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

    公开(公告)号：US20180215768A1

    公开(公告)日：2018-08-02

    申请号：US15745852

    申请日：2016-07-12

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

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

    IPC分类号： C07D495/04

    CPC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.

    ASYMMETRIC PROCESS FOR THE PREPARATION OF THIENO-INDOLES DERIVATIVES
    3.
    发明申请
    ASYMMETRIC PROCESS FOR THE PREPARATION OF THIENO-INDOLES DERIVATIVES 审中-公开

    公开(公告)号：US20190071451A1

    公开(公告)日：2019-03-07

    申请号：US16177551

    申请日：2018-11-01

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

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

    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 (la) 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.

    THIENO[2,3-e]INDOLE DERIVATIVES AS NEW ANTITUMOR AGENTS
    4.
    发明申请
    THIENO[2,3-e]INDOLE DERIVATIVES AS NEW ANTITUMOR AGENTS 审中-公开
    THIENO [2,3-e] INDOLE DERIVATIVES作为新的抗菌剂

    公开(公告)号：US20160229867A1

    公开(公告)日：2016-08-11

    申请号：US15023746

    申请日：2014-09-16

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

    发明人： Marina CALDARELLI ,  Michele CARUSO ,  Paolo ORSINI

    IPC分类号： C07D495/04 ,  A61K31/407 ,  A61K38/06 ,  C07K5/097 ,  A61K45/06

    CPC分类号： C07D495/04 ,  A61K31/27 ,  A61K31/4015 ,  A61K31/407 ,  A61K38/06 ,  A61K45/06 ,  C07K5/0821 ,  A61K2300/00

    摘要： The present invention relates to a novel class of alkylating agents comprising a thieno[2,3-e]indole moiety tethered to a DNA-binding moiety, 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 composition containing them. The invention also relates to the use of this novel class of alkylating agents in the preparation of conjugates.

    摘要翻译： 本发明涉及一类新颖的烷化剂，其包含与DNA结合部分连接的噻吩并[2,3-e]吲哚部分，其具有细胞毒活性并且可用于治疗疾病如癌症，细胞增殖病症和病毒 感染。 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和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。 本发明还涉及这种新型烷基化剂在制备缀合物中的用途。