Cyclosporin Analogs

Abstract

Disclosed herein are novel analogs of cyclosporin, pharmaceutical compositions containing them, and methods for their use in the treatment of dry eye and other conditions.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 A is —CH═CHR, —CH═CH—CH═CHR, or —CH 2 CH 2 R, 
 wherein R is —CH 3 ; —CH 2 SH; —CH 2 S—C n  wherein n is 1, 2, 3, 4, 5, or 6; —CH 2 -carboxyl; carboxyl; 
 
       
         
           
           
               
               
           
         
       
       wherein R10 is C 1 -C 6  alkyl;
 or 
 
       
         
           
           
               
               
           
         
       
       wherein R11=C 1 -C 6  alkyl;
 B is —CH 2 CH 3 , 1-hydroxyethyl, isopropyl, or n-propyl; 
 C is isobutyl, 2-hydroxyisobutyl, or 1-methylpropyl; 
 D is —CH 3  or —CH 2 OH; 
 R 1  and R 2 , which are identical or different, each represents hydrogen or C 1 -C 4  alkyl, or together represent C 3 -C 7  cycloalkyl; 
 X is sulfur or —S(O) n , wherein n is 1 or 2; 
 R 3  is hydrogen; straight or branched C 1 -C 6  alkyl; straight or branched C 2 -C 6  alkenyl; straight or branched C 2 -C 6  alkynyl; C 3 -C 7  cycloalkyl; C 4 -C 7  heterocyclyl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; aryl; heteroaryl; 
 —(CHR′) m —NH—CNH 2 NH; 
 —(CHR′) m —COOH; 
 —(CHR′) m —NHR″; 
 —(CHR′) m —NHCOR″; 
 wherein m is 1, 2, 3, 4, 5, or 6; 
 each R′ is independently H, straight or branched C 1 -C 6  alkyl, straight or branched C 2 -C 6  alkenyl; straight or branched C 2 -C 6  alkynyl; C 3 -C 7  cycloalkyl; C 4 -C 7  heterocyclyl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; aryl; heteroaryl; or is absent; 
 R″ is —(CHR) p N(CH 3 ) 2 , —(CHR′) p NHCOC, —(CHR′) p NHCOOH, wherein p is 0, 1, 2, 3, 4, 5, or 6; and 
 wherein R 3  may be optionally substituted with one or more groups, identical or different, of C 1 -C 6  alkyl; halogen; hydroxyl; alkoxycarbonyl; carboxyl; cycloalkyl; saturated or partially unsaturated 5-6 member heterocyclyl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which heterocyclyl is optionally substituted by one or more groups of C 1 -C 6  alkyl; aryl; heteroaryl; amino; monoalkylamino; dialkylamino; amidino; guanidine; or urea. 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1  selected from the group consisting of:
 [(S)-2-diethylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(4-pyridyl)ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-methylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-pentylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-aminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(R)-2-amino-2-carbomethoxy-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-dimethylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-(4-methylpiperidinyl)thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(morpholino)ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbomethoxymethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbomethoxyethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(S)-2-amino-2-carbomethoxy-1,1-dimethyl-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(R)-2-amino-2-carbohydroxy-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbohydroxymethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(S)-2-amino-2-carbohydroxy-1,1-dimethyl-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbohydroxyethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-isopropylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-guanidinoethylthiomethyl-Sar] 3  cyclosporin A; 
 [methylene-Sar] 3  cyclosporin A; 
 [dihydro-MeBmt] 1  [Methylene-Sar] 3  cyclosporin A; 
 [methylene-Sar] 3  cyclosporin D; 
 [(S)-2-diethylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [dihydro-MeBmt] 1  [(S)-2-diethylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-diethylaminoethylthiomethyl-Sar] 3  cyclosporin D; 
 [(S)-2-(4-pyridyl)ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-methylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-pentylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-aminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(R)-2-amino-2-carbomethoxy-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-dimethylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(4-methylpiperidinyl)thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(morpholino)ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbomethoxymethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(S)-2-Amino-2-carbomethoxy-1,1-dimethyl-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(N-imidazolyl)ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(N-pyrazolyl)ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-diethylamino-1,1-dimethyl-ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-morpholino-1,1-dimethyl-ethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-3-diethylaminopropylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-3-(morpholino)-propylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-mercaptomethyl-Sar] 3  cyclosporin A; 
 [(S)-allylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(R)-2-amino-2-carbohydroxy-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbohydroxymethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-{(S)-2-amino-2-carbohydroxy-1,1-dimethyl-ethyl}thiomethyl-Sar] 3  cyclosporin A; 
 [(S)-carbohydroxyethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-isopropylaminoethylthiomethyl-Sar] 3  cyclosporin A; 
 [(S)-2-guanidinoethyl-1-sulfanylmethyl-Sar] 3  cyclosporin A hydrochloride; 
 [(S)-2-diethylaminoethyl-1-sulfinylmethyl-Sar] 3  cyclosporin A; 
 [dihydro-MeBmt] 1  [(S)-2-diethylaminoethyl-1-sulfinylmethyl-Sar] 3  cyclosporin A; 
 [(S)-3-diethylaminopropyl-1-sulfonylmethyl-Sar] 3  cyclosporin A; 
 [(S)-3-(morpholino)propyl-1-sulfonylmethyl-Sar] 3  cyclosporin A; 
 [(S)-(4-methylpiperidinyl)-sulfonylmethyl-Sar] 3  cyclosporin A; 
 [(S)-(2-diethylamino-1,1-dimethyl)-ethyl-1-sulfonylmethyl-Sar] 3  cyclosporin A; 
 [(S)-(2-morpholino-1,1-dimethyl)-ethyl-1-sulfonylmethyl-Sar] 3  cyclosporin A; 
 [(S)-3-(4-oxy-morpholin-4-yl)-propyl-1-sulfonylmethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(3-carboxypropionylamino)ethyl-1-sulfanylmethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(4-carboxybutyrylamino)ethyl-1-sulfanylmethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(acetylamino-acetylamino)ethyl-1-sulfanylmethyl-Sar] 3  cyclosporin A; 
 [(S)-2-(dimethylamino-acetylamino)ethyl-1-sulfanylmethyl-Sar] 3  cyclosporin A; 
 and pharmaceutically acceptable salts of any of the foregoing compounds. 
 
     
     
         3 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is isobutyl, and D is —CH 3 . 
     
     
         4 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is 1-hydroxyethyl, C is isobutyl, and D is —CH 3 . 
     
     
         5 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is isopropyl, C is isobutyl, and D is —CH 3 . 
     
     
         6 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is n-propyl, C is isobutyl, and D is —CH 3 . 
     
     
         7 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is 1-methylpropyl, and D is —CH 3 . 
     
     
         8 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is isobutyl, and D is —CH 2 OH. 
     
     
         9 . A compound according to  claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is 2-hydroxy isobutyl, and D is —CH 3 . 
     
     
         10 . A compound according to  claim 1 , wherein R3 is selected from the group consisting of
 —(CHR′) m —NH—CNH 2 NH;   —(CHR′) m —COOH;   —(CHR′) m —NHR″;   —(CHR′) m —NHCOR″;   
       wherein m is 1, 2, 3, 4, 5, or 6;
 each R′ is independently H, straight or branched C 1 -C 6  alkyl, straight or branched C 2 -C 6  alkenyl; straight or branched C 2 -C 6  alkynyl; C 3 -C 7  cycloalkyl; C 4 -C 7  heterocyclyl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; aryl; heteroaryl or is absent; and 
 R″ is —(CHR) p N(CH 3 ) 2 , —(CHR′) p NHCOC, or —(CHR′) p NHCOOH, wherein p is 0, 1, 2, 3, 4, 5, or 6. 
 
     
     
         11 . A compound according to  claim 10 , wherein m is 1, 2, or 3; each R′ is independently H or is absent; and R″ is —(CHR) p N(CH 3 ) 2 , —(CHR′) p NHCOC, or —(CHR′) p NHCOOH, wherein p is 0, 1, or 2. 
     
     
         12 . A pharmaceutical composition comprising at least one compound of  claim 1 , the compound being present alone or in combination with one or more pharmaceutically acceptable excipients. 
     
     
         13 . A pharmaceutical composition comprising at least one compound of  claim 1 , the compound being present alone or in combination with one or more pharmaceutically acceptable excipients, wherein the concentration of the compound in the composition is about 0.01 to about 0.05 weight percent. 
     
     
         14 . A method for treating a condition selected from dry eye, blepharitis, meibomian gland disease, allergic conjunctivitis, atopic and vernal keratoconjunctivitis, ptyregia, ocular symptoms of graft versus host disease, ocular allergy, atopic keratoconjunctivitis, vernal keratoconjunctivitis, uveitis, anterior uveitis, Behcet's disease, Steven Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, ocular rosacea, pinguecula, to prevent corneal transplant rejection, and to restore corneal sensitivity that has been impaired due to surgery on the cornea or other surface of the eye, the method comprising administering to a mammal a compound of  claim 1 . 
     
     
         15 . The method according to  claim 14 , wherein the mammal is a human. 
     
     
         16 . The method of  claim 15 , comprising administering the compound of  claim 1  wherein R3 is selected from the group consisting of
 —(CHR′) m —NH—CNH 2 NH; 
 —(CHR′) m —COOH; 
 —(CHR′) m —NHR″; 
 —(CHR′) m —NHCOR″; 
 
       wherein m is 1, 2, 3, 4, 5, or 6;
 each R′ is independently H, straight or branched C 1 -C 6  alkyl, straight or branched C 2 -C 6  alkenyl; straight or branched C 2 -C 6  alkynyl; C 3 -C 7  cycloalkyl; C 4 -C 7  heterocyclyl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; aryl; heteroaryl or is absent; and 
 R″ is —(CHR) p N(CH 3 ) 2 , —(CHR′) p NHCOC, or —(CHR′) p NHCOOH, wherein p is 0, 1, 2, 3, 4, 5, or 6. 
 
     
     
         17 . The method of  claim 16 , wherein m is 1, 2, or 3; each R′ is independently H or is absent; and R″ is —(CHR) p N(CH 3 ) 2 , —(CHR′) p NHCOC, or —(CHR′) p NHCOOH, wherein p is 0, 1, or 2. 
     
     
         18 . A compound of formula (III): 
       
         
           
           
               
               
           
         
       
       wherein:
 A represents —CH═CHR or —CH 2 CH 2 R, wherein R represents —CH 3 , —CH 2 SH; —CH 2 S—C n , wherein n=1-6; —CH 2 -carboxyl, carboxyl, alkoxycarbonyl, or —CH 2 -alkoxycarbonyl; 
 B represents —CH 2 CH 3 , 1-hydroxyethyl, isopropyl, or n-propyl; 
 C represents isobutyl, 2-hydroxyisobutyl, or 1-methylpropyl; 
 D represents —CH 3  or —CH 2 OH; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A compound according to  claim 18 , wherein A is —CH═CHCH 3 , B is CH 2 CH 3 , C is isobutyl, and D is —CH 3 . 
     
     
         20 . A process for the preparation of a compound of formula (III) 
       
         
           
           
               
               
           
         
       
       wherein:
 A represents —CH═CHR or —CH 2 CH 2 R, wherein R represents —CH 3 , —CH 2 SH; —CH 2 S—C n , wherein n=1-6; —CH 2 -carboxyl, carboxyl, alkoxycarbonyl, or —CH 2 -alkoxycarbonyl; 
 B represents —CH 2 CH 3 , 1-hydroxyethyl, isopropyl, or n-propyl; 
 C represents isobutyl, 2-hydroxyisobutyl, or 1-methylpropyl; 
 D represents —CH 3  or —CH 2 OH; 
 
       the process comprising reacting a compound of the formula (II) 
       
         
           
           
               
               
           
         
         wherein A, B, C, and D are as previously defined, with a strong base, at a temperature in the range of −78° C. to −70° C., followed by treatment with a flow of carbon dioxide gas between −70° C. and 15° C., followed by treatment with excess chloromethylchloroformate between −50° C. and room temperature, followed by quenching of the reaction mixture with acetic acid at 0° C. to room temperature to generate a compound of formula (III). 
       
     
     
         21 . The method of  claim 20 , wherein the strong base is lithium diisopropylamide.