z <2> - ; Z 1和Z 2独立地是键，O，S，SO，SO 2，亚肟基或NR 10; Z 3为羟基，被保护的羟基，NR 10 R 11，保护的氨基，SH或被保护的SH; 条件是当R 1，R 1'，R 2和R 3都是氢时; n为0; R 4是萘基; R 14，R 15和R 16或R 15，R 16和R 17均为氢，则R 17或R 14分别为其它 比卤代，甲氧基或C 1-6烷基。 或其药学上可接受的盐或酯。

    Process for the manufacture of imidazolines
    44.
    发明公开
    Process for the manufacture of imidazolines 失效
    一种咪唑啉的制备方法。

    公开(公告)号：EP0002943A1

    公开(公告)日：1979-07-11

    申请号：EP78300886.5

    申请日：1978-12-21

    申请人： Albright & Wilson Limited

    发明人： Phillips, Brinley Morris ,  Lace, Robert Briscoe ,  Lambie, Alan James

    IPC分类号： C07D233/10 ,  C07D233/14 ,  C07D233/16

    CPC分类号： C07D233/10 ,  C07D233/14

    摘要： The invention provides a process for reducing the fiamide content of imidazolines having the formula:-
    wherein R represents an aliphatic group having from at least 4 carbon atoms and R 1 represents an alkyl or alkenyl group having from 1 to 4 carbon atoms.
    The mixture of imidazoline and diamide is reacted with a primary of secondary amine which deacylates the diamide to an amido-amine. The product of this deacyla- tion is an imidazoline solution which remains clear even on prolonged storage.
    The imidazoline is produced by reaction of an acid RCOOH with a diamine NH 2 (CH 2 ) 2 NHR 1 . Preferably this diamine is used as the deacylating agent.