Furazanobenzimidazoles as prodrugs to treat neoplastic or autoimmune diseases

1. A compound of formula (II)

wherein

represents 1,4-phenylene or a group of formula

R 1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; and

R 2 is selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

2. A compound of formula (II) according to claim 1 which is not a salt.

3. A compound according to claim 1 wherein

represents 1,4-phenylene.

4. A compound of claim 1 wherein

R 1 represents hydrogen or cyano-lower alkyl.

5. The compound of claim 4 selected from the group consisting of the compounds of formulae

6. The compound of claim 4 wherein

R 1 is cyanoethyl.

7. The compound of claim 6 selected from the group consisting of the compounds of formulae

8. The compound of claim 2 having the formula

9. The compound of claim 1 which is a pharmaceutically acceptable salt of the compound of formula

10. A process for the preparation of a compound of formula (II) as claimed in claim 1 , comprising the steps that:

(1) a compound of formula (I-II)

wherein

R 1 and the group

are as in claim 1 ; or

a derivative of such a compound comprising functional groups in protected form,

or a salt thereof is acylated with an amino acid of formula (III)

wherein

R 10 is selected from hydrogen (Gly), methyl (Ala) and protected aminobutyl (amino-protected Lys) and

R 11 is an amino protecting group, and

(2) any protecting groups in a protected derivative of the resulting compound are removed to yield a compound of formula (II) or a salt thereof and, if so desired,

(3) the obtained compound of formula (II) is converted to a salt or the obtained salt of the compound of formula (II) is converted to the compound of formula (II).

11. A process for the manufacture of a compound of formula (II-G):

or a salt thereof,

comprising the steps:

(a) reacting a compound of formula

with an alpha-amino acid derivative of the formula:

in the presence of an activating agent and optionally in the presence of suitable bases, catalysts or co-reagents to yield the compound of formula:

(b) reacting the product of Step (a) with a bromination agent to yield the bromo compound of formula:

(c) reacting said bromo compound obtained in Step (b) with a compound of formula:

to yield the compound of formula:

(d) removing any protection groups being present from the group “protected Amino acid” to yield the compound of formula (II-G) and, optionally,

(e) converting said compound of formula (II-G) to a salt thereof,

in which formulae

R 1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl,

represents 1,4-phenylene or a group of formula

R 2-G is a group of formula

“Amino acid” represents a residue derived from a natural alpha-amino acid selected from glycine, alanine, and lysine by removing the carboxyl group from the alpha-carbon atom of said amino acid; and

“protected Amino acid” means the same amino acid as “Amino acid”, primary amino groups and if required also other functional groups of said amino acid however being protected by a protecting group.

12. A process according to claim 11 , wherein

“Amino acid” represents lysine.

13. A compound of claim 1 for use as a medicament.

14. A compound according to claim 1 for the treatment of a solid neoplastic disease.

15. A pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof as claimed in claim 1 and a pharmaceutically acceptable, inert carrier.

16. A pharmaceutical composition according to claim 15 , which is an aqueous solution.

17. A pharmaceutical composition according to claim 15 , which is soluble in an aqueous carrier.

18. A composition according to claim 15 which is a composition for parenteral administration.

19. The process of claim 10 wherein the salt is a hydrochloride salt.

20. The compound of claim 9 wherein the pharmaceutically acceptable salt is a hydrochloride salt.