Macrolides and their use

1. Macrolide compound of formula I:

wherein

R1 is a residue -Y-X-Q;

Y is S, SO or SO 2 ;

X is a bond or a linear group consisting of hydrogen atoms and 1 to 9 atoms selected from C, N, O and S, of which up to 2 atoms can be N and one atom can be O or S, one carbon atom can appear as a CO group and the sulphur atom can appear as an SO 2 group and two adjacent C atoms can be present as —CH═CH— or —C≡C— and which group X is unsubstituted or is substituted with —COO—W or —CONH—W;

Q is a residue —V-A1-L-A2-W or, if X does not represent a bond, may also be —NR10R11

V is an optionally substituted divalent aromatic or heterocyclic group;

W is optionally substituted aryl or heterocyclyl;

A1 and A2 are, independently of each other, either absent or a C 1 -C 4 alkylene group;

L is —O—, —S—, —SO 2 —, —NH—, —CO—, —(CO)O—, —O(OC)—, —(CO)NH—, —NH(CO)—, —(SO 2 )NH—, —HN(SO 2 )—, —HN(CO)NH—, —O(CO)NH—, —NH(CO)O—, or can also be absent if A1 and/or A2 are present;

R2 is OR2a or

wherein

 represents the bond between said group and the carbon atom of said macrolide compound to which it is linked;

R2a is hydrogen, acetyl, —(C═O)CH 2 NR2bR2c, or —(C═O)CH 2 CH 2 NR2bR2c;

R2b and R2c independently of each other, are hydrogen or C1-C6 alkyl which can be substituted or unsubstituted and wherein up to two atoms can be N, O or S and one carbon atom can appear as C═O or, taken together with the nitrogen atom to which they are linked, form a 4-7 membered-ring of which up to two atoms can be N, O or S and one carbon can appear as C═O;

R3 is hydrogen or

R2 and R3 taken together with the carbon atom to which they are linked, represent a C═O group;

R4 is hydrogen or

R2 and R4 taken together with the bond between the carbon atoms to which they are linked, represent a double bond between said carbon atoms;

Z is

wherein

 represents the bond between said group and the carbon atom of said macrolide compound to which it is linked;

R5 is hydrogen or —OR5a or —NR5bR5c;

R6 is hydrogen or —OR6a or —NR6bR6c; or

R5 and R6 taken together with the carbon atom to which they are linked, represent a C═O group;

R7 is hydrogen or —OR7a or —NR7bR7c;

R8 is hydrogen or —OR8a or —NR8bR8c; or

R7 and R8 taken together with the carbon atom to which they are linked, represent a C═O group; or one of

R5 and R6 taken together with one of

R7 and R8 represent a group of formula —NR56(CO)O— or —O(CO)NR78—

R9 is hydrogen or

R8 and R9 taken together with the bond between the carbon atoms to which they are linked, represent a double bond between said carbon atoms;

R5a,

R7a and R8a, independently of each other, are hydrogen or C1-C6 alkyl which can be substituted or unsubstituted and wherein one or more single bonds can be replaced by double and/or triple bonds and where one carbon atom can appear as C═O and up to two atoms can be N, O or S;

R6a is hydrogen or C1-C6 alkyl;

R56 and R78 are hydrogen or C1-C6 alkyl;

R5b, R5c,

R6b, R6c,

R7b, R7c,

R8b and R8c independently of one another, are hydrogen, C1-C6alkyl which can be substituted or unsubstituted and up to two atoms can be N, O or S and where one carbon atom can appear as C═O, or —(C═O)heterocyclyl or, taken together with the nitrogen atom to which they are linked, form a 4-7 membered-ring of which up to two atoms can be N, O or S and one carbon can appear as C═O;

R10 and R11 are independently selected from optionally substituted groups selected from aryl; aralkyl; heterocyclyl and heterocyclylalkyl; groups, and one of R10 and R11 can also be a group -L-A2-W; and

* indicates a chiral centre which is in the (R) or (S) form;

provided that

Z is not a group of formula

wherein

 represents the bond between said group and the carbon atom of said macrolide compound to which it is linked,

or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof.

2. A compound or an acid addition salt, a N-oxide thereof or an in vivo cleavable ester thereof according to claim 1 , wherein one of

R5 and R6 and/or of R7 and R8 is hydrogen and the other is not hydrogen.

3. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R6a is hydrogen.

4. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R5 is —NR5bR5c or

R7 is —NR7bR7c.

5. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R6 is —OR6a or

R8 is —OR8a.

6. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R8 and R9 taken together with the bond between the carbon atoms to which they are linked, form a double bond.

7. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof compound according to claim 1 , wherein

R9 is hydrogen.

8. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof compound according to claim 1 , wherein R5a, R7a and R8a, independently of each other are hydrogen, C1-C6 alkyl or vinyl.

9. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof compound according to claim 1 , wherein R5a, R7a, R8a, R56 and R78, R5b, R5c, R6b, R6c, R7b, R7c, R8b and R8c, independently of each other, are hydrogen or C1-C6 alkyl.

10. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R2 is

wherein

 represents the bond between said group and the carbon atom of said macrolide compound to which it is linked.

11. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R2a is hydrogen.

12. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein R2 and R3 taken together with the carbon atom to which they are linked, represent a C═O group.

13. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

R2 and R4 taken together with the bond between the carbon atoms to which they are linked, form a double bond.

14. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

Y is SO 2 or S.

15. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

Q is a residue —V-A1-L-A2-W.

16. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

V is a divalent group of formula

wherein

is a phenylene ring or a x-member saturated or unsaturated divalent heterocycloaliphatic or heteroaromatic ring containing from 2 to (x−1) carbon atoms with x being 5 or 6, and from 1 to 4 hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen, R12 and R13 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyloxy, C 3 -C 7 cycloalkyl-C 1 -C 4 alkoxy, halogen, halogen-substituted C 1 -C 4 alkyl groups, halogen-substituted C 1 -C 4 alkoxy groups, cyano, nitro, amino, C 1 -C 4 alkylamino, di(C 1 -C 4 )alkylamino, C 1 -C 4 alkylthio, mercapto, hydroxy, carbamoyl, a carboxyl group, an oxo group; or when both substituents R12 and R13 are located at adjacent carbon atoms of the ring

 these two substituents, taken together with said adjacent carbon atoms, can also form a 5- or 6- member aromatic or a x-member saturated or unsaturated heterocycloaliphatic or heteroaromatic ring containing from 2 to (x−1) carbon atoms with x being 5 or 6, and from 1 to 4 hetero atoms selected from the group consisting of sulfur oxygen and nitrogen, and wherein V can have altogether one to four substituents of the kind as defined for R12 and R13 and the free valences can be located either on one or on both rings of the group V.

17. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 16 , wherein

V is a divalent group of formula

18. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

W is heterocyclyl.

19. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

W is a group of formula

wherein

is a phenyl ring or a x-membered saturated or unsaturated heterocycloaliphatic or heteroaromatic ring containing from 2 to (x−1) carbon atoms with x being 5 or 6, and from 1 to 4 hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen, R14 and R15 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyloxy, C 3 -C 7 cycloalkyl-C 1 -C 4 alkoxy, halogen, halogen-substituted C 1 -C 4 alkyl groups, halogen-substituted C 1 -C 4 alkoxy groups, cyano, nitro, amino, C 1 -C 4 alkylamino, di(C 1 -C4)alkylamino, C 1 -C 4 alkylthio, mercapto, hydroxy, carbamoyl, a carboxyl group, and an oxo group; or when both substituents R14 and R15 are located at adjacent carbon atoms of the ring

 these two substituents, taken together with said adjacent carbon atoms, can also form a 5- or 6-membered aromatic or a x-membered saturated or unsaturated heterocycloaliphatic or heteroaromatic ring containing from 2 to (x−1) carbon atoms with x being 5 or 6, and from 1 to 3 hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen, wherein W can have altogether one to four substituents of the kind as defined for R14 and R15 and the free valence can be located on either ring of the group W.

20. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 19 , wherein

W is a group of one of the formulae

wherein R16 is hydrogen or C 1 -C 4 alkyl.

21. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

Q is —NR10R11.

22. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

A1, A2 are independently of each other either absent or a C 1 -C 2 alkylene group; and

L is —NH—, —(CO)NH— or —NH(CO)— or is absent.

23. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 22 , wherein

A1, A2 are independently of each other either absent or a C 1 -C 2 alkylene group;

L is —NH—, —(CO)NH— or —NH(CO)—;

V is a divalent group of formula

W is a group of formula

24. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein

Y is —S— and

X is —CH 2 —CH 2 —CH 2 , —CH 2 —CH 2 —NH—, —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH 2 —NH— or —CH 2 —CH 2 —CH 2 —O— linked to the residue Q via the NH group or O atom respectively, or —CH 2 —CH 2 .

25. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 21 , wherein

—NR10R11 is a group of one of the following formulae

wherein

 means a methoxy residue.

26. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 said compound having the formula

27. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , said compound having one of the following formulae:

28. An in vivo cleavable ester of a compound according to claim 1 , which is an ester of the 2′-hydroxy group of the sugar moiety.

29. An ester of a compound according to claim 1 which is an acetate ester, pivaloyl ester, tartrate ester, maleate ester or succinate ester.

30. The macrolide compound of claim 1 , wherein said macrolide compound is an N oxide.

31. A medicament comprising a compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 and a pharmaceutically acceptable carrier.

32. A medicament according to claim 31 for use for treatment of inflammatory or allergic diseases or cancer, in said subject selected from an animal and a human.

33. A medicament according to claim 31 for use for the treatment of asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, psoriasis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), septic shock, ulcerative colitis, inflammatory bowel disease, e.g. Crohn's disease, adult respiratory distress syndrome or multiple sclerosis.

34. A medicament according to claim 31 for use for the treatment of chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, psoriasis or atopic dermatitis.

35. A compound according to claim 1 or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof for use for the treatment of inflammatory or allergic diseases or cancer in a subject selected from an animal and a human.

36. A method for treating an inflammatory or allergic disease or cancer in a subject selected from an animal and a human, in need of such treatment wherein an amount of a compound according to claim 1 or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof which amount is effective in treating said inflammatory or allergic disease or said cancer disease is administered to said subject.

37. A method for treating a human affected by a disorder or disease which can be ameliorated by inhibition of human phosphodiesterases, wherein an amount of a compound according to claim 1 or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof is administered to said human which amount is effective for ameliorating said disorder or disease, wherein said disorder or disease is an inflammatory or allergic disease or disorder or cancer.

38. A process for the manufacture of a compound of formula (I) according to claim 1 , comprising

a) converting a macrolide compound having the formula (II)

wherein the groups R2 to R9 are defined as in claim 1 , after appropriate protection where necessary, in a manner known per se to a compound of formula IV

b) converting said compound of formula IV in a manner known per se to a compound of formula VI

wherein R1 is as defined in claim 1 or is a group of formula —S-Rp 3 wherein Rp 3 is a sulfur protecting group,

c) reacting said compound of formula VI in an aprotic solvent with an alkali metal base to form a compound of formula VII

wherein R1 to R9 have the meaning above, and removing any protecting groups where necessary to form the compound of formula I,

with the proviso that in case that R1 is S-Rp 3 the compound of formula VII is transformed into the disulfide derivative of formula VIII, in the presence of a molecular sieve if R2 represents a cladinosyl group, before removing the hydroxyl protecting groups Rp 1 and Rp 2

wherein Rp 4 is C 1 -C 4 alkyl, in particular methyl, or 3-nitro-2-pyridinyl,

which compound is treated with a reducing agent, in particular trialkyl phosphine or triaryl phosphine, in a solvent, in particular aqueous acetone, aqueous DMF, aqueous dioxane or aqueous THF, to give a compound of formula IX

wherein R2 to R9 have the above meaning,

which compound is then reacted with a compound of formula Q-X-Lg, wherein Q and X are as defined in claim 1 and Lg is a leaving group or, when X represents a carbonyl or sulfonyl group, a vinyl group, to give the compound of formula VII wherein R1 is as defined in claim 1 .

39. A process for the manufacture of a compound of formula I according to claim 1 , comprising

converting a compound selected from the compounds of the formulae

wherein

R1, R2, R3 and R4 have on of the meanings as defined in claim 1 and

Z1 is a group of formula

wherein

 represents the bond between said group and the carbon atom of said macrolide compound to which it is linked;

in a manner known per se to the compound of formula (I) according to claim 1 .

40. A process according to claim 39 wherein the compounds of formula (I-1); (II-1); (IV-1); (VI-1) or (VII-1) are obtained according to the following process scheme:

a) converting a macrolide compound having the formula (II-1)

wherein the groups R2 to R4 and Z1 are defined as in claim 37 , after appropriate protection where necessary, in a manner known per se to the corresponding compound of formula (IV-1)

b) converting said compound of formula (IV-1) in a manner known per se to the corresponding compound of formula (VI-1)

wherein R1 is as defined in claim 1 or is a group of formula —S-Rp 3 wherein Rp 3 is a sulfur protecting group,

c) reacting said compound of formula (VI-1) in an aprotic solvent with an alkali metal base to form the corresponding compound of formula (VII-1)

and removing any protecting groups where necessary to foils the compound of formula (I-1), or, in case that R1 is S-Rp 3 , the compound of formula (VII-1) is transformed into the disulfide derivative of formula (VIII-1), in the presence of a molecular sieve if R2 represents a cladinosyl group, before removing any hydroxyl protecting groups

wherein Rp 4 is C 1 -C 4 alkyl, in particular methyl, or 3-nitro-2-pyridinyl, and the compound of formula (I-1); (II-1); (IV-1); (VI-1) or (VIII-1) are processed according to claim 39 .

41. A compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof according to claim 1 , wherein in Z,

R7 is —NR7bR7c selected from the group consisting of

42. The compound or an acid addition salt, a N-oxide or an in vivo cleavable ester thereof of claim 41 , wherein R6 is hydroxyl.