Il-8 inhibitors for use in the treatment of some sarcomas

Abstract

The present invention relates to IL-8 inhibitor compounds, preferably dual CXCR1 /CXCR2 receptor inhibitors, useful in the treatment and/or prevention of some sarcomas, preferably in the treatment and/or prevention of osteosarcoma, Ewing sarcoma, rhabdomyosarcoma or lung metastasis associated thereof.

1 - 18 . (canceled) 
     
     
         19 . A method of preventing and/or treating a bone or soft tissue sarcoma, the method comprising administering a therapeutically effective amount of an IL-8 inhibitor to a subject in need thereof. 
     
     
         20 . The method according to  claim 19 , wherein said IL-8 inhibitor is selected from small molecular weight molecules and antibodies. 
     
     
         21 . The method according to  claim 19 , wherein said IL-8 inhibitor is selected from 1,3-thiazol-2-ylaminophenylpropionic acid derivatives and pharmaceutically acceptable salts thereof. 
     
     
         22 . The method according to  claim 21 , wherein said IL-8 inhibitor is a 1,3-thiazol-2-ylaminophenylpropionic acid derivative compound of formula (l) 
       
         
           
           
               
               
           
         
       
       wherein
 R1 is hydrogen or CH 3 ; 
 R2 is hydrogen or linear C 1 -C 4  alkyl; 
 Y is a heteroatom selected from S, O, and N; 
 Z is selected from halogen, linear or branched C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, hydroxyl, carboxyl, C 1 -C 4  acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4  acylamino, halo C 1 -C 3  alkyl, halo C 1 -C 3  alkoxy, benzoyl, linear or branched C 1 -C 8  alkanesulfonate, linear or branched C 1 -C 8  alkanesulfonamide, or linear or branched C 1 -C 8  alkylsulfonylmethyl; and 
 X is OH or a residue of formula NHR 3 ; 
 wherein R 3  is selected from: 
 hydrogen, hydroxyl, linear or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 1 -C 5  alkoxy, or C 1 -C 6  phenylalkyl, wherein alkyl, cycloalkyl, or alkenyl group can be substituted by a COOH residue 
 a residue of formula SO 2 R4 wherein R4 is C 1 -C 2  alkyl, C 3 -C 6  cycloalkyl, or C 1 -C 3  haloalkyl, or a pharmaceutically acceptable salt thereof. 
 
 
     
     
         23 . The method according to  claim 22 , wherein:
 R1 is hydrogen or CH 3 ;   X is OH;   R2 is hydrogen or linear C 1 -C 4  alkyl;   Y is a heteroatom selected from S, O, and N; and   Z is selected from linear or branched C 1 -C 4  alkyl, linear or branched C 1 -C 4  alkoxy, halo C 1 -C 3  alkyl, and halo C 1 -C 3  alkoxy.   
     
     
         24 . The method according to  claim 22 , wherein R1 is hydrogen, and the chiral carbon atom of the phenylproprionic group is in the S configuration. 
     
     
         25 . The method according to  claim 21 , wherein said IL-8 inhibitor is 2-methyl-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino} phenyl) propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method according to  claim 21 , wherein said IL-8 inhibitor is (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl] amino} phenyl) propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method according to  claim 19 , wherein the IL-8 inhibitor is part of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and/or diluent, and the method comprises administering the pharmaceutical composition to the subject. 
     
     
         28 . The method according to  claim 27 , wherein the pharmaceutical composition further comprises one or more of (a) at least one IL-6 inhibitor and (b) at least one gp130 inhibitor. 
     
     
         29 . The method according to  claim 27 , wherein the pharmaceutical composition further comprises at least one chemotherapeutic agent which is optionally selected from the group consisting of doxorubicin, cisplatin, methotrexate, ifosfamide, epirubicin, etoposide, cyclophosphamide, vincristine, and actinomycin D. 
     
     
         30 . A method of preventing and/or treating bone sarcomas, the method comprising administering a product or a kit to a patient in need thereof, the product or kit comprising:
 (A) an IL-8 inhibitor according to  claim 19 , or a pharmaceutical composition comprising said inhibitor; and   (B) one or more of at least one IL-6 inhibitor and at least one gp130 inhibitor;   (A) and (B) being two separate formulations for simultaneous, separate, or sequential use.   
     
     
         31 . A method of preventing and/or treating bone sarcomas, the method comprising administering a product or a kit to a patient in need thereof, the product or kit comprising:
 (A′) an IL-8 inhibitor according to  claim 19 , or a pharmaceutical composition comprising said inhibitor; and   (B′) at least one chemotherapeutic agent which is optionally selected from the group consisting of doxorubicin, cisplatin, methotrexate, ifosfamide, epirubicin, etoposide, cyclophosphamide, vincristine, and actinomycin D;   (A′) and (B′) being two separate formulations for simultaneous, separate, or sequential use.   
     
     
         32 . The method according to  claim 19 , wherein said bone or soft tissue sarcoma is selected from the group consisting of osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and lung metastases thereof. 
     
     
         33 . The method according to  claim 32 , wherein said subject has osteosarcoma or Ewing sarcoma. 
     
     
         34 . The method according to  claim 32 , wherein said subject has lung metastasis associated with osteosarcoma or Ewing sarcoma. 
     
     
         35 . A method of preventing and/or treating soft tissue sarcomas, the method comprising administering a therapeutically effective amount of an IL-8 inhibitor to a subject in need thereof. 
     
     
         36 . The method according to  claim 20 , wherein said IL-8 inhibitor is an inhibitor of the activity of IL-8 mediated by the CXCR1 receptor of by both the CXCR1 and CXCR2 receptors. 
     
     
         37 . The method according to  claim 22 , wherein R2 is H. 
     
     
         38 . The method according to  claim 22 , wherein Y is S. 
     
     
         39 . The method according to  claim 22 , wherein Z is trifluoromethyl. 
     
     
         40 . The method according to  claim 25 , wherein the pharmaceutically acceptable salt is the sodium salt. 
     
     
         41 . The method according to  claim 26 , wherein the pharmaceutically acceptable salt is the sodium salt.