Epothilone derivatives

Abstract

The present invention relates to compounds of the formula in which the variables G, W, Q, X, Y, B 1 , B 2 , Z 1 , Z 2 , and R 1 -R 7 are as defined herein, methods for the preparation of the derivatives and intermediates thereof.

We claim: 
     
         1 . A compound of formula V, 
       
         
           
           
               
               
           
         
         wherein
 Q is selected from the. group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           G is selected from the group consisting of alkyl, substituted alkyl, substituted or unsubstituted aryl, heterocyclo, 
         
       
       
         
           
           
               
               
           
         
         
           W is O or NR 15 ; 
           X is O or H,H; 
           Y is selected from the group consisting of O; H 2 OR 16 ; OR 17 ,OR 17 ; NOR 18 ; H,NOR 19 ; H,NR 20 R 21 ; H,H; or CHR 22 ; OR 17 OR 17  can be a cyclic ketal; 
           Z 1  and Z 2  are selected from the group consisting of CH 2 , O, NR 23 , S, or SO 2 , wherein only one of Z and Z 2  is a heteroatom; 
           B 1  and B 2  are selected from the group consisting of OR 24 , or OCOR 25 , or O 2 CNR 26 R 27 ; when B 1  is H and Y is OH, H they can form a six-membered ring ketal or acetal; 
           D is selected from the group consisting of NR 28 R 29 , NR 30 COR 31  or saturated heterocycle; 
           R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 13 , R 14 , R 18 , R 19 , R 20 , R 21 , R 22 , R 26 , and R 27  are selected from the group H, alkyl, substituted alkyl, or aryl and when R 1  and R 2  are alkyl can be joined to form a cycloalkyl; R 3  and R 4  are alkyl can be joined to form a cycloalkyl; 
           R 9 , R 10 , R 16 , R 17 , R 24 , R 25 , and R 31  are selected from the group H, alkyl, or substituted alkyl; 
           R 8 , R 11 , R 12 , R 28 , R 30 , R 32 , R 33 , and R 30  are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or heterocyclo; 
           R 15 , R 23  and R 29  are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R 32 C═O, R 33 SO 2 , hydroxy, O-alkyl or O-substituted alkyl, the pharmaceutically acceptable salts thereof and any hydrates, solvates or geometric, optical and stereoisomers thereof, with the proviso that compounds wherein 
           W and X are both O; and 
           R 1 , R 2 , R 7 , are H; and 
           R 3 , R 4 , R 6 , are methyl; and 
           R 8 , is H or methyl; and 
           Z 1 , and Z 2 , are CH 2 ; and 
           G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and 
           Q is as defined above 
         
         are excluded,
 wherein, 
 “alkyl” means a straight or branched chain unsubstituted hydrocarbon group of 1 to 7 carbon atoms; 
 “substituted alkyl” means an alkyl group substituted with one to four substituents selected from trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, —SO 2 NH 2 , substituted sulfonamido, nitro, cyano, carboxy, —CONH 2 , —CONH alkyl, CONHaryl, CONHaralkyl, alkoxycarbonyl, aryl, substituted aryl, guanidine, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, and pyrimidyl; wherein when the alkyl substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl; 
 “cycloalkyl” means an optionally-substituted, saturated cyclic hydrocarbon ring systems containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 -C 7  carbocyclic ring, wherein when substituted, the substituents will include one or more substituents as recited above as alkyl substituents; 
 “aryl” means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion; 
 “substituted aryl” means an aryl group substituted by one to four substituents selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, and aryloxy, wherein when the aryl substitute is further substituted, it will be with halo, hydroxy, alkyl, alkoxy, aryl, substituted alkyl or aralkyl; 
 “heterocyclo” means an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring, each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms, wherein the term “heteroatoms” shall include oxygen, sulfur and nitrogen; and wherein when substituted, the substituted heterocyclo group will include one or more substituents as recited above as alkyl substituents. 
 
       
     
     
         2 . A compound according to  claim 1 , wherein,
 Q is selected from the group consisting of   
       
         
           
           
               
               
           
         
         G is selected from the group consisting of alkyl; substituted alkyl; substituted aryl; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; 
       
       
         
           
           
               
               
           
         
         W is O or NR 15 ; 
         X is O or H, H; 
         Y is selected from the group consisting of O; H, OR 16 ; OR 17 , OR 17 ; NOR 18 ; H, NHOR 19 ; H, NR 2 OR 21 ; H, H; and CHR 22 ; wherein OR 12 , OR 12  can be a cyclic ketal; 
         Z 1  and Z 2  are independently CH 2 ; 
         B 1  and B 2  are independently selected from the group consisting of OR 24 , OCOR 25 , and O—C(═O)—NR 26 R 27 , and when B 1  is H and Y is OH, H, they can form a six-membered ring ketal or acetal; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 18 , R 19 , R 20 , R 21 , R 22 , R 26  and R 27  are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R 1  and R 2  are alkyl they can be joined to form a cycloalkyl, and when R 3  and R 4  are alkyl they can be joined to form a cycloalkyl; 
         R 6  is methyl; 
         R 9 , R 10 , R 16 , R 17 , R 24 , R 25  and R 31  are selected from the group consisting of H, alkyl, and substituted alkyl; 
         R 8  is hydrogen or methyl; 
         R 28 , R 30 , R 32 , and R 33  are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; 
         R 15 , R 23  and R 29  are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R 32 C═O, R 33 SO 2 , hydroxy, O-alkyl or O-substituted alkyl; 
       
     
     
         3 . A compound according to  claim 2 , wherein,
 Q is   
       
         
           
           
               
               
           
         
         R 8  is methyl; 
         G is selected from optionally-substituted aryl and heterocyclo; 
         X is O; 
         Y is O; 
         Z 1  and Z 2  are CH 2 ; 
         B 1  and B 2  are OH; 
         R 1 , R 2 , and R 7  are hydrogen; and 
         R 3 , R 4 , and R 5  are each alkyl groups containing from one to four carbon atoms. 
       
     
     
         4 . A compound according to  claim 3 , wherein G is optionally-substituted benzothiazolyl. 
     
     
         5 . A compound according to  claim 3 , wherein G is optionally-substituted quinolinyl. 
     
     
         6 . A compound having the formula, 
       
         
           
           
               
               
           
         
         wherein,
 G is an optionally-substituted bicyclic heterocyclic group selected from benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl; 
 R 3 , R 4 , R 5 , and R 7  are selected from the group consisting of H, alkyl, substituted alkyl, and aryl; 
 R 6  is methyl; and 
 R 8  is hydrogen or methyl, 
 wherein “alkyl” means a straight or branched chain unsubstituted (saturated or unsaturated) hydrocarbon group of 1 to 7 carbon atoms; 
 “substituted alkyl” means an alkyl group substituted with one to four substituents selected from trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, —SO 2 NH 2 , substituted sulfonamido, nitro, cyano, carboxy, —CONH 2 , —CONH alkyl, CONHaryl, CONHaralkyl, alkoxycarbonyl, aryl, substituted aryl, guanidine, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, and pyrimidyl; wherein when the alkyl substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl; and 
 “aryl” means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion. 
 
       
     
     
         7 . A compound according to  claim 6 , wherein
 R 8  is methyl;   G is selected from optionally-substituted benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, and quinolinyl;   R 7  is hydrogen; and   R 3 , R 4 , and R 5  are each alkyl groups containing from one to four carbon atoms.   
     
     
         8 . A pharmaceutical composition comprising one or more compounds according to any one of  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         9 . A method of treating cancer in a patient which comprises providing an effective amount of a compound of  claim 1  to said patient. 
     
     
         10 . A method of treating a hyperproliferative cellular disease in a patient which comprises providing an effective amount of a compound of  claim 1  to said patient. 
     
     
         11 . A method of providing an antiangiogenic effect in a patient in need of said treatment which comprises providing an effective amount of a compound of  claim 1  to said patient.