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    ASYMMETRIC PROCESS FOR THE PREPARATION OF THIENO-INDOLES DERIVATIVES
    1.
    发明公开
    ASYMMETRIC PROCESS FOR THE PREPARATION OF THIENO-INDOLES DERIVATIVES 审中-公开

    公开(公告)号：EP3325489A1

    公开(公告)日：2018-05-30

    申请号：EP16739449.3

    申请日：2016-07-12

    申请人： NERVIANO MEDICAL SCIENCES S.R.L.

    发明人： BERIA, Italo ,  CARUSO, Michele ,  DONATI, Daniele ,  ORSINI, Paolo

    IPC分类号： C07D495/04

    摘要： The present invention relates to a new process for the preparation of thieno-indole derivatives of formula (Ia) or (Ib), exploiting an asymmetric synthesis for the preparation of key (8S) or (8R) 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, and to useful intermediate compounds of such process. Thieno-indole derivatives are described and claimed in GB2344818, WO2013/149948 and WO2013/149946, which also disclose processes for their preparation. Thieno-indole enantiopure derivatives can now be advantageously prepared through a new asymmetric synthesis of the key 8-(halomethyl)-7,8-dihydro-6H-thieno[3,2-e]indol intermediates, which, avoiding the chiral resolution step, provides benefits in terms of reducing time and costs of the whole process for their preparation. The synthesis starts from the N-alkylation of 5-amino-4-halo-3-alkyl-1-benzothiophene-7-ol derivatives with enantiopure glycidyl 3-nosylate, followed by intramolecular 6-endo-tet cyclization using alkyl Grignard reagents; Mitsunobu activation of the secondary alcohol promotes internal spirocyclization, affording the 4,4a,5,6-tetrahydro-8H-cyclopropa[c]thieno[3,2-e]indol-8-one derivatives; finally, stereo-electronically controlled regioselective cyclopropane opening yields the key enantiopure 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, which can be further derivatized following teachings disclosed in WO2013/149948 or WO2013/149946, to prepare the final thieno-indole derivatives of formula (Ia) or (Ib). Such compounds are disclosed to be alkylating compounds with cytotoxic activity, therefore useful as such in the treatment of a variety of cancers and in cell proliferative disorders, or, conjugated with different types of nucleophiles, in the preparation of Antiboby Drug Conjugated derivatives.

    FUNCTIONALIZED MORPHOLINYL ANTHRACYCLINE DERIVATIVES
    2.
    发明公开
    FUNCTIONALIZED MORPHOLINYL ANTHRACYCLINE DERIVATIVES 审中-公开
    功能化吗啉基蒽环衍生物

    公开(公告)号：EP3215513A1

    公开(公告)日：2017-09-13

    申请号：EP15788447.9

    申请日：2015-11-04

    申请人： Nerviano Medical Sciences S.r.l.

    发明人： BERIA, Italo ,  CARUSO, Michele ,  LUPI, Vittoria

    IPC分类号： C07D498/14 ,  A61K31/5383 ,  A61P35/00

    CPC分类号： A61K31/5383 ,  A61K45/06 ,  A61K47/542 ,  A61K47/545 ,  A61K47/64 ,  C07D498/14 ,  A61K2300/00

    摘要： The present invention relates to new functionalized morpholinyl anthracycline derivatives which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds, or the pharmaceutical compositions containing them. The invention also relates to the use of these derivatives in the preparation of conjugates. The morpholinyl anthracycline derivatives are of the formula Ant-L-W-Z-RM (I) wherein RM is null or a reactive moiety; Z is null or a peptidic, non peptidic or hybrid—peptidic and non peptidic—linker; W is null or a self-immolative system, comprising one or more self-immolative groups; L is null or a conditionally-cleavable moiety; Ant is an anthracycline moiety selected from the formulas (II), (III), (IV) and (V), wherein the wavy line indicates the attachment to the conditionally-cleavable moiety L, or to the self-immolative system W, or to the linker Z, or to the reactive moiety RM; provided that at least one of L, W, Z and RM is not null; R1 is halogen or NR4R5; R2 is OR6, NR7R8 or an optionally substituted group selected from straight or branched C1-C4alkyl-, NR7R8-C1-C4alkyl- and R60-C1-C4alkyl-; R4 and R5 are independently hydrogen, a monosubstituted-benzyl, a disubstituted-benzyl, or an optionally substituted group selected from straight or branched C1-C6alkyl, NR7R8-C1-C6alkyl-, R60-C1-C6alkyl-, R7R8N—C1-C6alkylcarbonyl-, R60-C1-C6alkylcarbonyl-, R7R8N—C1-C6alkoxycarbonyl- and R60-C1-C6alkoxycarbonyl-; or R4 and R5, taken together with the nitrogen atom to which they are bound, form a heterocyclyl substituted with R4′, wherein R4′ is hydrogen or a group selected from straight or branched C1-C6alkyl and NR7R8-C1-C6alkyl-; R15 is null or an optionally substituted bivalent group selected from —NR7-C1-C6alkyl*, —O—C1-C6alkyl*, —NR7-C1-C6alkylcarbonyl*, —O—C1-C6alkylcarbonyl*, —NR7-C1-C6alkoxycarbonyl* and —O—C1-C6alkoxycarbonyl*, wherein * indicates the point of attachment to —NH-Ant; R6, R7 and R8 are independently hydrogen or an optionally substituted straight or branched C1-C6alkyl; or a pharmaceutically acceptable salt thereof.

    摘要翻译： 本发明涉及具有细胞毒性活性并可用于治疗诸如癌症，细胞增殖性病症和病毒感染等疾病的新型功能化吗啉基蒽环类衍生物。 本发明还提供了制备这些化合物的方法，包含它们的药物组合物以及使用这些化合物治疗疾病的方法或含有它们的药物组合物。 本发明还涉及这些衍生物在制备缀合物中的用途。 吗啉基蒽环类衍生物的结构式为Ant-L-W-Z-RM（I），其中RM为无效或反应性部分; Z不存在或为肽，非肽或杂化的肽和非肽 - 接头; W不存在或包含一个或多个自我牺牲基团的自毁系统; L为无效或有条件可切割的部分; Ant是选自式（II），（III），（IV）和（V）的蒽环类部分，其中波浪线表示与条件可切割的部分L或自身降解系统W的连接，或 连接体Z或反应性部分RM; 条件是L，W，Z和RM中的至少一个不为空; R1是卤素或NR4R5; R 2是OR 6，NR 7 R 8或选自直链或支链C 1 -C 4烷基 - ，NR 7 R 8 -C 1 -C 4烷基 - 和R 60 -C 1 -C 4烷基 - 的任选取代的基团; R 4和R 5独立地为氢，单取代的苄基，二取代的苄基或任选取代的选自直链或支链C 1 -C 6烷基，NR 7 R 8 -C 1 -C 6烷基 - ，R 60 -C 1 -C 6烷基 - ，R 7 R 8 N -C 1 -C 6烷基羰基 - ，R60-C1-C6烷基羰基 - ，R7R8N-C1-C6烷氧基羰基 - 和R60-C1-C6烷氧基羰基 - 或者R 4和R 5与它们所连接的氮原子一起形成被R 4'取代的杂环基，其中R 4'为氢或选自直链或支链C 1 -C 6烷基和NR 7 R 8 -C 1 -C 6烷基的基团; R15为空或选自-NR7-C1-C6烷基*，-O-C1-C6烷基*，-NR7-C1-C6烷基羰基*，-O-C1-C6烷基羰基*，-NR7-C1-C6烷氧基羰基* 和-O-C1-C6烷氧基羰基*，其中*表示与-NH-Ant的连接点; R6，R7和R8独立地为氢或任选取代的直链或支链C1-C6烷基; 或其药学上可接受的盐。

    FUNCTIONALIZED THIENO-INDOLE DERIVATIVES FOR THE TREATMENT OF CANCER
    6.
    发明公开
    FUNCTIONALIZED THIENO-INDOLE DERIVATIVES FOR THE TREATMENT OF CANCER 有权
    FUNKTIONALISIERTE THIENOINDOLDERIVATE ZUR BEHANDLUNG VON KREBS

    公开(公告)号：EP2836493A1

    公开(公告)日：2015-02-18

    申请号：EP13713180.1

    申请日：2013-03-28

    申请人： Nerviano Medical Sciences S.r.l.

    发明人： BERIA, Italo ,  CARUSO, Michele ,  LUPI, Vittoria ,  ORSINI, Paolo ,  SALSA, Matteo

    IPC分类号： C07D495/04 ,  A61K31/407 ,  A61P35/00

    CPC分类号： A61K47/48338 ,  A61K31/496 ,  A61K45/06 ,  A61K47/65 ,  C07D495/04

    摘要： The invention relates to new functionalized thieno-indole derivatives of formula (I) or (II) which have cytotoxic activity and are useful in treating diseases such as cancer and cellular proliferation disorders. The invention also relates to the use of these functionalized thieno-indole derivatives in the preparation of conjugates. Formula (I) or (II) wherein R1 and R2 taken together form a group (D) or (G): wherein R5 is hydrogen or C1-C4 alkyl; R3 and R4 are independently hydrogen, C1-C4 alkyl or C1-C4 hydroxyalkyl; n is 0, 1 or 2; each of X is independently —O—, —S— or —NR4—; each of Y is independently —CH═ or —N═; R7 and R8 are independently hydrogen, halogen, hydroxy, C1-C4 alkoxy, cyano, —NHCOOR3, —C(NH)NH2 or —NR3R4; A is —O—, —NH— or —CO—; L is null or a conditionally-cleavable moiety; W is null or a self-immolative moiety comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid peptidic and non peptidic linker; RM is null or a reactive moiety; R6 is a leaving group; A1 is null or A; L1 is hydrogen or L.

    摘要翻译： 本发明涉及具有细胞毒活性并且可用于治疗疾病如癌症和细胞增殖障碍的式（I）或（II）的新的官能化噻吩并吲哚衍生物。 本发明还涉及这些官能化噻吩并吲哚衍生物在共轭物的制备中的用途。 式（I）或（II）其中R 1和R 2一起形成基团（D）或（G）：其中R 5是氢或C 1 -C 4烷基; R3和R4独立地是氢，C1-C4烷基或C1-C4羟基烷基; n为0,1或2; X各自独立地为-O - ， - S-或-NR 4 - ; Y中的每一个独立地为-CH =或-N =; R 7和R 8独立地是氢，卤素，羟基，C 1 -C 4烷氧基，氰基，-NHCOOR 3，-C（NH）NH 2或-NR 3 R 4; A是-O - ， - NH-或-CO-; L为无效或条件可切割部分; W是无效的或包含一个或多个自褪色基团的自褪色部分; Z是无效或肽，非肽或杂交肽和非肽接头; RM为无效或反应性部分; R6是离职团体; A1为零或A; L1是氢或L.

    FUNCTIONALIZED THIENO-INDOLE DERIVATIVES FOR THE TREATMENT OF CANCER
    10.
    发明授权
    FUNCTIONALIZED THIENO-INDOLE DERIVATIVES FOR THE TREATMENT OF CANCER 有权

    公开(公告)号：EP2836493B1

    公开(公告)日：2018-06-20

    申请号：EP13713180.1

    申请日：2013-03-28

    申请人： Nerviano Medical Sciences S.r.l.

    发明人： BERIA, Italo ,  CARUSO, Michele ,  LUPI, Vittoria ,  ORSINI, Paolo ,  SALSA, Matteo

    IPC分类号： C07D495/04 ,  A61K31/407 ,  A61P35/00

    CPC分类号： A61K45/06 ,  A61K31/496 ,  A61K47/65 ,  C07D495/04

    摘要： The invention relates to new functionalized thieno-indole derivatives of formula (I) or (II) which have cytotoxic activity and are useful in treating diseases such as cancer and cellular proliferation disorders. The invention also relates to the use of these functionalized thieno-indole derivatives in the preparation of conjugates. Formula (I) or (II) wherein R1 and R2 taken together form a group (D) or (G): wherein R5 is hydrogen or C1-C4 alkyl; R3 and R4 are independently hydrogen, C1-C4 alkyl or C1-C4 hydroxyalkyl; n is 0, 1 or 2; each of X is independently —O—, —S— or —NR4—; each of Y is independently —CH═ or —N═; R7 and R8 are independently hydrogen, halogen, hydroxy, C1-C4 alkoxy, cyano, —NHCOOR3, —C(NH)NH2 or —NR3R4; A is —O—, —NH— or —CO—; L is null or a conditionally-cleavable moiety; W is null or a self-immolative moiety comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid peptidic and non peptidic linker; RM is null or a reactive moiety; R6 is a leaving group; A1 is null or A; L1 is hydrogen or L.