Cyclosporins and their use as pharmaceuticals

Claim 2

A cyclosporin (i) of formula II wherein A is -3′-O-acetyl-MeBmt- B is -αAbu-, -Thr-, -Val- or Nva-; and when B is -αAbu-, X is -(D)Ala- and Y is -Val-; when B is -Thr- or -Val-, X is -Sar- and Y is -Val-; or when B is -Nva-, X is -Sar- and Y is -Val-, or X is -(D)Ala- and Y is -Val-; or wherein A is -3′-O-acetyl-dihydro-MeBmt- or -cis-MeBmt-, B is -αAbu-, X is -Sar- and Y is -Val-: or ii) of formula II′ wherein A is -3′-O-acyl-MeBmt- or -3′-O-acyl-dihydro-MeBmt- residue, B is -αAbu-, -Thr-, -Val-, -Nva-, or the residue of a β-O-acyl-α-amino acid, X is -Sar- or the residue of an optically active α-N-methylated α-amino acid residue having the (D)-configuration, Y is -Val- or additionally, when B is -Nva-, -Nva-, and W is the residue of a β-hydroxy- or β-O-acyl-α-amino acid having the (D)-configuration; or iii) wherein the residue at the position 1-position is an -8′-C₁₋₈alkoxy­-cis-MeBmt- or -dihydro-MeBmt- or -3′-O-acyl-8′-C₁₋₈alkoxy­-cis-MeBmt- or -dihydro-MeBmt- residue; a -3′-O-acyl-cis-MeBmt- residue; a -7′-desmethyl-7′-hydrocarbyl- -MeBmt- or -cis-MeBmt- or -3′-O-acyl-7′-desmethyl-7′-hydrocarbyl- -MeBmt- or -cis-MeBmt- residue wherein the hydrocarbyl moiety comprises at least two carbon atoms; or a -7′-desmethyl-7′-hydrocarbyl-dihydro-MeBmt- or -3′-O-acetyl-7′-desmethyl-7′-hydrocarbyl-dihydro-MeBmt- residue wherein the hydrocarbyl moiety comprises at least two carbon atoms and wherein any aliphatic group or moiety as or comprising said hydrocarbyl moiety is saturated; or (iv) wherein the 3′-carbon atom of the residue at the 1-position is oxo, C₁₋₄alkoxyimino, azidoalkylcarbonyloxy or alkoxycarbonyloxy substituted, or wherein the β-carbon atom of the residue at the 2-position is β-oxo substituted or is an (L)-isoleucyl residue; or (v) of formula XI wherein A is -N-desmethyl-dihydro-MeBmt, B is -Thr- and Z is -MeVal-, or A is -dihydro-MeBmt-, B is -Thr- and Z is -Val-, or A is -MeLeu-, B is -αAbu- and Z is -Val-; or which is (vi) a dicarboxylic acid di-ester of a cyclosporin having a β-hydroxy-(L)-α-amino acid residue at the 2-position.

Claim 3

A cyclosporin according to claim 1 wherein the residue at the 1-position is a residue of formula XXI wherein R a is -x′-y′-R c in which -x′-y′- is cis -CH=CH- or -CH₂-CH₂ and R c is C₂₋₉ alkoxymethyl or -x′-y′ is cis or trans -CH=CH- or CH₂-CH₂- and R c is hydrocarbyl having at least two carbon atoms, whereby, when -x′-y′ is -CH₂-CH₂- any aliphatic group or moiety as or comprising R c is saturated, and R b is hydrogen or acyl.

Claim 4

A cyclosporin according to claim 1 wherein the residue at the 1-position is -3′-desoxy-3′-oxo-MeBmt-, a -3′-desoxy-3′-(C₁₋₄ alkoxyimino)-MeBmt- residue, a -3′-O-(C₁₋₄ azidoalkyl)-carbonyl-­-MeBmt- or -dihydro-MeBmt- residue or a -3′-O-(C₁₋₄alkoxy)-­carbonyl- -MeBmt- or -dihydro-MeBmt- residue, or wherein the residue at the 2-position is -α-methylketo-Gly- or -Ile-.

Claim 5

A cyclosporin according to claim 1 selected from the group consisting of: 1.2 [3′-O-acetyl-MeBmt]¹-[Val]²-Ciclosporin; 1.3 [3′-O-acetyl-MeBmt]¹-[Thr]²-Ciclosporin; 1.5 [3′-O-acetyl-MeBmt]¹-[Nva]²-[Nva]⁵-Ciclosporin; 1.6 [3′-O-acetyl-MeBmt]¹-[(D)Ala]³-Ciclosporin; 1.7 [3′-O-acetyl-MeBmt]¹-[Nva]²-[(D)Ala]³-Ciclosporin; 1.10 [3′-O-acetyl-dihydro-MeBmt]¹-Ciclosporin; 1.11 [3′-O-methoxycarbonyl-MeBmt]¹-Ciclosporin; 1.12 [3′-O-(4-azidobutanoyl)-MeBmt]¹-Ciclosporin; 1.15 [3′-O-acetyl-MeBmt]¹-[O-acetyl-(D)Ser]⁸-Ciclosporin; 1.16 [3′-O-acetyl-8′-methoxy-cis-MeBmt]¹-Ciclosporin; 1.17 [3′-O-acetyl-8′-t.butoxy-cis-MeBmt]¹-Ciclosporin; 1.18 [3′-O-acetyl-8′-methoxy-cis-MeBmt]¹-[O-acetyl-Thr]²-Ciclosporin; 1.19 [3′-O-acetyl-8′-t.butoxy-cis-MeBmt]¹-[O-acetyl-Thr]²-Ciclosporin; 1.20 [3′-O-acetyl-8′-methoxy-cis-MeBmt]¹-[Val]²-Ciclosporin; 1.21 [3′-O-acetyl-8′-methoxy-cis-MeBmt]¹-[Nva]²-Ciclosporin; 1.22 [3′-O-acetyl-7′-desmethyl-7′-phenyl-MeBmt]¹-Ciclosporin; 1.23 [3′-O-acetyl-cis-MeBmt]¹-Ciclosporin; 1.24 [3′-O-acetyl-7′-desmethyl-7′-vinyl-cis-MeBmt]¹-Ciclosporin; 1.25 [3′-O-acetyl-7′-desmethyl-7′-vinyl-cis-MeBmt]¹-[O-acetyl-Thr]²-­Ciclosporin; 1.26 [3′-O-acetyl-7′-desmethyl-7′-i.pentyl-cis-MeBmt]¹-Ciclosporin; 1.27 [3′-O-acetyl-7′-desmethyl-7′-phenyl-cis-MeBmt]¹-Ciclosporin; 1.28 [3′-O-acetyl-7′-desmethyl-7′-n.propyl-cis-MeBmt]¹-Ciclosporin; 1.29 [3′-O-acetyl-7′-desmethyl-7′-(β-allyl)-cis-MeBmt]¹-Ciclosporin; 1.30 [3′-O-acetyl-7′-desmethyl-7′-phenyl-MeBmt]¹-[Val]²-Ciclosporin; 1.31 [3′-O-acetyl-7′-desmethyl-7′-phenyl-cis-MeBmt]¹-[Val]²-Ciclosporin; 1.32 [3′-O-acetyl-7′-desmethyl-7′-vinyl-cis-MeBmt]¹-[Val]²-Ciclosporin; 1.33 [3′-O-acetyl-7′-desmethyl-7′-vinyl-cis-MeBmt]¹-[Nva]²-Ciclosporin; 1.34 [3′-O-acetyl-7′-desmethyl-7′-(3-bromo-n.propyl)-cis-MeBmt]¹-­Ciclosporin; 1.36 1,2-ethanedicarboxylic acid-[O-threonyl]²-Ciclosporin di-ester; 1.37 [3′-desoxy-3′-oxo-MeBmt]¹-Ciclosporin; 1.38 [3′-desoxy-3′-oxo-MeBmt]¹-[Val]²Ciclosporin; 1.39 [3′-desoxy-3′-oxo-MeBmt]¹-[Nva]²Ciclosporin; 1.40 [α-methylketo-Gly]²-Ciclosporin; 1.41 [dihydro-MeBmt]¹-[α-methylketo-Gly]²-Ciclosporin; 2.1 [3′-desoxy-3′-methoxyimino-MeBmt]¹-Ciclosporin; 2.2 [Ile]²-Ciclosporin; 3.6 [N-desmethyl-dihydro-MeBmt]¹-[Thr]²-Ciclosporin; 3.8 [dihydro-MeBmt]¹-[Thr]²-[Val]¹¹-Ciclosporin; 3.10 [MeLeu]¹-Ciclosporin; 4.1 [8′-methoxy-cis-MeBmt]¹-Ciclosporin; 4.2 [8′-t.butoxy-cis-MeBmt]¹-Ciclosporin; 4.3 [8′-methoxy-cis-MeBmt]¹-[Thr]²-Ciclosporin; 4.4 [8′-t.butoxy-cis-MeBmt]¹-[Thr]²-Ciclosporin; 4.5 [8′-methoxy-cis-MeBmt]¹-[Val]²-Ciclosporin; 4.6 [8′-methoxy-cis-MeBmt]¹-[Nva]²-Ciclosporin; 4.7 [8′-methoxy-dihydro-MeBmt]¹-Ciclosporin; 4.8 [8′-methoxy-dihydro-MeBmt]¹-[Thr]²-Ciclosporin; 4.9 [8′-methoxy-dihydro-MeBmt]¹-[Val]²-Ciclosporin; 4.10 [8′-methoxy-dihydro-MeBmt]¹-[Nva]²-Ciclosporin; 6.1 [7′-desmethyl-7′-phenyl-MeBmt]¹-Ciclosporin; 6.2 [7′-desmethyl-7′-phenyl-cis-MeBmt]¹-Ciclosporin; 6.3 [7′-desmethyl-7′-vinyl-cis-MeBmt]¹-Ciclosporin; 6.4 [7′-desmethyl-7′-vinyl-cis-MeBmt]¹-[Thr]²-Ciclosporin; 6.5 [7′-desmethyl-7′-(3-methyl-n.butyl-cis-MeBmt]¹-Ciclosporin; 6.6 [7′-desmethyl-7′-n.propyl-cis-MeBmt]¹-Ciclosporin; 6.7 [7′-desmethyl-7′-(β-allyl)-cis-MeBmt]¹-Ciclosporin; 6.8 [7′-desmethyl-7′-phenyl-MeBmt]¹-[Val]²-Ciclosporin; 6.9 [7′-desmethyl-7′-phenyl-cis-MeBmt]¹-[Val]²-Ciclosporin; 6.10 [7′-desmethyl-7′-vinyl-cis-MeBmt]¹-[Val]²-Ciclosporin; 6.11 [7′-desmethyl-7′-vinyl-cis-MeBmt]¹-[Nva]²-Ciclosporin; 6.12 [7′-desmethyl-7′-(3-bromo-n.propyl-cis-MeBmt]¹-Ciclosporin; 6.13 [7′-desmethyl-7′-phenyl-dihydro-MeBmt]¹-Ciclosporin; 6.14 [7′-desmethyl-7′-n.propyl-dihydro-MeBmt]¹-Ciclosporin; 6.15 [7′-desmethyl-7′-ethyl-dihydro-MeBmt]¹-[Thr]²-Ciclosporin; 6.16 [7′-desmethyl-7′-(3-methyl-n.butyl)-dihydro-MeBmt]¹-Ciclosporin; 6.17 [7′-desmethyl-7′-i.propyl-dihydro-MeBmt]¹-Ciclosporin; 6.18 [7′-desmethyl-7′-ethyl-dihydro-MeBmt]¹-[Val]²-Ciclosporin; 6.19 [7′-desmethyl-7′-ethyl-dihydro-MeBmt]¹-[Nva]²-Ciclosporin; 6.20 [7′-desmethyl-7′-phenyl-dihydro-MeBmt]¹-[Val]²-Ciclosporin; 6.18 [7′-desmethyl-7′-ethyl-dihydro-MeBmt]¹-Ciclosporin; and [cis-MeBmt]¹-Ciclosporin.

Claim 6

A pharmaceutical composition comprising a cyclosporin as claimed in any one of claims 1 to 4, together with a pharmaceutically acceptable diluent or carrier therefore.

Claim 7

A cyclosporin as claimed in any one of claims 1 to 4 for use as a pharmaceutical.

Claim 8

A cyclosporin (i) wherein the 3′-carbon atom of the residue at the 1-position or the β-carbon atom of the residue at the 2-position is O-acyl or oxo substituted, or (ii) wherein the 3′-carbon atom of the residue at the 1-position is C₁₋₄­alkoxyimino substituted, wherein the residue at the 2-position is an (L)-isoleucyl residue, or the residue at the 11-position is an N-methyl-(L)-alanyl, N-methyl-(L)-isoleucyl or N-methyl-(L)-alloisoleucyl residue; or (iii) of formula XI as illustrated in claim 1 wherein: Z is -Val- or -MeVal-: when Z is -Val-, A is -MeBmt- or -dihydro-MeBmt-; or when Z is -MeVal- A is -3′-desoxy-MeBmt-, -3′-desoxy-dihydro-MeBmt-, -N-desmethyl-MeBmt-, -N-desmethyl-dihydro-MeBmt, -3′-desoxy-4′-desmethyl-dihydro-MeBmt- or -MeLeu-: and when Z is -Val-, B is -αAbu- or -Thr-; when Z is -MeVal- and A is -3′-desoxy-MeBmt-, -3′-desoxy-dihydro-MeBmt-, -3′-desoxy-­-4′-desmethyl-dihydro-MeBmt- or -MeLeu-, B is -αAbu-; or when Z is -MeVal- and A is -N-desmethyl-MeBmt- or -N-desmethyl-dihydro-MeBmt-, B is -Thr-; for use as a pharmaceutical, especially for use in improving or increasing the efficacy of, or increasing sensitivity to, other chemotherapeutic drug therapy, or for use in reducing effective chemotherapeutic dosage rate for a second chemotherapeutic drug substance, or for use as an adjuvant in treating morbid conditions characterised by resistance to a second chemotherapeutic drug substance, or for use in enhancing or improving chemotherapeutic treatment of morbid conditions exhibiting or characterised by resistance to said treatment, or for use in reversing or reducing resistance to chemotherapeutic treatment, or for use in restoring sensitivity to chemotherapeutic treatment, or for use as an adjuvant to other chemotherapeutic drug therapy.

Claim 9

A cyclosporin according to claim 7 which is a cyclosporin as defined under any one of (i), (ii), (iv), (v) or (vi) of claim 1 or a cyclosporin as defined under (iii) of claim 1 wherein the residue at the 1-position is a 3′-O-acyl substituted.

Claim 10

A cyclosporin according to claim 7 selected from the group consisting of: 1.1 [3′-O-acetyl-MeBmt]¹-Ciclosporin; 1.4 [3′-O-acetyl-MeBmt]¹-[Nva]²-Ciclosporin; 1.8 [3′-O-acetyl-MeBmt]¹-[(D)MeVal]¹¹-Ciclosporin; 1.9 [3′-O-acetyl-MeBmt]¹-[Val]¹¹-Ciclosporin; 1.13 [3′-O-acetyl-MeBmt]¹-[O-acetyl-Thr]²-Ciclosporin; 1.14 [3′-O-acetyl-N-desmethyl-MeBmt]¹-[O-acetyl-Thr]²-Ciclosporin; 1.35 [O-acetyl-Thr]²-Ciclosporin; 2.3 [MeAla]¹¹-Ciclosporin; 2.4 [MeIle]¹¹-Ciclosporin; 2.5 [MealloIle]¹¹-Ciclosporin; 2.6 [MeLeu]¹¹-Ciclosporin; 3.1 [Val]¹¹-Ciclosporin; 3.2 [dihydro-MeBmt]¹-[Val]¹¹-Ciclosporin; 3.3 [3′-desoxy-MeBmt]¹-Ciclosporin; 3.4 [3′-desoxy-dihydro-MeBmt]¹-Ciclosporin; 3.5 [N-desmethyl-MeBmt]¹-[Thr]²-Ciclosporin; 3.7 [Thr]²-[Val]¹¹-Ciclosporin; 3.9 [3′-desoxy-4′-desmethyl-dihydro-MeBmt]¹-Ciclosporin; and individual cyclosporins 1.2 through 1.41, 2.1 and 2.2, and 3.6 through 3.10 of claim 4.

Claim 11

A pharmaceutical composition comprising a cyclosporin of structure as defined in any one of claims 7 to 9, together with a pharmaceutically acceptable diluent or carrier therefor.

Claim 12

A cyclosporin according to claim 1, wherein the residue at the 1-position is -cis-MeBmt-; a -8′-C₁₋₈alkoxy-cis-MeBmt- or -dihydro-MeBmt- residue; a -7′-desmethyl-7′-hydrocarbyl-MeBmt- or -cis-MeBmt- residue wherein the hydrocarbyl moiety comprises at least two carbon atoms; a -7′-desmethyl-7′-hydrocarbyl-dihydro-MeBmt-­residue wherein the hydrocarbyl moiety comprises at least two carbon atoms and wherein any aliphatic group or moiety as or comprising said hydrocarbyl moiety is saturated; for use as an immunosuppressant, for use as an anti-inflammatory agent for use as an anti-parasitic agent.

Claim 13

A cyclosporin according to claim 11 selected from the group consisting of cyclosporins 4.1 through 4.10 and 6.1 through 6.21 of claim 4 and [cis-MeBmt]¹-Ciclosporin.

Claim 14

A cyclosporin wherein the residue at the 1-position is -5′-des-­(1-propenyl)-5′-formyl-MeBmt- in free or 3′-O-protected form.

Claim 15

A cyclosporin wherein the residue at the 1-position is -5′-des-­(1-propenyl)-5′-formyl-MeBmt- in free or 3′-O-protected form.

Claim 16

A cyclosporin according to claim 13 selected from the group consisting of: 5.1 [3′-O-acetyl-5′-des-(1-propenyl)-5′-formyl-MeBmt]¹-Ciclosporin; 5.2 [3′-O-acetyl-5′-des-(1-propenyl)-5′-formyl-MeBmt]¹-[O-acetyl-­Thr]²-Ciclosporin; 5.3 [3′-O-acetyl-5′-des-(1-propenyl)-5′-formyl-MeBmt]¹-[Val]²-­Ciclosporin; and 5.4 [3′-O-acetyl-5′-des-(1-propenyl)-5′-formyl-MeBmt]¹-[Nva]²-­Ciclosporin;