Extended Triterpene Derivatives

Abstract

The present invention concerns novel pharmaceutically active triterpene derivatives, pharmaceutical compositions containing the same, their use as medicaments, and the use of the compounds for the manufacture of specific medicaments. The present invention also concerns a method of treatment involving administration of the compounds. Specifically, the compounds are derivatives of betulinic acid having substitutions at one or more of the C-3, C2-8 and C-19 positions as further described herein. The novel compounds are useful as antiretroviral agents. In particular, the novel compounds are useful for the treatment of Human Immunodeficiency Virus (HIV).

1 . A compound according to formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, tautomer, or ester thereof, wherein: 
         Y is a linker selected from the group consisting of a covalent bond, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, heterocyclyl, carbocyclyl, carbonyl, iminyl, diazenyl, O, S, SO, SO 2 , carboxyalkyl, carboxyalkenyl, carboxyalkynyl, and N—R 39 ; 
         X is a linker selected from the group consisting of a covalent bond, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, carbonyl, iminyl, diazenyl, O, S, SO, SO 2 , and N—R 39 ; 
         m is an integer from one to six; 
         n is an integer from zero to five; 
         q is one or two; 
         R 1  is selected from the group consisting of C 3 -C 20  alkanoyl, carboxyalkanoyl, carboxyalkenoyl, alkoxycarbonylalkanoyl, alkenyloxycarbonylalkanoyl, cyanoalkanoyl, hydroxyalkanoyl, aminocarbonylalkanoyl, hydroxyaminocarbonylalkanoyl, monoalkylaminocarbonylalkanoyl, dialkylaminocarbonylalkanoyl, heteroarylalkanoyl, heterocyclylalkanoyl, heterocycylcarbonylalkanoyl, heteroarylaminocarbonylalkanoyl, heterocyclylaminocarbonylalkanoyl, cyanoaminocarbonylalkanoyl, alkylsulfonylaminocarbonylalkanoyl, arylsulfonylaminocarbonylalkanoyl, sulfoaminocarbonylalkanoyl, phosphonoaminocarbonylalkanoyl, phosphono, sulfo, phosphonoalkanoyl, sulfoalkanoyl, alkylsulfonylalkanoyl, and alkylphosphonoalkanoyl; 
         R 2  is selected from the group consisting of formyl, carboxyalkenyl, heteroaryl, CH 2 SR 14 , CH 2 SOR 14 , CH 2 SO 2 R 14 , 
       
       
         
           
           
               
               
           
         
         R 3  is hydrido, hydroxyl, isopropenyl, isopropyl, 1′-hydroxyisopropyl, 1′-haloisopropyl, 1′-thioisopropyl, 1′-trifluoromethylisopropyl, 2′-hydroxyisopropyl, 2′-haloisopropyl, 2′-thioisopropyl, 2′-trifluoromethylisopropyl, 1′-hydroxyethyl, 1′-(alkoxy)ethyl, 1′-(alkoxyalkoxy)ethyl, 1′-(arylalkoxy)ethyl; 1′-(arylcarbonyloxy)ethyl, acetyl, 1′-(hydroxyl)-1′-(hydroxyalkyl)ethyl, (2′-oxo)tetrahydrooxazolyl, 1′,2′-epoxyisopropyl, 3′-haloisopropenyl, 3′-hydroxyisopropenyl, 3′-aminoisopropenyl, 3′-thioisopropenyl, 1′-alkoxyethyl, 1′-hydroxyiminoethyl, and 1′-alkoxyiminoethyl; 
         R 4  is hydrido: or R 3  and R 4  are taken together to form a radical selected from the group consisting of oxo, alkylimino, alkoxyimino and benzyloxyimino; 
         R 5  is selected from the group consisting of C 2 -C 20  alkyl, alkenyl, alkynyl, carboxy(C 2 -C 20 )alkyl, amino, aminoalkyl, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, sulfo, phosphono, sulfoalkyl, phosphonoalkyl, alkylsulfonyl, alkylphosphono, alkanoylaminoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, heterocyclylcarbonylalkyl, cycloalkycarbonylalkyl, heteroarylalkylaminocarbonyalkyl, arylalkylaninocarbonylalkyl, heterocyclylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, alkylsulfonylaminocarbonylalkyl, arylphosphonoaminocarbonylalkyl, alkylphosphonoaminocarbonylalkyl, and hydroxyimrinoaminoalkyl; 
         R 6  is selected from the group consisting of hydrido, phosphono, sulfo, alkyl, sulfoalkyl, phosphonoalkyl, alkylsulfonyl, alkylphosphono, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl; CH 2 CONR 7 R 8 , trialkylsilyl, ethoxyethyl, and tetrahydropyranyl ether; 
         R 6  and R 8  are independently selected from the group consisting of hydrido, alkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonylaminoalkoxyalkyl, alkoxycarbonylaminoalkyl, aminoalkoxyalkyl, alkylcarbonylaminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, arylcarbonylaminoalkyl, alkylsulfonyl, arylsulfonyl, heteroarlsulfonyl, heterocyclylsulfonyl, and cycloalkyl, or R.sub.7 and R.sub.8 can together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group, wherein the heterocyclyl or heteroaryl can optionally include one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; 
         R 9  is selected from the group consisting of hydrido, phosphono, sulfo, alkyl, alkenyl, trialkylsilyl, cycloalkyl, carboxyalkyl, alkoxycarbonloxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, phosphonoalkyl, sulfoalkyl, alkylsulfonyl, alkylphosphono, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclyalkyl, and dialkoxyalkyl; 
         R 12  and R 13  independently selected from the group consisting of hydrido, alkyl, alkenyl, alkylamino, alkynyl, alkoxy, alkoxycarbonyl, alkoxyaminoalkyl, cycloalkyloxo, heterocyclylaminoalkyl, cycloalkyl, cyanoalkyl, cyano, sulfo, phosphono, sulfoalkyl, phosphonoalkyl, alkylsulfonyl, alkylphosphono, alkoxyalkyl, heteroaryl, heteroarylalkyl, dialkylaminoalkyl, and heterocyclylalkyl, or R 12  and R 13  can together with the nitrogen atom to which they are attached form a heterocyclyl group or a heteroaryl group, wherein the heterocyclyl or heteroaryl can optionally include one or more additional heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or R 12  and R 13  can together with the nitrogen atom to which they are attached form an alkylazo group, and d is one to six; 
         R 14  is selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, carboxyalkyl, carboxyalkenyl, alkoxycarbonylalkyl, alkenyloxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, carboxybenzyl, and aminocarbonylalkyl; 
         R 18  and R 19  are independently selected from the group consisting of hydrido, methyl and ethyl; d is one to six; and 
         R 35  and R 36 , are radicals independently selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, C 1 -C 6  alkoxy, and amino; or R 35  and R 36  are taken together to form a carbonyl; 
         R 37  and R 38  are radicals independently selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, C 1 -C 6  alkoxy, and amino; or where R 37  and R 38  are taken together to form a carbonyl; 
         R 39  is a radical selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, hydroxyl, alkyl, alkanoyl, alkylsulfonyl, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, C 1 -C 6  alkoxy, and amino; 
         wherein any hydrido of Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , R 35 , R 36 , R 37 , R 38 , or R 39  is independently, optionally replaced with one or more moieties selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, alkoxy, carboxy, amiino, azido, monoalkylamino, dialkylamino, cyano, acetyl, acetamido, C 3 -C 7  cycloalkyl, C 2-6  alkenyl, C 2 -C 6  alkynl aryl, and heteroaryl; and 
         R 41  and R 42  are independently selected from the group consisting of hydrido, alkyl, and alkenyl; 
         with the proviso that when there is an unsaturation between carbons 18 and 19 then R 4  is not present. 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1  wherein formula I is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1  wherein formula I is: 
       
         
           
           
               
               
           
         
         wherein m is an integer from one to five. 
       
     
     
         6 . The compound of  claim 1  wherein R 3  is isopropenyl, R 4  is hydrido, and R 1  is selected from the group consisting of alkanoyl, carboxyalkanoyl, carboxyalkenoyl, and alkoxycarbonylalkanoyl. 
     
     
         7 . The compound of  claim 1  wherein R 2  is selected from the group consisting of formyl, carboxyalkenyl, heteroaryl, CH 2 SR 14 , CH 2 SOR 14 , and CH 2 S0 2 R 14 ; wherein any hydrido of R 1 , R 2 , R 3 , R 4 , or R 14  is independently, optionally substituted with one or more moieties selected from the group consisting of halo, lower alkyl, hydroxyl, alkoxy, carboxy, amino, azido, monoalkylamino, dialkylamino, cyano, acetyl, acetamido, C 1 -C 6  alkyl, C 3 -C 1  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, aryl, and heterocyclyl. 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1  wherein R 2  is a heteroaryl selected from the group consisting of tetrazolyl, pyridinyl, imidazolyl, isoxazolyl, furanyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, pyrazolyl, triazolyl, oxazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; where one or more hydrido radicals is independently, optionally replaced with one or more moieties selected from the group consisting of halo, lower alkyl, hydroxyl, alkoxy, carboxy, amino, azido, monoalkylamino, dialkylamino, cyano, acetyl, acetamido, unsubstituted C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, unsubstituted C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, unsubstituted C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, unsubstituted C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl. 
     
     
         10 . The compound of  claim 1  wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10  wherein R 5  is selected from the group consisting of C 2 -C 20  alkyl, alkenyl, alkynyl, carboxy(C 2 -C 20 )alkyl, amino, aminoalkyl dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, alkanoylaminoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, heterocyclylcarbonylalkyl, cycloalkylcarbonylalkyl, heteroarylalkylaminocarbonylalkyl, arylalkylaminocarbonylalkyl, heterocyclylalkylaminocarbonylalkyl, carboxyalkylaminocarbonalkyl, arylsulfonylaminocarbonylalkyl, alkylsulfonylaminocarbonylalkyl, and hydroxyimino(amino)alkyl. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 10  wherein R 5  is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heterocycloalkanoyl, and heteroarylalkyl. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 1  wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         21 . (canceled) 
     
     
         22 . The compound of  claim 20  wherein R 6  is selected from the group consisting of alkyl, sulfoalkyl, phosphonoalkyl, alkylsulfonyl, alkylphosphono, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl; CH 2 CONR 7 R 8 , trialkylsilyl, ethoxyethyl (OEE), heterocycloalkyl, and tetrahydropyranyl ether (OTHP). 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 28  wherein R 9  is selected from the group consisting of hydrido, phosphono, sulfo, alkyl, alkenyl, trialkylsilyl, carboxyalkyl, alkoxycarbonyloxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, phosphonoalkyl, sulfoalkyl, alkylsulfonyl, alkylphosphono, aryl, heteroaryl, heterocyclyl, and dialkoxyalkyl. 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . The compound of  claim 1  wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 40  wherein one of R 12  and R 13  is hydrido and one of R 12  and R 13  is selected from the group consisting of alkylamino, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, cycloalkyl, cycloalkyloxo, heteroaryl, heteroarylalkyl, hydrido, dialkylaminoalkyl, and cyanoalkyl. 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . The compound of  claim 40  wherein R 12  and R 13  together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl optionally including one or more additional heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen. 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . The compound of  claim 40  wherein, d is one. 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . A pharmaceutical composition comprising (a) a compound according to  claim 1 , and (b) a pharmaceutically acceptable carrier. 
     
     
         57 . The pharmaceutical composition of  claim 56 , further comprising at least one antiretroviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors, HIV maturation inhibitors, CCR5 antagonist, CxCR4 coreceptor antagonist and HIV fusion inhibitors. 
     
     
         58 . The compound of  claim 1 , wherein when q is 1 then R 4  is alkyl or alkenyl, R 41  and R 42  are hydrido, the bond between carbons 12 and 13 is fully saturated; and the bond between carbons 18 and 19 is fully saturated. 
     
     
         59 . (canceled) 
     
     
         60 . (canceled)