A method for the total synthesis of cyclosporins and novel cyclosporins

Claim 2

Process for the production of a cyclosporin of formula I, 5 wherein A is a residue of formula Ia, wherein R 1 is hydrogen or methyl and -x-y- is -CH 2 -CH 2 - or -CH=CH- and the positions 2, 3 and 4 have the configuration S,R and R or R,S and S respectively, and B is ethyl, 1-hydroxyethyl, isopropyl or n-propyl, which process comprises a) removing the O-protecting group(s) from a cyclosporin of formula I in O-protected form; b) cyclising a straight-chain endecapeptide having the sequence indicated in formula I, commencing with H-(D)-Ala- as N-terminal and terminating with -Ala-OII as C-terminal, in unprotected or O-protected form and, when required, carrying out process step (a); and, when desired, c) hydrogenating a cyclosporin of formula I thus obtained wherein -x-y-is -CH=CH- to obtain the corresponding cyclosporin wherein -x-y- is -CH 2 CH 2 -.

Claim 3

A cyclosporin of formula I as defined in claim 1 whenever prepared by a process as claimed in claim 1.

Claim 4

A cyclosporin of formula I as defined in claim 1 which is synthetic.

Claim 5

A cyclosporin according to claim 2 or 3 which is cyclosporin A.

Claim 6

A cyclosporin of formula I as illustrated in claim 1 wherein A is a residue of formula Ia as defined in claim 1, with the proviso that, when R 1 is methyl and -x-y- is -CH 2 -CH 2 - or trans -CH=CH- the positions 2,'3 and 4 have the configuration R,S and S respectively.

Claim 7

A synthetic [1S,2R,3R]- or [1R,2S,3S]-1-nitrilo- l-carbonyl-3-methyl-2-oxy-heptane or -hept-5-ene.

Claim 8

A synthetic [1S,2R,3R]- or [1R,2S,3S]-1-nitrilo- l-carbonyl-3-methyl-2-oxy-heptane or -hept-5-ene.

Claim 9

A [lS,2R,3R]- or [lR,2S,3S]-l-nitrilo-l-carboxy-3-methyl-2-oxy-heptane or -hept-5-ene in free or in carboxy-protected or -activated form.

Claim 10

A [lS,2R,3R]- or [lR,2S,3S]-l-nitrilo-l-carboxy-3-methyl-2-oxy-heptane or -hept-5-ene in free or in carboxy-protected or -activated form.

Claim 11

A [lS,2R,3R]- or [1R,2S,3S]-1-amino- or -1-methylamino-l-carbonyl-3-methyl-2-oxy-heptane or -hept-5-ene in free or in N-protected form.

Claim 12

A [lS,2R,3R]- or [1R,2S,3S]-1-amino- or -1-methylamino-l-carbonyl-3-methyl-2-oxy-heptane or -hept-5-ene in free or in N-protected form.

Claim 13

A compound of formula II, wherein R 1 is hydrogen or methyl, -x-y- is -CH 2 -CH 2 - or -CH=CH- and the positions 2, 3 and 4 have the configuration S,R and R or R,S and S respectively, in free form, or in protected and/or activated form.

Claim 14

A compound of formula II, wherein R 1 is hydrogen or methyl, -x-y- is -CH 2 -CH 2 - or -CH=CH- and the positions 2, 3 and 4 have the configuration S,R and R or R,S and S respectively, in free form, or in protected and/or activated form.

Claim 15

A compound according to claim 9, wherein R 1 and -x-y- have the meanings given in claim 9, with the proviso that, when R 1 is methyl and -x-y-is -CH 2 -CH 2 - or trans -CH=CH-, the positions 2, 3 and 4 have the configuration R,S and S respectively.

Claim 16

ll. A compound according to claim 9 or 10 in free form.

Claim 17

A compound according to claim 11 selected from the group consisting of: (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-methylamino- oct-6-enoic acid; (2R,3S,4S,6E)-3-hydroxy-4-methyl-2-methylamino- oct-6-enoic acid; (2S,3R,4R,6Z)-3-hydroxy-4-methyl-2-methylamino- oct-6-enoic acid; (2R,3S,4S,6Z)-3-hydroxy-4-methyl-2-methylamino- oct-6-enoic acid; (2S,3R,4R)-3-hydroxy-4-methyl-2-methylamino- octanoic acid; (2R,3S,4S)-3-hydroxy-4-methyl-2-methylamino- octanoic acid; (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-amino-oct-6-enoic acid; and (2R,3S,4S,6E)-3-hydroxy-4-methyl-2-amino-oct-6-enoic acid.

Claim 18

A compound according to claim 9 or 10 in free-or activated-carboxy and N-protected,or in carboxy-protected and free-N form.

Claim 19

A compound according to claim 9 of formula III, wherein -x-y- is -CH 2 -CH 2 - or -CH=CH-, R 1 is hydrogen or methyl, X 1 is hydroxy or a carboxy-protecting or -activating group, X 2 is hydrogen or an N-protecting group, and X 3 is hydrogen or an O-protecting group, or (X 2 + X 3 ) is a protecting group bridging the 2-N and 3-O functions or (X 2 + R 1 ) is a divalent N-protecting group, whereby at least one protecting group is present, and wherein the positions 2, 3 and 4 have the configuration S,R and R or R,S and S respectively.

Claim 20

A compound according to claim 14 wherein X 1 is hydroxy or a carboxy-activating group and the 2-N function is'in N-protected form, or X 1 is a carboxy-protecting group and the 2-N function is in free form.

Claim 21

A compound according to claim 15, selected from the group consisting of: (4R,5S)-4-(hex-2E-en-5R-yl)-1-methyl-2-oxo-oxazo- lin-5-carboxylic acid; (4S,5R)-4-(hex-2E-en-5S-yl)-l-methyl-2-oxo-oxazo- lin-5-carboxylic acid; (4R,5S)-4-(hex-2Z-en-5R-yl)-l-methyl-2-oxo-oxazo- lin-5-carboxylic acid; (4S,5R)-4-(hex-2Z-en-5S-yl)-1-methyl-2-oxo-oxazo- lin-5-carboxylic acid; (4R,5S)-4-(2R-hexyl)-l-methyl-2-oxo-oxazolin-5-carboxylic acid; (4S,5R)-4-(2S-hexyl)-l-methyl-2-oxo-oxazolin-5-carboxylic acid; (4R, 5S) -4- (hex-2E-en-5R-yl) -2-oxo-oxazolin-5-carboxylic acid; (4S,5R)-4-(hex-2E-en-5S-yl)-2-oxo-oxazolin-5-carboxylic acid; (4R,5S)-4-(hex-2E-en-5R-yl)-1,2-trimethyl-oxazolin-5-carboxylic acid; (4S,5R)-4-(hex-2E-en-5S-yl)-1,2-trimethyl-oxazolin-5-carboxylic acid; (2S,3R,4R,6E)-2-(N-t.-butyloxy-carbonyl)-methyl- amino-3-hydroxy-4-methyl-oct-6-enoic acid; (2R,3S,4S,6E)-2-(N-t.-butyloxy-carbonyl)-methyl- amino-3-hydroxy-4-methyl-oct-6-enoic acid; (2S, 3R, 4R, 6E) -2- (N-t.-butyloxy-carbonyl) -amino-3-hydroxy-4-methyl-oct-6-enoic acid; and (2R, 3S, 4S, 6E) -2- (N-t-butyloxy-carbonyl) -amino-3-hydroxy-4-methyl-oct-6-enoic acid

Claim 22

A [lS,2R,3R]- or [1R,2S,3S]-1-nitrilo-1-carbonyl-3-methyl-2-oxy-heptane or -hept-5-ene obtained from a compound according to claim 9.

Claim 23

A peptide in free or protected form, said peptide comprising a [lS,2R,3R]- or [lR,2S,3S]-1-nitrilo- l-carbonyl-3-methyl-2-oxy-heptane or hept-5-ene residue and containing at least one synthetically formed peptide linkage.

Claim 24

A peptide in free or protected form, said peptide comprising a [lS,2R,3R]- or [lR,2S,3S]-1-nitrilo- l-carbonyl-3-methyl-2-oxy-heptane or hept-5-ene residue and containing at least one synthetically formed peptide linkage.

Claim 25

A linear peptide comprising a [lS,2R,3R]- or [lR,2S,3S]-l-nitrilo-l-carbonyl-3-methyl-2-oxy- heptane or -hept-5-ene residue said peptide being in free or protected and in substantially pure form.

Claim 26

A linear peptide comprising a [lS,2R,3R]- or [lR,2S,3S]-l-nitrilo-l-carbonyl-3-methyl-2-oxy- heptane or -hept-5-ene residue said peptide being in free or protected and in substantially pure form.

Claim 27

A peptide in free or protected form according to claim 18 or 19 comprising a residue of formula Ia as defined in claim 1.

Claim 28

A compound according to claim 7, wherein a free valency of the nitrilo radical is satisfied by a peptide linkage.

Claim 29

A compound according to claim 8, wherein the free valency of the carbonyl function is satisfied by a peptide linkage.

Claim 30

A compound according to any one of claims 7, 8 and 17 to 22 in free form.

Claim 31

Process for the production of a compound of formula II as defined in claim 9 in free form,or in protected and/or activated form, which process comprises: i) for the production of a compound of formula II in free form, removing protecting groups from a compound of formula II in protected form; or ii) for the production of a compound of formula II in protected and/or activated form; a) introducing one or more protecting and/or activating groups into a compound of formula II in free form; b) selectively removing at least one protecting group from a compound of formula II in protected and, optionally, activated form and containing at least two protecting groups, so as to leave at least one protecting group remaining; or c) selectively hydrolysing and isomerising a compound of formula (IV), wherein R 1 and -x-y- have the meanings given in claim 9, (X 2 + X 3 ) represents a protecting group bridging the N and O functions and completing a 6- or, preferably, 5-membered ring, and the positions 2 and 3 have the configuration R and R, or S and S respectively, in an aqueous alkaline medium or in the presence of an alcoholic alkali metal- or alkaline-earth metal-alcoholate, to produce a compound of formula III as illustrated in claim 14, wherein R 1 is hydrogen or methyl, -x-y- is -CH 2 -CH 2 - or -CH=CH-, X 1 is hydroxy or C 1-4 alkoxy, (X 2 + X 3 ) represents a protecting group as defined above, bridging the 2-N and 3-O functions, and the positions 2, 3 and 4 have the configuration R,S and S or S,R and R respectively, and, when required selectively hydrolysing a compound thus obtained wherein X 1 is C 1-4 alkoxy to produce the corresponding compound wherein X l is hydroxy.

Claim 32

A compound of formula wherein -x-y- is -CH 2 -CH 2 - or -CH=CH- and either i) R 6 is a group of formula -CH 2 OH or -CHO and X 3 is hydrogen or an 0-protecting group; or ii) R 6 is a group of formula R 1 is hydrogen or methyl, X 2 is hydrogen and X 3 is hydrogen or an O-protecting group or (X 2 + X 3 ) represents a protecting group bridging the 1-N and 2-O functions and completing a 6- or preferably 5-membered ring, in particular a carbonyl, thiocarbonyl or isopropylidene group; and the positions 1 and 2 have the configuration R and R, or S and S respectively: or of formula wherein R 3 is methyl or ethyl and R 7 is a group of formula -CH 2 OH; -CH 3 OSO 2 R 4 wherein R4 is tolyl; -CH 2 CN; -CH 2 CHO; -CH 2 -CH 2 -CH 2 -CH 3 or CH 2 -CH=CH-CH 3 ; and the positions A and B have the configuration R and R, or S and S respectively: or of formula wherein X' and X" represent O-protecting groups selected from C l-4 alkyl and C 7-10 aralkyl, or X' and X" are each hydrogen, and the positions 2 and 3 have the configuration R and R, or S and S respectively: or of formula wherein X' and X" represent O-protecting groups selected from C 1-4 alkyl and C 7-10 aralkyl and either (i) R 8 and R 9 together represent a direct bond and the positions 2 and 3 have the configuration S and S, or R and R respectively, or (ii) R 8 is halogen, R 9 is phenylcarbonyl and the positions 2 and 3 have the configuration R and S, or S and R respectively.

Claim 33

A compound of formula wherein -x-y- is -CH 2 -CH 2 - or -CH=CH- and either i) R 6 is a group of formula -CH 2 OH or -CHO and X 3 is hydrogen or an 0-protecting group; or ii) R 6 is a group of formula R 1 is hydrogen or methyl, X 2 is hydrogen and X 3 is hydrogen or an O-protecting group or (X 2 + X 3 ) represents a protecting group bridging the 1-N and 2-O functions and completing a 6- or preferably 5-membered ring, in particular a carbonyl, thiocarbonyl or isopropylidene group; and the positions 1 and 2 have the configuration R and R, or S and S respectively: or of formula wherein R 3 is methyl or ethyl and R 7 is a group of formula -CH 2 OH; -CH 3 OSO 2 R 4 wherein R4 is tolyl; -CH 2 CN; -CH 2 CHO; -CH 2 -CH 2 -CH 2 -CH 3 or CH 2 -CH=CH-CH 3 ; and the positions A and B have the configuration R and R, or S and S respectively: or of formula wherein X' and X" represent O-protecting groups selected from C l-4 alkyl and C 7-10 aralkyl, or X' and X" are each hydrogen, and the positions 2 and 3 have the configuration R and R, or S and S respectively: or of formula wherein X' and X" represent O-protecting groups selected from C 1-4 alkyl and C 7-10 aralkyl and either (i) R 8 and R 9 together represent a direct bond and the positions 2 and 3 have the configuration S and S, or R and R respectively, or (ii) R 8 is halogen, R 9 is phenylcarbonyl and the positions 2 and 3 have the configuration R and S, or S and R respectively.