Novel cyclosporins

Claim 2

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

Claim 3

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

Claim 4

A cyclosporin according to claim 2, wherein Z has the formula I wherein R is: i) C 1-6 alkyl or halo-substituted C l - 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 l - 6 alkyl); xi) aminocarbonyl-(C l-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) Ci- 6 alkylthio or hydroxy-(C l - 6 alkylthio); xvii) (C 1-6 alkoxy)-(C 1-6 alkylthio); xviii) (C 2-11 alkanoyloxy)-(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 aminoalkanoyl- oxy)-(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 -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 B-carbon atom of the completed residue I.

Claim 5

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 6

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

Claim 7

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

Claim 8

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

Claim 9

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

Claim 10

A pharmaceutical composition comprising a cyclosporin as claimed in anyone of claims 1 and 8, together with a pharmaceutically acceptable diluent or carrier therefor.

Claim 11

A cyclosporin according to any one of claims 1 to 8 for use as a pharmaceutical, e.g. for use as an immunosuppressant, anti-inflammatory agent or as an anti-parasitic agent.

Claim 12

A cyclosporin polyanion having a de-protonated sarcosyl residue at the 3-position.

Claim 13

A polyanion according to claim 11 of formula VII wherein Ra has the formula CH 3 -x-y-CH 2 -CH(CH 3 )-CH(R e )-(R) (R) in which -x-y- is -CH=CH-(trans) or -CH 2 -CH 2 -and R e is hydroxy in protected form or is E, R b is C 2 H5-, wherein R e has the meaning given above, i.C 3 H 7 - or nC 3 H 7 -, R C is i.C 4 H 9 -, R d is i.C 3 H 7 - and E is [-O Θ M ⊕ ] in which M ⊕ is an alkali metal ion.

Claim 14

CLAIMS FOR AUSTRIA

Claim 15

Process for the production of a cyclosporin having an optically active, a-N-methylated a-amino acid residue at the 3-position, for example a cyclosporin of formula II wherein X is -MeBmt- or -dihydro-MeBmt-, Y is -αAbu-, -Thr-, -Val- or -Nva-, and Z is a residue of formula I wherein R is: i) C 1-6 alkyl or halo-substituted G 1-6 alkyl; ii) hydroxy-(C 1-6 alkyl); iii) thio-(C l - 6 alkyl); iv) amino-(C l - 6 alkyl); v) (C 2 - 5 alkoxycarbonylamino)-(C l - 4 alkyl); vi) nitro-(C l - 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 l - 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 l - 6 alkylthio or hydroxy-(C l - 6 alkylthio); xvii) (C 1-6 alkoxy)-(C 1-6 alkylthio), xviii) (C 2-11 alkanoyloxy)-(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 aminoalkanoyl- oxy)-(C 2-4 alkylthio); xxi) aminocarbonyloxy-(C 2-4 alkylsulfinyl) or -(C 2 - 4 alkylsulfonyl), or (C 2-11 aminoalkanoyloxy)-(C 2-4 alkylsuifinyl) or -(C 2- 4alkylsulfonyl); 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 -0) n -CO-0-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, which process comprises: a) De-protecting a cyclosporin as defined above, said cyclosporin being in protected form; b) Reacting a polyanion of a cyclosporin having a de-protonated sarcosyl residue at the 3-position, for example a polyanion represented by the formula VII wherein R a has the formula CH 3 -x-y-CH 2 -CH(CH 3 )-CH(R e )-(R) (R) in which -x-y- is -CH=CH-(trans) or -CH 2 -CH 2 -and R e is hydroxy in protected form or is E, R b is C 2 H 5 -, wherein R e has the meaning given above, i.C 3 H 7 - or nC 3 H 7-, R C is i.C 4 H 9 -, R d is i.C 3 H 7 - and E is [-O Θ M ⊕ ] in which M ⊕ is an alkali metal ion in particular Li ⊕ , with an electrophile, so as to introduce a group R at the said de-protonated sarcosyl residue, e.g. b l ) reacting a polyanion as defined above with a compound of formula III wherein R 1 has the meanings given for R under i) through xiv) inclusive, xxiii) through xxvi) inclusive, xxix) and xxxi) above and Hal is halogen, to produce a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g., in relation to formula I, the residue Z) is a residue of formula I as illustrated above wherein R has the meanings given for R 1 above, or b 2 ) reacting a polyanion as defined above with a compound of formula IV wherein R 2 is C 1-6 alkyl, hydroxy-C l-6 alkyl, (C 1-6 alkoxy)-(C 1-6 alkyl), (C 2-11 alkanoyloxy)-(C 2-4 alkyl), aminocarbonyl- O xy-(C 2-4 alkyl), (C 2-11 aminoalkanoyloxy)-(C 2-4 alkyl), aryl or heteroaryl, to produce a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R has the meanings given under xvi), xvii), xviii), xx), xxvii) or xxviii) above, or b 3 ) reacting a polyanion as defined above with a compound of formula V wherein R 3 is C 1-5 alkyl, C 3 -salkenyl or aryl-C 1-5 alkyl, to produce a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) wherein R is a group of formula R 3- CH(OH)-, wherein R 3 has the meaning given above, or b 4 ) reacting a polyanion of a cyclosporin as defined above with carbon dioxide, to produce a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is carboxy, or b 5 ) reacting a polyanion as defined above with a compound of formula VI wherein R 5 is C 1-4 alkyl, to produce a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g.in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is a group of formula R 5- NH-CO-, or b 6 ) reacting a polyanion of a cyclosporin as defined above with a halogenating agent, for example a halogen gas or perchlorofluoride, to produce a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is halogen, for example fluorine, and, when required, carrying out process step a); c) Reducing a cyclosporin in which the residue at the 1-position is -MeBmt- and/or the residue at the 3-position is an optically active, a-N-methylated a-amino acid residue comprising an olefinic or acetylenic linkage, said residue having the (D)-configuration, for example a cyclosporin of formula II as illustrated above wherein X is -MeBmt-, Y has the meanings given for formula II and Z is a residue of formula I as defined above, or wherein X is -MeBmt- or -dihydro-MeBmt-, Y has the meanings given for formula II and Z is a residue of formula I as illustrated above wherein R has the meanings given under xxiii), xxiv) or xxvi) above, said cyclosporin being in unprotected or protected form, to-produce the corresponding cyclosporin in which the residue at the 1-position is -dihydro-MeBmt- and/or the aforesaid linkage of the residue at the 3-position is saturated, for example to produce a cyclosporin of formula II as illustrated above wherein X is -dihydro-MeBmt-, Y has the meanings given for formula II and Z is a residue of formula I as illustrated above, wherein R has the meanings given for formula I or is C 3 - 6 alkyl, halo-substituted C 3-6 alkyl, hydroxy-substituted C 3 - 6 alkyl, aryl-C 3 - 6 alkyl or hydroxy-substituted aryl-C 3 - 6 alkyl, and, when required, carrying out process step a); and d) Subjecting a cyclosporin in which the residue at the 3-position is an optically active, a-N-methylated a-amino acid residue, said residue having the (D)-configuration and said cyclosporin being in unprotected or protected form, to chemical modification so as to convert said residue into another optically active, a-N-methylated a-amino acid residue having the (D)-configuration, for example: d l ) reacting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is carboxy with a C 1-6 alkylating agent, to produce a corresponding cyclosporin wherein R has the meanings given under xv) above, d 2 ) oxidising a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R has the meaning given under xviii) or xx) above, to produce a corresponding cyclosporin, wherein R has the meanings given under xix) or xxi) above, d 3 ) subjecting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is (C 2-7 alkoxycarbonyl)-(C I _ 6 alkyl) to reductive cleavage, to produce a corresponding cyclosporin wherein R has the meaning given under ii) above, d 4 ) subjecting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g.in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is (C 1-6 alkoxy)-(C 1-6 alkyl) or (C 1-6 alkoxy)-(C 1-6 alkyithio) or hydroxy-(C l - 6 a1kyl) or hydroxy-(C 1-6 alkylthio) each in hydroxy protected form, to ether cleavage or other de-protective means, to produce a corresponding cyclosporin wherein R has the meanings given under ii) or xvi) above, d 5 ) hydrolysing a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is (C 2-7 alkoxycarbonyl)-(C l - 6 alkyl) or (C 2-5 alkoxycarbonylamino)-(C 1-4 alkyl) to produce a corresponding cyclosporin wherein R is carboxy-(C 1-6 - alkoxy) or amino-(Ci- 4 alkyl), d 6 ) esterifying a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is carboxy-(C 1-6 alkyl) or carboxy-(C 1-4 alkyl) so as to produce a corresponding cyclosporin wherein R is (C 2 - 7 alkoxycarbonyl)-(C l - 6 alkyl) or amino-(C 2- galkoxycarbonyl)-(Ci- 4 alkyl) in amino-protected form, d 7 ) reacting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is hydroxymethyl with a compound of formula VIII wherein R 7 is an amino protecting group, n is 1, 2 or 3 and Q is a leaving group, so as to produce a corresponding cyclosporin wherein R is a group of formula IX wherein R 7 and n have the meanings given above, d 8 ) reacting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is hydroxy-(C I - 6 alkyl) with a compound of formula X wherein R 8 is C I - 6 alkyl or diazo-(C l - 6 alkyl) and Q is a leaving group, to produce a corresponding cyclosporin wherein R has the meaning given under viii) or ix) above, d 9 ) reacting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is a residue of formula I as illustrated above, wherein R is hydroxy-(G 1-6 alkyithio) with a compound of formula XI wherein Rg is C 1-10 alkyl or amino-(C 1-10 alkyl) in which the amino moiety is in protected form, so as to produce a corresponding cyclosporin wherein R is (C 2-11 alkanoyloxy)-(C 2-4 - alkylthio) or (C 2-11 aminoalkanoyloxy)-(C 2-4 alkylthio), d 10 ) converting a cyclosporin (e.g. a cyclosporin of formula I as illustrated above wherein X and Y have the meanings given for formula I) wherein the residue at the 3-position (e.g. in relation to formula I, the residue Z) is -(D)MeSer- into the corresponding cyclosporin wherein the residue at the 3-position is a residue of formula I as illustrated above, wherein R is halomethyl, for example fluoromethyl, e.g. by reaction with (diethylamino)-sulfur-trichloride, and when required, carrying out process step a).

Claim 16

Process for the production of a cyclosporin polyanion having a de-protonated sarcosyl residue at the 3-position, for example a polyanion of a cyclosporin of formula II wherein X is -MeBmt- or -dihydro-MeBmt-Y is -aAbu-, -Thr-, -Val- or -Nva- and Z is -Sar-, in which the residue -Sar- as Z is de-protonated, e.g. for the production of a cyclosporin polyanion represented by formula VII wherein R a has the formula CH 3 -x-y-CH 2 -CH(CH 3 )-CH(R e )-(R) (R) in which -x-y- is -CH=CH-(trans) or -CH 2 -CH 2 -and R e is hydroxy in protected form or is E, R b is C 2 H 5 -, wherein R e has the meaning given above, i.C 3 H 7 - or nC 3 H 7 -, R C is i.C 4 Hg-, R d is i.C 3 H 7 - and E is [-⊖M⊕] in which M⊕is an alkali metal ion in particular Li⊕, which process comprises treating a cyclosporin, for example a cyclosporin of formula II as defined above, with a sufficient amount of an alkali metal amide, for example lithium diisopropylamide, to effect de-protonation of the sarcosyl residue in the 3-position, e.g. in relation to formula II, to effect de-protonation of the residue Z.

Claim 17

A cyclosporin polyanion having a de-protonated sarcosyl residue at the 3-position.

Claim 18

A polyanion according to claim 3 which is a polyanion of a cyclosporin having the formula II wherein X is -MeBmt- or -dihydro-MeBmt-, Y is -aAbu-, -Thr-, -Val- or -Nva- and Z is -Sar-.

Claim 19

A cyclosporin polyanion according to claim 3 which is a polyanion of formula VII as defined in claim 2.