Method for identifying modulators of notch signaling

Abstract

The present invention relates to use of inhibitors of Notch signalling pathway selected from the group consisting of 6-(4-Tert-Butylphenoxy)Pyridin-3-Amine (I3), its derivatives, in treating and/or preventing cancers.

1 - 21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a compound of formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 m is an integer selected from 1 to 4; 
 n is an integer selected from 1 to 15; 
 W is selected from the group consisting of H, F—, Cl—, Br— and I—; 
 R 4 , R 15  are each independently selected from the group consisting in H, phenyl, 2-, 3- or 4-substituted phenyl, 2- or 3-naphthyl, pyrrolyl, furanyl, thiofuranyl, pyrimidinyl, imidazolyl, benzyl, isopropyl, tertbutyl, (CH 2 )nCH 3 , alkenyl, alkynyl; the subscript n is an integer selected from 0 to 15; 
 X is O, S, CR 5 R 6 , NR 7 , NHCOR 8  or NHSO 2 R 9 ; R 5 , R 6  and R 7  are each independently selected from the group consisting in H, phenyl, 2-, 3- or 4-substituted phenyl, 2- or 3-naphthyl, pyrrolyl, furanyl, thiofuranyl, pyrimidinyl, imidazolyl, benzyl, isoPropyl, tertButyl, (CH 2 ) n CH 3 ; R 8  and R 9  are each independently selected from the group consisting in phenyl, 2-, 3- or 4-substituted phenyl, 2- or 3-naphthyl, or heteroaromatics selected from the group comprising pyrrolyl, furanyl, thiofuranyl, pyrimidinyl, imidazolyl, benzyl, (CH 2 ) n CH 3 ; the subscript n is an integer independently selected from 1 to 15; 
 Y is N or CH; and 
 Z is H, NO 2 , OH, NR 10 R 11  where R 10  and R 11  are each independently selected from the group consisting in H, (CH 2 ) n CH 3 , NHCOR 12  where R 12  is (CH 2 ) n CH 3 , aromatic and heteroaromatics selected from the group comprising phenyl, naphthyl, pyrrolyl, furanyl, thiofuranyl, pyrimidinyl, imidazolyl, COOR 13  where R 13  is H, (CH 2 ) n CH 3 , aromatic and heteroaromatics selected from the group comprising phenyl, naphthyl, pyrrolyl, furanyl, thiofuranyl, pyrimidinyl, imidazolyl, NHSO2R14 where R 14  is phenyl, 2-, 3- or 4, substituted phenyl, naphthyl, heteroaromatics selected from the group comprising pyrrolyl, furanyl, thiofuranyl, pyrimidinyl, imidazolyl, benzyl, (CH 2 ) n CH 3 , the subscript n is an integer independently selected from 1 to 15; 
 
       and a pharmaceutically acceptable carrier. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein:
 m is an integer selected from 1 to 2;   n is 6;   W is selected from the group consisting of H, F—, Cl—, Br— and I—;   R 4 , R 15  are each independently selected from the group consisting in H, phenyl, isopropyl, tertbutyl, (CH 2 )nCH 3 , alkenyl, alkynyl; n is an integer selected from 0 to 15;   Xis O, or S;   Y is N or CH; and   Z is H, or NR 10 R 11  where R 10  and R 11  are each independently selected from the group consisting in H, (CH 2 ) n CH 3 , the subscript n is an integer independently selected from 1 to 15.   
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein:
 m is 1;   n is 6;   W is selected from the group consisting of H, and F—;   R 4 , R 15  are each H;   X is O or NH;   Y is N; and   Z is NH 2 ,   
       and a pharmaceutically acceptable carrier. 
     
     
         25 . A pharmaceutical composition wherein the compound is selected from the group consisting of:
 a) 4-(4-cyclohexylphenoxy)aniline,   
       
         
           
           
               
               
           
         
         b) 4-(4-cyclohexylphenoxy)-3-fluoroaniline 
       
       
         
           
           
               
               
           
         
       
       and
 c) 6-(4-cyclohexylphenoxy)pyridin-3-amine, 
 
       
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical composition of  claim 22 , formulated for administration 1 or 2 times per day. 
     
     
         27 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutically acceptable carrier is an excipient. 
     
     
         28 . The pharmaceutical composition of  claim 22 , further comprising a chemotherapeutic agent. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the chemotherapeutic agent is selected from the group consisting of: altretamine, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclo phosphamid, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, idarubicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, pentostatin, procarbazine, strep tozocin, taco, temozolomide, tioguanine/thioguanine, thiotepa, topotecan, treosulfan, vinblastine, vincristine, vindesine and vinorelbine. 
     
     
         30 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutical composition is formulated in a tablet or in a capsule. 
     
     
         31 . The pharmaceutical composition of  claim 25 , formulated for administration 1 or 2 times per day. 
     
     
         32 . The pharmaceutical composition of  claim 25 , wherein the pharmaceutically acceptable carrier is an excipient. 
     
     
         33 . The pharmaceutical composition of  claim 25 , further comprising a chemotherapeutic agent. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the chemotherapeutic agent is selected from the group consisting of: altretamine, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclo phosphamid, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, idarubicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, pentostatin, procarbazine, strep tozocin, taco, temozolomide, tioguanine/thioguanine, thiotepa, topotecan, treosulfan, vinblastine, vincristine, vindesine and vinorelbine. 
     
     
         35 . The pharmaceutical composition of  claim 25 , wherein the pharmaceutical composition is formulated in a tablet or in a capsule. 
     
     
         36 . A kit comprising the pharmaceutical composition of  claim 22 , optionally with reagents and/or instructions for use. 
     
     
         37 . The kit of  claim 35 , further comprising a chemotherapeutic agent.