Nerviano Medical Sciences S.r.l.

Pharmacia & Upjohn

Pharmacia Italia S.p.a.

Genentech, Inc.

Pharmacia Corporation

Genetech, Inc.

Italo Beria

Michele Caruso

Paolo Cozzi

Marina Caldarelli

Matteo Salsa

Maria Gabriella Brasca

Vittoria Lupi

Barbara Valsasina

Pier Giovanni Baraldi

Paolo Orsini

Laura Capolongo

Helena Posteri

Maria Cristina Geroni

Andrea Lombardi Borgia

Enrico Pesenti

Romeo Romagnoli

Paul Polakis

John A Flygare

Andrew G Polson

Susan D Spencer

Ron Ferguson

Rita Perego

Tiziano Bandiera

Daniele Fancelli

Achille Panzeri

Nicola Mongelli

Francesco Casuscelli

Roberto D'Alessio

Ettore Perrone

Robert L Cohen

Mauro Angiolini

Sten Christian Orrenius

Daniele Donati

Arturo Galvani

Gabriella Traquandi

Ilaria Candiani

Dario Ballinari

Fabrizio Orzi

Giovanni Biasoli

Daniela Faiardi

Claudia Piutti

Massimo Zampieri

Walter Ceccarelli

Maria Cristina Rosa Geroni

Giampiero Spalluto

Antonella Ciavolella

Valter Domenico Croci

Juergen Moll

Annalisa Airoldi

Roberto d'Alessio

Nicoletta Colombo

Riccardo Frigerio

M Cristina Geroni

Gabriele Fachin

Giulia Pennella

Cristina Franzetti

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 Antibody Drug Conjugated derivatives.

Asymmetric process for the preparation of thieno-indoles derivatives

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 Antibody Drug Conjugated derivatives.

The present invention relates to a novel class of alkylating agents comprising a thieno-indole moiety linked 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. The present invention also relates to methods of treating ovarian cancer by administration of compounds of formula (II): 

Thieno-indole moieties and methods of treating using the same

The present invention relates to new 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.

Morpholinyl anthracycline derivatives

The present invention relates to conjugates of therapeutically useful anthracyclines with carriers such as polyclonal and monoclonal antibodies, proteins or peptides of natural or synthetic origin; methods for their preparation, pharmaceutical composition containing them and use thereof in treating certain mammalian tumors.

Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds

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 Rand Rtaken together form a group (D) or (G): wherein Ris hydrogen or C-Calkyl; Rand Rare independently hydrogen, C-Calkyl or C-Chydroxyalkyl; n is 0, 1 or 2; each of X is independently &#x2014;O&#x2014;, &#x2014;S&#x2014; or &#x2014;NR&#x2014;; each of Y is independently &#x2014;CH&#x2550; or &#x2014;N&#x2550;; Rand Rare independently hydrogen, halogen, hydroxy, C-Calkoxy, cyano, &#x2014;NHCOOR, &#x2014;C(NH)NHor &#x2014;NRR; A is &#x2014;O&#x2014;, &#x2014;NH&#x2014; or &#x2014;CO&#x2014;; 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; Ris a leaving group; Ais null or A; Lis hydrogen or L. 

Functionalized thieno-indole derivatives for the treatment of cancer

The present disclosure is directed to a compound of formula (I) wherein L is null or a conditionally-cleavable moiety; W is null or a self-immolative system, comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid &#x2014;peptidic and non peptidic&#x2014;linker; RM is null or a reactive moiety that can be attached to one or more of L, W or Z groups, or RM is attached to oxygen when L, W and Z are all null; provided that at least one of L, W, Z and RM is not null; or a pharmaceutically acceptable salt thereof.

Functionalized 9-bromo-camptothecin derivatives

The present invention relates to a novel class of alkylating agents comprising a thieno-indole moiety linked 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.

The present invention relates to substituted isoxazolo-quinazolines which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular human MPS1 and PERK. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them. 

Isoxazolo-quinazolines as modulators of protein kinase activity

The present invention relates to tricyclic pyrrolo derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

Tricyclic pyrrolo derivatives, process for their preparation and their use as kinase inhibitors

The present invention relates to tricyclic pyrrolo derivatives of Formula (I), which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them. 

The present invention provides a combination comprising (a) a compound of formula (I) and (b) one or more antineoplastic agents selected from the group consisting of an antimetabolite agent, analkylating or alkylating-like agent, an intercalating agent, a topoisomerase I or II inhibitor, an antimitotic agent, a kinase inhibitor, a proteasome inhibitor and an antibody inhibiting a growth factor or its receptor, wherein active ingredients of the combination are present in each case in free form or in the form of a pharmaceutically acceptable salt or any hydrate or solvate thereof, useful in the treatment of tumors. 

Therapeutic combination comprising a PLK1 inhibitor and an antineoplastic agent

The present invention relates to novel crystalline, water-soluble salts of a plk inhibitor. Such crystal salts are for example L-tartrate, succinate, phosphate, mesylate, maleate, L-malate, hydrochloride, fumarate (half mole of counterion), fumarate, citrate (half mole of counterion), benzenesulfonate and L-aspartate (half mole of counterion). New crystal forms of the base as well as solvates and hydrates of such new salt forms, a process for their preparation, their utility in therapy and to the pharmaceutical compositions containing them are also claimed and described in the present application.

PLK inhibitor salts

Compounds which are &#x3b1;-halogenoacryloyl distamycin derivatives of formula (I) wherein Ris a bromine or chlorine atom; Ris a distamycin or distamycin-like framework as set forth in the specification; or a pharmaceutically acceptable salt thereof; are cytotoxic agents particularly effective in the treatment of tumors over expressing GSH/GSTs system and which are poorly responsive or even resistant to conventional antitumor therapies.

Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and platinum derivatives

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Nerviano, Italy

Italo Beria