Novel cyclosporins

Claim 2

A cyclosporin having an optically active, α-N-methylated α-amino acid residue at the 3-position, said residue having the (D)-configuration.

Claim 3

A cyclosporin according to claim 1 of formula II ##STR21## wherein X is -MeBmt- or -dihydro-MeBmt-, Y is -αAbu-, -Thr-, -Val- or -Nva-, and Z is an optically active, α-N-methylated α-amino acid residue having the (D)-configuration.

Claim 4

A cyclosporin according to claim 2, wherein Z has the formula I ##STR22## wherein R is: (i) C 1-6 -alkyl or halo-substituted C 1-6 alkyl; (ii) hydroxy-(C 1-6 alkyl); (iii) thio-(C 1-6 alkyl); (iv) amino-(C 1-6 alkyl); (v) (C 2-5 alkoxycarbonylamino)-(C 1-4 alkyl); (vi) nitro-(C 1-6 alkyl) or cyano-(C 1-5 alkyl); (vii) (C 1-6 alkoxy)-(C 1-6 alkyl) or (C 1-6 alkylthio)-(C 1-6 alkyl); (viii) (C 2-7 alkanoyloxy)-(C 1-6 alkyl); (ix) (C 2-7 diazoalkanoyloxy)-(C 1-6 alkyl); (x) carboxy-(C 1-6 alkyl) or (C 2-7 alkoxycarbonyl)-(C 1-6 alkyl); (xi) aminocarbonyl-(C 1-4 alkyl); (xii) aminocarbonyloxy-(C 1-4 alkyl) or amino-(C 2-9 alkanoyloxy)-(C 1-4 alkyl); (xiii) amino-(C 2-9 alkoxycarbonyl)-(C 1-4 alkyl); (xiv) C 2-7 -alkylcarbonyl; (xv) C 2-7 -alkoxycarbonyl; (xvi) C 1-6 alkylthio or hydroxy-(C 1-6 -alkylthio); (xvii) (C 1-6 alkoxy)-(C 1-6 alkylthio); (xviii) (C 2-11 akanoyloxy)-(C 2-4 -alkylthio); (xix) (C 2-11 alkanoyloxy)-(C 2-4 alkylsulfinyl) or -(C 2-4 -alkylsulfonyl); (xx) aminocarbonyloxy-(C 2-4 alkylthio) or (C 2-11 aminoalkanoyloxy)-(C 2-4 alkylthio); (xxi) aminocarbonyloxy-(C 2-4 alkylsulfinyl) or -(C 2-4 alkylsulfonyl), or (C 2-11 aminoalkanoyloxy)-(C 2-4 alkylsulfinyl) or -(C 2-4 alkylsulfonyl); (xxii) aminocarbonyl; (xxiii) C 3-6 alkenyl, C 3-6 alkinyl, or halo-substituted C 3-6 alkenyl or C 3-6 alkinyl; (xxiv) hydroxy-(C 3-6 alkenyl); (xxv) aryl-(C 1-6 alkyl) or hydroxy-substituted aryl-(C 1-6 alkyl); (xxvi) aryl-(C 3-6 alkenyl), aryl-(C 3-6 alkinyl), or hydroxy-substituted aryl-(C 3-6 alkenyl) or aryl-(C 3-6 alkinyl); (xxvii) arylthio; (xxviii) heteroarylthio; (xxix) aryl-(C 2-5 alkoxycarbonylamino)-(C 1-4 alkyl); (xxx) halogen; (xxxi) cyano; or (xxxii) a group of formula X--(CH 2 --CH 2 --O) n --CH 2 --CO--O--CH 2 -- wherein n is 1, 2 or 3 and X is amino whereby the multiple bond in groups under (xxiii), (xxiv) and (xxvi) may not be at the β-carbon atom of the completed residue I.

Claim 5

A cyclosporin according to claim 3, wherein R is: (1.a) methyl, ethyl, n-propyl, difluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl; (1.b) fluoromethyl; (ii) hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or 1-hydroxy-n-hexyl; (iv) aminomethyl, 2-aminoethyl, 3-amino-n-propyl, 4-amino-n-butyl or dimethylaminomethyl; (vi) 2-nitroethyl or cyanomethyl; (vii) methoxymethyl or methylthiomethyl; (viii) acetoxymethyl; (ix) diazoacetoxymethyl; (x) carboxymethyl, methoxycarbonylmethyl or t-butoxycarbonyl methyl; (xi) the group of formula ##STR23## (xv) methoxycarbonyl; (xvi) methylthio or 2-hydroxy-ethylthio; (xvii) 2-methoxy-ethylthio; (xviii) 2-acetoxy-ethylthio; (xxii) aminocarbonyl or methylaminocarbonyl; (xxiii.a) allyl, 2-chlorallyl, 3-chloroallyl, 4,4,4-trifluoro-2-butenyl or propargyl; (xxiii.b) 2-methylallyl or 3,3-dichloroallyl; (xxiv) 1-hydroxy-6-hexenyl; (xxv) benzyl, 2-phenethyl, α-hydroxybenzyl or p-hydroxybenzyl; (xxvii) phenylthio; (xxviii) 2-pyridylthio; (xxx.a) iodine; (xxx.b) fluorine; (xxxi) cyano; or (xxxii) a group of formula X--(CH 2 --CH 2 --O) n --CO--O--CH 2 -- wherein n is 2 and X is NH 2 -- or BOC--NH--.

Claim 6

A cyclosporin according to claim 3, wherein R has the meanings given under (i) through (iv) inclusive, (vi), (vii), (viii), (x), (xiv) through (xviii) inclusive, (xxii) through (xxv) inclusive, (xxvii) or (xxx).

Claim 7

A cyclosporin according to claim 4, wherein R has the meanings given under (1.a), (ii) through (xxii) inclusive, (xxiii.a), (xxiv) through (xxviii), inclusive, (xxx.a), (xxxi) and (xxxii).

Claim 8

A cyclosporin according to claim 4, wherein X is -MeBmt-, Y is -Val- and R is CH 3 --S--.

Claim 9

A cyclosporin according to claim 4, wherein X is -dihydro-MeBmt-, Y is -Val- and R is CH 3 --S--.

Claim 10

A cyclosporin according to claim 4, wherein X is -MeBmt-, Y is -αAbu- and R is F.

Claim 11

A cyclosporin according to claim 4, wherein X is -MeBmt-, Y is -αAbu- and R is F--CH 2 --.

Claim 12

A cyclosporin according to claim 4, wherein X is -MeBmt-, Y is -αBu- and R is selected from the group consisting of CH 3 --, CH 2 ═CH--CH 2 --, CH.tbd.C--CH 2 --, t.C 4 H 9 O--CO--CH 2 --, CH 3 --N(CH 3 )--CH 2 --, CH 3 --S--, 2-pyridylthio, phenylthio, CH 3 O--CO--, HO--CH 2 --, (L)α-hydroxybenzyl, CH 3 CO--O--CH 2 --, HOOC--CH 2 -- and CH 3 O--CO--CH 2 --; or X is -MeBMt-, Y is -Nva- and R is selected from the group consisting of CH 3 --, CH 2 ═CH--CH 2 --, CH 3 --S-- and CH 3 O--CO--; or X is -MeBmt-, Y is -Thr- and R is selected from the group consisting of CH 3 -- and CH 3 O--CO--; or X is -MeBmt-, Y is -Val- and R is selected from the group consisting of CH 3 --, CH 2 ═CH--CH 2 -- and CH 3 O--CO--; or X is --dihydro-MeBmt-, Y is -αABu- and R is CH 2 ═CH--CH 2 --.

Claim 13

A cyclosporin according to claim 4, wherein X is -MeBmt-, Y is -αAbu- and R is selected from the group consisting of C 2 H 5 --, benzyl, (CIS) Cl--CH═CH--CH 2 --, (TRANS) Cl--CH═CH--CH 2 --, Cl--C(Cl)═CH--CH 2 --, CH 2 ═CCl--CH 2 --, CH 2 ═C(CH 3 )--CH 2 --, --CN, CH 3 --CH(OH)--, CH 3 --NH--CO--, HO--(CH 2 ) 2 --S--, CH 3 CO--O--(CH 2 ) 2 --S--, NH 2 ═CH--CO--O--CH 2 -- and t.C 4 H 9 O--CO--NH--(CH 2 ) 2 --O--(CH 2 ) 2 --O--CH 2 --CO--O--CH 2 --; or X is -dihydro-MeBmt-, Y is -Val- and R is selected from the group consisting of CH 2 ═CH--CH 2 -- and nC 3 H 7 AA--.

Claim 14

A cyclosporin according to claim 1 having the formula II ##STR24## wherein Z is a group of formula I ##STR25## and X is -MeBmt-, Y is -αAbu- and R in formula I is selected from the group consisting of tetrahydropyranyl --O--CH 2 --CH 2 --S--, C 3 H 7 -- and ##STR26## X is -3'-Acetoxy-MeBmt-, Y is -αAbu- and R in formula I is selected from the group consisting of CH 3 CO--O--CH 2 --, HO--CH 2 -- and F--CH 2 --.

Claim 15

A pharmaceutical composition comprising a cyclosporin as claimed in claim 1, together with a pharmaceutically acceptable diluent or carrier therefor.

Claim 16

A pharmaceutical composition comprising a cyclosporin as claimed in claim 3, together with a pharmaceutically acceptable diluent or carrier therefor.

Claim 17

A method of inducing immunosuppression or of treating inflammatory conditions or of treating parasitic disease, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a cyclosporin as claimed in claim 1.

Claim 18

A method of inducing immunosuppression or of treating inflammatory conditions or of treating parasitic disease, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a cyclosporin as claimed in claim 3.