Basilea Pharmaceutica Ag

Novartis Ag

Takeda Pharmaceutical Company Limited

Ruprecht-Karls-Universitat Heidelberg

Basilea Pharmaceutica International Ag

Felix Bachmann

Heidi Alexandra Lane

Martin Eberle

Goutam Saha

Alessandro Strebel

Subho Roy

Sudhir Srivastava

Michael Boutros

Daniel Gilbert

Xian Zhang

Madlaina Breuleux

Daniel Obrecht

Jens Pohlmann

Anatol Luther

Philipp Ermert

Heidi Lane

Rohit Saxena

Franck Lach

Subir Kumar Sadhukhan

Godhuli Nandi

Frank Lach

Allessandro Strebel

Paul McSheehy

Max M Burger

The present invention provides pharmaceutical combinations comprising (a) a compound of formula (I) wherein R represents phenyl or pyridinyl; wherein phenyl is optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy, hydroxyl, amino, lower alkylamino, lower dialkylamino, acetylamino, halogen and nitro; and wherein pyridinyl is optionally substituted by amino or halogen; R1 represents hydrogen or cyano-lower alkyl; and wherein the prefix lower denotes a radical having up to and including a maximum of 4 carbon atoms; or a pharmaceutically acceptable derivative thereof; and (b) a compound of Formula (II) (eribulin) or a pharmaceutically acceptable salt thereof and the use of the pharmaceutical combinations in the treatment of neoplastic diseases. 

Pharmaceutical combinations for use in the treatment of neoplastic diseases

Use of phospho-Akt as a biomarker for predicting the response, such as resistance, to a compound, wherein phospho-Akt is Akt that has been phosphorylated on one or more residues, with the proviso that fir Akt1, Akt2, and Akt3 the designation phospho-Akt is used to indicate phosphorylation at a site other than T308, T309 or T305 respectively, wherein the compound is a compound of general formula (I) wherein R represents phenyl, thienyl or pyridinyl wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacent substituents are methylenedioxy; and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen; X represents a group C&#x2550;Y, wherein Y stands for oxygen or nitrogen substituted by hydroxy or lower alkoxy; Rrepresents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; R, Rand Rrepresent hydrogen; Rand R, independently of each other, represent hydrogen, lower alkyl or lower alkoxy, or Rand Rtogether represent methylenedioxy, and pharmaceutically acceptable derivatives thereof; or wherein R represents phenyl or pyridinyl wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkoxycarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, formyl, cyano, halogen, and nitro; and wherein two adjacent substituents are methylenedioxy; and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen; X represents oxygen; Rrepresents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; R, Rand Rrepresent hydrogen; Rand R, independently of each other, represent hydrogen, lower alkyl or lower alkoxy, or Rand Rtogether represent methylenedioxy; and pharmaceutically acceptable derivatives thereof. Methods of treatment of neoplastic and autoimmune diseases with these compounds we also disclosed.

Use of phospho-Akt as a biomarker of drug response

Use of glu-tubulin as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject to said compound, wherein the compound is a furazanobenzimidazole compound of general formula (I). 

Use of glu-tubulin as a biomarker of drug response to furazanobenzimidazoles

Use of BUBR1 as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject, wherein the compound is a furazanobenzimidazole compound of general formula (I). 

Use of BUBR1 as a biomarker of drug response to furazanobenzimidazoles

Use of acetylated tubulin as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject to said compound, wherein the compound is a furazanobenzimidazoles compound of general formula (I). 

Use of acetylated tubulin as a biomarker of drug response to furazanobenzimidazoles

Use of phospho-Akt as a biomarker for predicting the response, such as resistance, to a compound, wherein phospho-Akt is Akt that has been phosphorylated on one or more residues, with the proviso that for Akt1, Akt2, and Akt3 the designation phospho-Akt is used to indicate phosphorylation at a site other than T308, T309 or T305 respectively, wherein the compound is a compound of general formula (I).

Use of BUBR1 as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject, wherein the compound is a compound of general formula I wherein

Use of stathmin as a biomarker for predicting the response, such as resistance, to a compound, wherein the compound is a furazanobenzimidazole compound of general formula (I). 

Use of stathmin as a biomarker of drug response to furazanobenzimidazoles

A compound of formula II in which Z is C or N and the Z ring is optionally further substituted; Ris H, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; and Ris a group selected from (b), (c), and (d): 

Furazanobenzimidazoles as prodrugs to treat neoplastic or autoimmune diseases

The invention relates to novel substituted 2-(phenyl-, pyridyl- or pyrimidyl-carbonyl)-furanes and -thiophenes and related phenoxy/phenylthio-acetophenones and corresponding heterocyclic compounds, processes for the preparation thereof, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of neoplastic diseases and autoimmune diseases, and a method for the treatment of such a diseases.

Aroylfuranes and aroylthiophenes

The invention relates to novel substituted 3-phenylamino-5-(3-aminophenyl)pyridines and corresponding pyrazines of formula (I), wherein A is CH or N, Rrepresents C(&#x2550;O)R, S(&#x2550;O)R, P(&#x2550;O)(OR), optionally substituted phenyl or optionally substituted heteroaryl, and the other substituents have the meaning described in the specification, processes for the preparation thereof, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of neoplastic diseases and autoimmune diseases, and a method for the treatment of such a diseases.

Phenylaminopyridines

The invention relates to compounds of formula (I) wherein R represents aryl or heteroaryl, X is oxygen, a carbonyl group, an oxime derivative of a carbonyl group or an &#x3b1;,&#x3b2;-unsaturated carbonyl group, and the substituents Rto Rhave the meanings given in the specification, for use as medicaments, to novel compounds of formula (I), to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same

Furazanobenzimidazoles

The invention relates to compounds of formula (I) wherein R represents aryl or heteroaryl, X is a bond, a carbonyl group, a derivative of a carbonyl group, an ethylene group or an ethylenecarbonyl group, Ris optionally substituted amino or hydroxy, and the substituents Rto Rhave the meanings given in the specification, to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to intermediates, to the use of a compounds of formula (I) as a medicament and for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.

Growing community of inventors

Basel, Switzerland

Felix Bachmann