Novel process for the preparation of cyclosporin derivatives

Abstract

The invention concerns a novel method for preparing an intermediate polyanion for preparing cyclosporin derivatives by treating a cyclosporin with a hexamethyldisilazane metal salt, optionally in the presence of a metal halide. The treated cyclosporin has one or several free hydroxy groups and/or non-methylated nitrogen atoms in position α and/or any other acid group capable of deprotonation which are optionally deprotonated or in protected form.

1 - 14 . (canceled) 
     
     
         15 . A method for preventing or treating a retrovirus infection or an associated syndrome, comprising administering to a mammal in need or desire thereof an effective amount of a cyclosporin derivative substituted at the 3-position having the formula: 
       
         
           
           
               
               
           
         
         in which: 
         2) the radicals R 1  to R 11  and Z 1  to Z 11  are defined as for cyclosporin A, with the exception of R 4  and Z 4 , which are defined so as to have, at the 4-position, the amino acid 4′-hydroxy-methylleucine and R 3  is —S—CH 3  or a radical —S-Alk-R° in which:
 Alk is an alkylene radical comprising from 2 to 6 straight- or branched-chain carbon atoms or a cycloalkylene radical comprising from 3 to 6 carbon atoms; and 
 R° is
 a hydroxyl, carboxyl, or alkyloxycarbonyl radical; or 
 an —NG 1 G 2  radical or a radical of formula: 
 
 
       
       
         
           
           
               
               
           
         
         
           
             as defined above; or 
           
         
         3) the radicals R 2  and R 5  to R 11 , and Z 2  and Z 5  to Z 11  are defined as for cyclosporin A; and
 Z 1  is a methyl group and R 1  has the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             in which R is a radical of formula —CH 2 —CH═CH—CH 2 —R′, in which R′ is an alkylthio, aminoalkylthio, alkylaminoalkylthio, dialkylaminoalkylthio, pyrimidinylthio, thiazolylthio, N-alkylimidazolylthio, hydroxyalkylphenylthio, hydroxyalkylphenyloxy, nitrophenylamino, or 2-oxopyrimidin-1-yl radical; or 
             R is a radical of formula —CH 2 —S-Alk in which Alk is an alkyl group; and 
           
           Z 4  and R 4  are radicals such that there is, at the 4-position, an amino acid methylleucine or 4′-hydroxy-methylleucine; and 
           R 3  a radical of structure —S-Alk-R° in which:
 Alk is an alkylene radical comprising from 2 to 6 straight- or branched-chain carbon atoms or a cycloalkylene radical comprising from 3 to 6 carbon atoms; and 
 R° is
 a hydrogen atom or a hydroxyl, carboxyl, or alkyloxycarbonyl radical; or 
 an —NG 1 G 2  radical in which G 1  and G 2 , which are identical or different, are each 
  a hydrogen atom; or 
  a phenyl, cycloalkyl (C 3-6 ), or alkyl radical, each of which is optionally substituted by a halogen atom, or an alkyloxy, alkyloxycarbonyl, amino, alkylamino, or dialkylamino radical; or 
  a benzyl radical or a saturated or unsaturated heterocyclyl radical comprising 5 or 6 ring members and from 1 to 3 heteroatoms; or 
  G 1  and G 2  form with the nitrogen atom to which the are attached, a 5- or 6-membered heterocycle which can comprise another heteroatom chosen from nitrogen, oxygen, and sulphur and which is optionally substituted by alkyl; or 
 a radical of formula: 
 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
               as defined above; or 
             
           
         
         4) Z 1  and R 1  are radicals such that there is, at the 1-position, a substituted homothreonine of formula:
   R i —CH 2 CH(CH 3 )—CH(OH)—CH(NHCH 3 )—COOH  (IIIb) 
 in which R i  is n-propyl or propenyl; and 
 R 2  and Z 2  are radicals such that there is, at the 2-position, α-aminobutyric acid, valine, norvaline, or threonine; and 
 R 4  and Z 4  are radicals such that there is at the 4-position N-methyl-γ-hydroxyleucine or N-methyl-γ-acetyloxyleucine; and 
 R 5  and Z 5  are radicals such that there is at the 5-position valine; and 
 R 6 , Z 6 , R 9 , Z 9 , R 10  and Z 10  are radicals such that there is, at the 6-, 9-, and 10-positions, N-methylleucine; and 
 Z 7  and R 7  are radicals such that there is, at the 7-position, alanine; and 
 Z 8  and R 8  are radicals such that there is, at the 8-position, D-alanine or D-serine; and 
 Z 11  and R 11  are radicals such that there is, at the 11-position, N-methylvaline; and 
 R 3  is a radical chosen from:
 straight or branched alkyl (C 2-6 ), alkenyl, or alkynyl, each of which is optionally substituted by a hydroxyl, amino, C 1-4  alkylamino, C 1-3  dialkylamino, alkyloxy, or acyloxy group; 
 COOG 4  or CONHG 4 , in which G 4  is a straight or branched alkyl comprising from 1 to 4 carbon atoms; 
 —Y-G 5  in which Y is S or O, and G 5  is a straight or branched C 1  to C 4  alkyl, a straight or branched alkenyl, or a straight or branched alkynyl, and in which, if Y is S, G 5  can also be an aryl or a heteroaryl; 
 a halo or cyano group; and 
 CHG 6 G 7 , in which G 6  is a hydrogen atom or a methyl, ethyl, or phenyl group and G 7  is a hydrogen atom or a hydroxyl, halo, amino, C 1-4  alkylamino, C 1-4  dialkylamino, acyloxy, t-butoxycarbonylaminoethoxy-acetyloxy, or alkyloxycarbonyl group; or 
 
 
         5) the radicals R 7  to R 11  and Z 7  to Z 11  are defined as for cyclosporin A; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, the amino acid MeBmt, dihydro-MeBmt, or 8′-hydroxy-MeBmt; and 
 Z 2  and R 2  are radicals such that there is, at the 2-position, the amino acid α-aminobutyric acid, valine, threonine, norvaline, or MeOThr; and 
 Z 4  and R 4  are radicals such that there is, at the 4-position, the amino acid methylleucine, γ-hydroxy-MeLeu, Melle, MeVal, MeThr, MeAla, Mealle, or MeaThr; and 
 Z 5  and R 5  are radicals such that there is, at the 5-position, the amino acid valine, Leu, MeVal, or methylleucine; and 
 Z 6  and R 6  are radicals such that there is, at the 6-position, the amino acid methylleucine, γ-hydroxy-MeLeu, or MeAla; and 
 R 3  is a radical such that there is, at the 3-position, an amino acid D-MeAla; 
 provided that, when R 4  and Z 4  are MeLeu, then R 5  and Z 5  are MeVal or methylleucine, or R 1  and Z 1  are 8′-hydroxy-MeBmt; and 
 
         one or more hydroxyl groups and optionally one or more non-methylated nitrogen atoms at the α position and optionally any other deprotonatable acidic group present in said formula (IV) are optionally deprotonated or in the protected form. 
       
     
     
         16 . (canceled) 
     
     
         17 . A method for treating a chronic inflammatory disease or an autoimmune disease, comprising administering to a mammal in need or desire thereof an effective amount of a cyclosporin derivative substituted at the 3-position having the formula: 
       
         
           
           
               
               
           
         
         in which: 
         Z 1  and R 1  are radicals such that there is, at the 1-position, an methyl (4R)-4-[E-2-butenyl]-4-methyl-L-threonine (MeBmt) radical or a radical having the formula: 
       
       
         
           
           
               
               
           
         
         
           in which R i  is a hydrogen atom or a lower alkyl group, a lower alkenyl, a lower haloalkyl, an aryl, a lower alkyloxy, an alkoxyC 1-6 alkyl, a hydroxymethyl, a lower alkylthio, an alkylthioC 1-6 alkyl, a C 1-6  mercaptoalkyl, or a heteroaryl;
 it being possible for the aryl and heteroaryl groups to be substituted with one or more functional groups chosen from: C 1-6  alkyl; C 1-6  alkanoyl; C 1-6  haloalkyl; halo; cyano; C 1-3  hydroxyalkyl; C 1-6  alkyloxy; C 1-6 alkyl-S(O) n , where n=0, 1, or 2; NR b COR c , in which R b  and R c  independently are H or a C 1-6  alkyl, —NO 2 , —NR b R c , —OR b , —CONR b R c , —COR b , —NR b CONR b R c , NR b COR c , —OCOR b , —SCOR b , or —OCH 2 O—; and 
 
           R a  is a lower alkyl; and 
           Z 1  is a lower alkyl, a lower phenylalkyl, or an aryl; and 
           X is S, SO, SO 2 , O, or NR b ; and 
         
         Z 2  and R 2  are radicals such that there is, at the 2-position, the amino acid L-2-aminobutyric acid, Norvaline, L-Thr, or the same amino acid as at the 1-position; and 
         Z 4  and R 4  are radicals such that there is, at the 4-position, the amino acid N-methyl-L-leucine; and 
         Z 5  and R 5  are radicals such that there is, at the 5-position, the amino acid L-valine or norvaline; and 
         Z 6  and R 6  are radicals such that there is, at the 6-position, the amino acid N-methyl-L-leucine; and 
         Z 7  and R 7  are radicals such that there is, at the 7-position, the amino acid L-alanine, L-2-aminobutyric acid, or L-phenylalanine; and 
         Z 8  and R 8  are radicals such that there is, at the 8-position, the amino acid D-alanine or L-alanine; and 
         Z 9  and R 9  are radicals such that there is, at the 9-position, the amino acid N-methyl-L-leucine or N-methyl-L-valine; and 
         Z 10  and R 10  are radicals such that there is, at the 10-position, the amino acid N-methyl-L-leucine or L-leucine; and 
         Z 11  and R 11  are radicals such that there is, at the 11-position, the amino acid N-methyl-L-valine, L-valine, or L-2-aminobutyric acid; and 
         R 3  is a radical such that there is, at the 3-position, an 
         α-(methylmercapto)sarcosyl or N-methyl-D-alanyl residue; and 
         one or more hydroxyl groups and optionally one or more non-methylated nitrogen atoms at the α position and optionally any other deprotonatable acidic group present in said formula (IV) are optionally deprotonated or in the protected form. 
       
     
     
         18 . A method for preventing or treating an autoimmune disease or preventing rejection of a transplanted organ, comprising administering to a mammal in need or desire thereof an effective amount of a cyclosporin derivative substituted at the 3-position having the formula: 
       
         
           
           
               
               
           
         
         in which: 
         1) the radicals R 4  to R 11  and Z 4  to Z 11  are defined as for cyclosporin A; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, the amino acid MeBmt or dihydro-MeBmt; and 
 Z 2  and R 2  are radicals such that there is, at the 2-position, the amino acid α-aminobutyric acid, threonine, valine, or norvaline; and 
 R 3  is a C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, mercaptoC 1-6 alkyl, aminoC 1-6 alkyl, C 2-5 alkoxycarbonylamino(C 1-4 alkyl), nitroC 1-6 alkyl, cyanoC 1-5 alkyl, C 1-6 alkoxy(C 1-6 alkyl), C 1-6 alkylthio-(C 1-6 alkyl), C 2-7 alkanoyloxy(C 1-6 alkyl), C 2-7 diazoalkanoyloxy(C 1-6 alkyl), carboxy(C 1-6 alkyl), C 2-7 alkoxycarbonyl(C 1-6 alkyl), aminocarbonyl(C 1-4 alkyl), aminocarbonyloxy(C 1-4 alkyl), amino(C 1-4 alkanoyloxy)-(C 1-4 alkyl), amino(C 2-9 alkoxycarbonyl)(C 1-4 alkyl), C 2-7  alkylcarbonyl, C 2-7 alkoxycarbonyl, C 1-6 alkylthio, hydroxyC 1-6 alkylthio, C 1-6 alkoxy(C 1-6 alkylthio), C 2-11 alkanoyloxy(C 2-4 alkylthio), C 2-11 alkanoyloxy(C 2-4 alkylsulphinyl), C 2-11 alkanoyloxy(C 2-4 alkylsulphonyl), aminocarbonyloxy(C 2-4 alkylthio), C 2-11 aminoalkanoyloxy(C 2-4 alkylthio), aminocarbonyloxy(C 2-4 alkylsulphinyl), aminocarbonyloxy(C 2-4 alkylsulphonyl), aminoalkanoyloxy(C 2-4 alkylsulphinyl), aminoalkanoyloxy(C 2-4 alkylsulphonyl), aminocarbonyl, C 3-6 alkenyl, C 3-6 alkynyl, haloC 3-6 alkenyl, haloC 3-6 alkynyl, hydroxyC 3-6 alkenyl, aryl(C 1-6 alkyl), hydroxylated aryl(C 1-6 alkyl), aryl(C 3-6 alkenyl), aryl(C 3-6 alkynyl), hydroxylated aryl(C 3-6 alkenyl), hydroxylated aryl(C 3-6 alkynyl), arylthio, heteroarylthio, aryl(C 2-5 alkoxycarbonylamino)(C 1-4 alkyl), halo, or cyano radical, or a radical of formula Q-(CH 2 —CH 2 —O) n —CO—O—CH 2 —, in which n is 1, 2, or 3 and Q is amino; or 
 
         2) the radicals R 1 , R 2 , and R 4  to R 11 , and Z 1 , Z 2 , and Z 4  to Z 11  define a cyclosporin in which the 3′ carbon of the residue at the 1-position or the β carbon of the residue at the 2-position is substituted by O-acyl or oxo; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, a residue of formula 
 
       
       
         
           
           
               
               
           
         
         
           
             in which —V—W— is CH 2 —CH 2  or trans CH═CH and ACYL 1  is an acyl group; and 
           
           Z 2  and R 2  are radicals such that there is, at the 2-position, an amino acid α-aminobutyric acid, valine, threonine, norvaline, or a β-O-acylated α-amino acid; and 
           Z 5  and R 5  are radicals such that there is, at the 5-position, an amino acid valine or norvaline when there is simultaneously an amino acid norvaline at the 2-position; and 
           Z 8  and R 8  are radicals such that there is, at the 8-position, an amino acid D-alanine or a β-O-acylated or β-hydroxylated α-amino acid having the D configuration; and 
           the radicals at the 4-, 6-, 7-, and 9- to 11-positions are defined as for cyclosporin A; and 
           R 3  is a radical such that there is, at the 3-position, an α-amino acid which is N-methylated at the α position and which has the D configuration; and 
         
         one or more hydroxyl groups and optionally one or more non-methylated nitrogen atoms at the α position and optionally any other deprotonatable acidic group present in said formula (IV) are optionally deprotonated or in the protected form. 
       
     
     
         19 . A method for treating inflammation, comprising administering to a mammal in need or desire thereof an effective amount of a cyclosporin derivative substituted at the 3-position having the formula: 
       
         
           
           
               
               
           
         
         in which: 
         1) the radicals R 4  to R 11  and Z 4  to Z 11  are defined as for cyclosporin A; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, the amino acid MeBmt or dihydro-MeBmt; and 
 Z 2  and R 2  are radicals such that there is, at the 2-position, the amino acid α-aminobutyric acid, threonine, valine, or norvaline; and 
 R 3  is a C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, mercaptoC 1-6 alkyl, aminoC 1-6 alkyl, C 2-5 alkoxycarbonylamino(C 1-4 alkyl), nitroC 1-6 alkyl, cyanoC 1-5 alkyl, C 1-6 alkoxy(C 1-6 alkyl), C 1-6 alkylthio-(C 1-6 alkyl), C 2-7 alkanoyloxy(C 1-6 alkyl), C 2-7 diazoalkanoyloxy(C 1-6 alkyl), carboxy(C 1-6 alkyl), C 2-7 alkoxycarbonyl(C 1-6 alkyl), aminocarbonyl(C 1-4 alkyl), aminocarbonyloxy(C 1-4 alkyl), amino(C 1-4 alkanoyloxy)-(C 1-4 alkyl), amino(C 2-9 alkoxycarbonyl)(C 1-4 alkyl), C 2-7 alkylcarbonyl, C 2-7 alkoxycarbonyl, C 1-6 alkylthio, hydroxyC 1-6 alkylthio, C 1-6 alkoxy(C 1-6 alkylthio), C 2-11 alkanoyloxy(C 2-4 alkylthio), C 2-11 alkanoyloxy(C 2-4 alkylsulphinyl), C 2-11 alkanoyloxy(C 2-4 alkylsulphonyl), aminocarbonyloxy(C 2-4 alkylthio), C 2-11 aminoalkanoyloxy(C 2-4 alkylthio), aminocarbonyloxy(C 2-4 alkylsulphinyl), aminocarbonyloxy(C 2-4 alkylsulphonyl), aminoalkanoyloxy(C 2-4 alkylsulphinyl), aminoalkanoyloxy(C 2-4 alkylsulphonyl), aminocarbonyl, C 3-6 alkenyl, C 3-6 alkynyl, haloC 3-6 alkenyl, haloC 3-6 alkynyl, hydroxyC 3-6 alkenyl, aryl(C 1-6 alkyl), hydroxylated aryl(C 1-6 alkyl), aryl(C 3-6 alkenyl), aryl(C 3-6 alkynyl), hydroxylated aryl(C 3-6 alkenyl), hydroxylated aryl(C 3-6 alkynyl), arylthio, heteroarylthio, aryl(C 2-5 alkoxycarbonylamino)(C 1-4 alkyl), halo, or cyano radical, or a radical of formula Q-(—CH 2 —CH 2 —O) n —CO—O—CH 2 —, in which n is 1, 2, or 3 and Q is amino; or 
 
         2) the radicals R 1 , R 2 , and R 4  to R 11 , and Z 1 , Z 2 , and Z 4  to Z 11  define a cyclosporin in which the 3′ carbon of the residue at the 1-position or the β carbon of the residue at the 2-position is substituted by O-acyl or oxo; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, a residue of formula 
 
       
       
         
           
           
               
               
           
         
         
           in which —V—W— is CH 2 —CH 2  or trans CH═CH and ACYL 1  is an acyl group; and 
         
         Z 2  and R 2  are radicals such that there is, at the 2-position, an amino acid α-aminobutyric acid, valine, threonine, norvaline, or a β-O-acylated α-amino acid; and 
         Z 5  and R 5  are radicals such that there is, at the 5-position, an amino acid valine or norvaline when there is simultaneously an amino acid norvaline at the 2-position; and 
         Z 8  and R 8  are radicals such that there is, at the 8-position, an amino acid D-alanine or a β-O-acylated or β-hydroxylated α-amino acid having the D configuration; and 
         the radicals at the 4-, 6-, 7-, and 9- to 11-positions are defined as for cyclosporin A; and 
         R 3  is a radical such that there is, at the 3-position, an α-amino acid which is N-methylated at the α position and which has the D configuration; and 
         one or more hydroxyl groups and optionally one or more non-methylated nitrogen atoms at the α position and optionally any other deprotonatable acidic group present in said formula (IV) are optionally deprotonated or in the protected form. 
       
     
     
         20 . The method of  claim 19 , in which the inflammation is an arthritis or a rheumatic disease. 
     
     
         21 . A method for treating schistosomiasis, filariasis, leishmaniasis, coccidioidomycosis, or malaria, comprising administering to a mammal in need or desire thereof an effective amount of a cyclosporin derivative substituted at the 3-position having the formula: 
       
         
           
           
               
               
           
         
         in which: 
         1) the radicals R 4  to R 11  and Z 4  to Z 11  are defined as for cyclosporin A; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, the amino acid MeBmt or dihydro-MeBmt; and 
 Z 2  and R 2  are radicals such that there is, at the 2-position, the amino acid α-aminobutyric acid, threonine, valine, or norvaline; and 
 R 3  is a C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, mercaptoC 1-6 alkyl, aminoC 1-6 alkyl, C 2-5 alkoxycarbonylamino(C 1-4 alkyl), nitroC 1-6 alkyl, cyanoC 1-5 alkyl, C 1-6 alkoxy(C 1-6 alkyl), C 1-6 alkylthio-(C 1-6 alkyl), C 2-7 alkanoyloxy(C 1-6 alkyl), C 2-7 diazoalkanoyloxy(C 1-6 alkyl), carboxy(C 1-6 alkyl), C 2-7 alkoxycarbonyl(C 1-6 alkyl), aminocarbonyl(C 1-4 alkyl), aminocarbonyloxy(C 1-4 alkyl), amino(C 1-4 alkanoyloxy)-(C 1-4 alkyl), amino(C 2-9 alkoxycarbonyl)(C 1-4 alkyl), C 2-7 alkylcarbonyl, C 2-7 alkoxycarbonyl, C 1-6 alkylthio, hydroxyC 1-6 alkylthio, C 1-6 alkoxy(C 1-6 alkylthio), C 2-11 alkanoyloxy(C 2-4 alkylthio), C 2-11 alkanoyloxy(C 2-4 alkylsulphinyl), C 2-11 alkanoyloxy(C 2-4 alkylsulphonyl), aminocarbonyloxy(C 2-4 alkylthio), C 2-11 aminoalkanoyloxy(C 2-4 alkylthio), aminocarbonyloxy(C 2-4 alkylsulphinyl), aminocarbonyloxy(C 2-4 alkylsulphonyl), aminoalkanoyloxy(C 2-4 alkylsulphinyl), aminoalkanoyloxy(C 2-4 alkylsulphonyl), aminocarbonyl, C 3-6 alkenyl, C 3-6 alkynyl, haloC 3-6 alkenyl, haloC 3-6 alkynyl, hydroxyC 3-6 alkenyl, aryl(C 1-6 alkyl), hydroxylated aryl(C 1-6 alkyl), aryl(C 3-6 alkenyl), aryl(C 3-6 alkynyl), hydroxylated aryl(C 3-6 alkenyl), hydroxylated aryl(C 3-6 alkynyl), arylthio, heteroarylthio, aryl(C 2-5 alkoxycarbonylamino)(C 1-4 alkyl), halo, or cyano radical, or a radical of formula Q-(CH 2 —CH 2 —O) n —CO—O—CH 2 —, in which n is 1, 2, or 3 and Q is amino; or 
 
         2) the radicals R 1 , R 2 , and R 4  to R 11 , and Z 1 , Z 2 , and Z 4  to Z 11  define a cyclosporin in which the 3′ carbon of the residue at the 1-position or the β carbon of the residue at the 2-position is substituted by O-acyl or oxo; and
 Z 1  and R 1  are radicals such that there is, at the 1-position, a residue of formula 
 
       
       
         
           
           
               
               
           
         
         
           
             in which —V—W— is CH 2 —CH 2  or trans CH═CH and ACYL 1  is an acyl group; and 
           
           Z 2  and R 2  are radicals such that there is at the 2-position, an amino acid α-aminobutyric acid, valine, threonine, norvaline, or a β-O-acylated α-amino acid; and 
           Z 5  and R 5  are radicals such that there is, at the 5-position, an amino acid valine or norvaline when there is simultaneously an amino acid norvaline at the 2-position; and 
           Z 8  and R 8  are radicals such that there is, at the 8-position, an amino acid D-alanine or a β-O-acylated or β-hydroxylated α-amino acid having the D configuration; and 
           the radicals at the 4-, 6-, 7-, and 9- to 11-positions are defined as for cyclosporin A; and 
           R 3  is a radical such that there is, at the 3-position, an α-amino acid which is N-methylated at the α position and which has the D configuration; and 
         
         one or more hydroxyl groups and optionally one or more non-methylated nitrogen atoms at the α position and optionally any other deprotonatable acidic group present in said formula (IV) are optionally deprotonated or in the protected form. 
       
     
     
         22 . (canceled) 
     
     
         23 . (canceled)