Cyclic depsipeptide compounds and their uses

Abstract

The present invention relates to novel cycloundecadepsipeptide compounds and their analogues which bind and inhibit cyclophilins, have reduced immunosuppressive activity and improved physicochemical properties including water solubility. The present invention further relates to pharmaceutical compositions containing said depsipeptide compounds and their analogues for use in the treatment or prevention of diseases and pathologies which may be ameliorated by the inhibition of cyclophilin activity.

1 . A compound having the formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, tautomer or N-oxide thereof, wherein 
         L represents an optionally partially unsaturated chain of 1-6 carbon atoms which may be optionally branched, 
         R1 and R2 may independently represent H, alkyl, substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally R1 and R2 may together with the nitrogen atom to which they are attached form a 4-7 membered aryl, cycloalkyl or heterocyclic ring which may be further fused or optionally substituted, 
         X represents H, OH, OC(═O)-alkyl, OC(═O)-substituted alkyl, O-alkyl, O-substituted alkyl or carbonyl (═O), 
         R a  represents hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylthio, substituted alkylthio or ═CH 2 , and 
         R b  represents hydrogen or is absent where R a  is ═CH 2 . 
       
     
     
         2 . The compound according to  claim 1  wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-7 membered aryl, cycloalkyl or heterocyclic ring which may be further fused or optionally substituted. 
     
     
         3 . The compound according to  claim 2  wherein R1 and R2 together with the nitrogen atom to which they are attached form a 5-7 membered cycloalkyl or heterocyclic ring which may be further fused or optionally substituted. 
     
     
         4 . The compound according to  claim 3  wherein NR1R2 is a ring selected from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1  wherein L is —(CH 2 ) n — where n is 1-4. 
     
     
         6 . The compound according to  claim 1  wherein R1 and R2 are independently H, alkyl or substituted alkyl. 
     
     
         7 . The compound according to  claim 6  wherein R1 and R2 are independently H, alkyl or alkyl substituted with an aliphatic or aromatic ring optionally containing one or more heteroatoms. 
     
     
         8 . The compound according to  claim 7  wherein R1 and/or R2 are selected from H, methyl, ethyl, isopropyl, (CH 2 ) n -pyridyl, (CH 2 ) n -pyrazoyl, (CH 2 ) n -tetrazoyl, (CH 2 ) n -1,4-dioxanyl, (CH 2 ) n —OMe, (CH 2 ) n -tetrahydropyranyl, (CH 2 ) n —CN where n is 1, 2 or 3. 
     
     
         9 . The compound according to  claim 1  wherein X represents H or OH or O-alkyl. 
     
     
         10 . The compound according to  claim 1  wherein R a  and R b  represent hydrogen. 
     
     
         11 . The compound according to  claim 1  which is a compound selected from the group consisting of:
 cyclo-[(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(methyl-pyridin-4-ylmethyl-amino)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-[methyl-2-(pyridin-2-yl)-ethyl-amino]-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-[methyl-(2-methyl-2H-pyrazol-3-ylmethyl)-amino]-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-[methyl-(1H-tetrazol-5-ylmethyl)-amino]-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-[(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid-(O-methyl-Thr)-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-([1,4]dioxan-2-ylmethyl-methyl-amino)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-[3-trifluoromethyl-piperidinyl]-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-[(2-methoxy-ethyl)-methyl-amino]-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(3-methoxy-azetidinyl)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-{(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(methyl-(tetrahydro-pyran-4-yl)-amino)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal}; 
 cyclo-[(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid-Abu-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(8-oxa-3-aza-bicyclo[3.2.1]octane)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(thiomorpholine 1,1-dioxide)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(4,4-difluoro-piperidine)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-((4-fluoro-piperidin-4-yl)-methanol)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N—((S)-1-Pyrrolidin-2-yl-methanol)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(3-methylamino-propionitrile)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(methyl-pyridin-2-yl-amine)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N—((R)-3-Methyl-morpholine)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(bis-pyridin-2-ylmethyl-amine)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N-(methyl-pyridin-2-ylmethyl-amino)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-N—(N′-methylpiperazine)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5 S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-(4-phenyl-1-piperidyl)-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5S)-1-benzylamino-3-methyl-5-methylamino-4-hydroxy-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 cyclo-[(3R,4R,5S)-4-hydroxy-1-isopropylamino-3-methyl-5-methylamino-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal]; 
 
       and
 cyclo-[(2R,3R,4S)-4-hydroxy-1-(2-hydroxymethyl-piperidin-1-yl)-3-methyl-5-methylamino-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal] 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A pharmaceutical composition containing the compound according to  claim 1 . 
     
     
         13 . A pharmaceutical composition containing a compound according to  claim 11 . 
     
     
         14 . A method of treating a disorder, wherein the disorder is selected from the group consisting of chronic and acute inflammatory disorders, comprising administering an effective amount of the compound of formula 1 as described in  claim 1  to a subject in need thereof. 
     
     
         15 . A method of treating a disorder, wherein the disorder is selected from the group consisting of chronic and acute inflammatory disorders, comprising administering an effective amount of a compound according to  claim 11  to a subject in need thereof.