Method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production

Claim 2

Process for the production of a cyclosporin of formula I, wherein A is a residue of formula Ia, ##STR7## 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-OH 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 process according to claim 1, in which the straight-chained endecapeptide, in free -N and carboxy-activated form is cyclized to produce the cyclosporin of formula (I).

Claim 4

A process according to claim 2, in which the carboxy-activated form is a carbonyl azide.

Claim 5

A process according to claim 3, in which the carbonyl azide is cyclized by the addition of a base at -20° to 0° C.

Claim 6

A process according to claim 4, in which the base is triethylamine or ethyldiisopropylamine.

Claim 7

A process according to claim 2, in which the carboxy-activated form is a Castro-ester.

Claim 8

A process according to claim 6, in which preparation of the Castro-ester and cyclisation of the ester are carried out concurrently in the presence of a base, at a temperature of from -20° to 30° C. in an inert solvent.

Claim 9

A process according to claim 7, in which the base is triethylamine or N-methylmorpholine and the solvent is chloroform or methylene chloride.

Claim 10

A process according to claim 1 for the production of a cyclosporin of formula (I), in which the residue A is an unprotected or O-protected C 9 -amino acid of formula (Ia) occupying position l and the remaining amino acid residues of the of the molecule are numbered from 1 clockwise and in sequence, comprising the steps of: 1. Preparation of a tetrapeptide having the sequence 4 through 7, commencing with 7 and proceeding by successive linkage of the residues 6, 5 and 4 to the N-terminal; 2. Preparation of a dipeptide having the unprotected or O-protected sequence 2-3 and linkage of this dipeptide to the N-terminal of the tetrapeptide obtained in step 1, to obtain a hexapeptide having the sequence 2 through 7; 3. Linkage of the C 9 -amino acid to the N-terminal of the hexapeptide obtained in step 2, to obtain a heptapeptide having the sequence 1 through 7; 4. Preparation of a tetrapeptide having the sequence 8 through 11 and linkage of this tetrapeptide to the N-terminal of the heptapeptide obtained in step 3 to obtain a linear endecapeptide having the sequence 8 through 7; 5. Cyclisation of the straight-chain endecapeptide obtained in step 4 in unprotected or O-protected form and, when required removing the O-protecting groups to obtain a cyclosporin wherein -X-Y- is -CH═CH-; and, when desired; 6. Hydrogenation of the cyclosporin obtained in step 5 to obtain the corresponding cyclosporin wherein -X-Y- is -CH 2 -CH 2 -.

Claim 11

A process according to claim 9, in which the cyclosporin obtained is cyclosporin A, B, C, D or G or a corresponding dihydro derivative thereof.

Claim 12

A process according to claim 9, in which the straight-chained endecapeptide, in free --N and carboxy-activated form is cyclized to produce the cyclosporin of formula (I).

Claim 13

A process according to claim 11, in which the carboxy-activated form is a carbonyl azide.

Claim 14

A process according to claim 12, in which the carbonyl azide is cyclized by the addition of a base at -20° to 0° C.

Claim 15

A process according to claim 13, in which the base is triethylamine or ethyldiisopropylamine.

Claim 16

A process according to claim 11, in which the carboxy-activated form is a Castro-ester.

Claim 17

A process according to claim 11, in which preparation of the Castro-ester and cyclisation of the ester are carried out concurrently in the presence of a base, at a temperature of from -20° to 30° C. in an inert solvent.

Claim 18

A process according to claim 16, in which the base is triethylamine or N-methylmorpholine and the solvent is chloroform or methylene chloride.