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US 4,798,823 AGranted
New cyclosporin analogs with modified "C-9 amino acids"
AssigneeMerck & Co., Inc.
InventorBruce E. Witzel
Life of this patent
Estimating the term…
Abstract
New cyclosporin analogs with modified "C-9 amino acids" have been made and are found to be effective immunosuppressive agents.
Claims19
A compound of formula ##STR18## wherein ##STR19## where X, R, R.sub.a and R.sub.e are as defined below;
- R is
- (1) hydrogen;
- (2) loweralkyl;
- (3) loweralkenyl;
- (4) haloloweralkyl;
- (5) aryl;
- (6) oxyloweralkyl comprising alkoxy lower alkyl and hydroxy lower alkyl;
- (7) thioloweralkyl comprising alkyl thio lower alkyl and mercapto lower alkyl;
- (8) heteroaryl;
- the aryl or hetoroaryl group can be substituted with one or more functional groups selected from a group consisting of
- (a) C.sub.1-6 alkyl,
- (b) C.sub.1-6 alkanoyl;
- (c) C.sub.1-6 haloalkyl;
- (d) halo;
- (e) cyano;
- (f) hydroxy C.sub.1-3 alkyl;
- (g) C.sub.1-6 alkoxy;
- (h) ##STR20## where n is 0, 1 or 2;
- (i) --NR.sub.b COR.sub.c wherein R.sub.b and R.sub.c independently are H or C.sub.1-6 alkyl;
- (j) --NO.sub.2 ;
- (k) --NR.sub.b R.sub.c ;
- (l) --OR.sub.b ;
- (m) --CONR.sub.b R.sub.c
- (n) --COR.sub.b ;
- (o) --NR.sub.b CONR.sub.b R.sub.c ;
- (p) --NR.sub.b COR.sub.c ;
- (q) --OCOR.sub.b ;
- (r) --SCOR.sub.b ;
- or
- (s) --OCH.sub.2 O--;
- and
- x is S, SO, SO.sub.2, or NR.sub.6.
- R.sub.a is loweralkyl;
- R.sub.e is loweralkyl;
- loweralkylphenyl;
- or aryl;
- R.sup.2 is L-2-aminobutyryl;
- norvalyl;
- L-threonyl;
- or R.sup.1 ;
- R.sup.3 is sarcosyl;
- .alpha.-(methylmercapto)-sarcosyl;
- N-methyl-D-alanyl;
- N-methyl-L-alanyl;
- or D-prolyl;
- R.sup.4 is N-methyl-L-leucyl;
- R.sup.5 is L-valyl;
- or norvalyl;
- R.sup.6 is N-methyl-L-leucyl;
- R.sup.7 is L-analyl;
- L-2-aminobutyryl;
- or L-phenylalanyl;
- R.sup.8 is D-alanyl or L-alanyl;
- R.sup.9 is N-methyl-L-leucyl;
- or N-methyl-L-valyl;
- R.sup.10 is N-methyl-L-leucyl;
- or L-leucyl;
- and
- R.sup.11 is N-methyl-L-valyl;
- L-valyl;
- N-methylleucyl;
- or L-2-aminobutyryl.
59 more elements
A compound of formula ##STR21## wherein R.sub.1 is H or C.sub.1-6 alkyl;
- R is
- (1) hydrogen;
- (2) loweralkyl;
- (3) loweralkenyl;
- (4) haloloweralkyl;
- (5) aryl;
- (6) oxyloweralkyl comprising alkoxy lower alkyl and hydroxy lower alkyl;
- (7) thioloweralkyl comprising alkyl thio lower alkyl and mercapto lower alkyl;
- (8) heteroaryl;
- the aryl or heteroaryl group above can be substituted with one or more functional groups selected from a group consisting of
- (a) C.sub.1-6 alkyl,
- (b) C.sub.1-6 alkanoyl;
- (c) C.sub.1-6 haloalkyl;
- (d) halo;
- (e) cyano;
- (f) hydroxy C.sub.1-3 alkyl;
- (g) C.sub.1-6 alkoxy;
- (h) ##STR22## where n is 0, 1 or 2;
- (i) --NR.sub.b COR.sub.c wherein R.sub.b and R.sub.c independently are H or C.sub.1-6 alkyl;
- (j) --NO.sub.2 ;
- (k) --NR.sub.b R.sub.c ;
- (l) --OR.sub.b ;
- (m) --CONR.sub.b R.sub.c
- (n) --COR.sub.b ;
- (o) --NR.sub.b CONR.sub.b R.sub.c ;
- (p) --NR.sub.b COR.sub.c ;
- (q) --OCOR.sub.b ;
- (r) --SCOR.sub.b ;
- or
- (s) --OCH.sub.2 O--;
- and
- n is 0, 1 or 2.
29 more elements
Dependencies are inferred from the claim text.