Conjugates of immune cell specific macrolide compounds with anti-inflammatory compounds for improved cellular targeting of anti-inflammatory therapy

1. A compound of the structure I

characterized in that M is a macrolide subunit selected from M1, M2, M3, M4, M5 and M6:

i)

wherein

R 1 is hydrogen or methyl group,

R 2 and R 3 are both hydrogen or together form a bond, or

R 2 is an amino group represented by the substructure —NR′R″

wherein R′ and R″ independently represent hydrogen, alkyl or cycloalkyl group having 1-6 carbon atoms, with the proviso that R 3 is then hydrogen,

R 4 is a hydroxy or cladinosyl group represented by the structure

or R 4 and R 5 together form a carbonyl group, with the proviso that R 1 is then methyl group:

ii)

wherein

R 1 is hydrogen or methyl group,

R 2 and R 3 are both hydrogen or together form a bond, or

R 2 is an amino group represented by the substructure —NR′R″,

wherein R′ and R″ independently represent hydrogen, alkyl or cycloalkyl group having 1-6 carbon atoms, with the proviso that R 3 is then hydrogen,

R 4 represents alkyl group having 1-4 carbon atoms;

iii)

wherein

R 1 is hydrogen or methyl group,

R 2 and R 3 are both hydrogen or together form a bond, or

R 2 is an amino group represented by the substructure —NR′R″,

wherein R′and R″ independently represent hydrogen,alkyl or cycloalkyl group having 1-6 carbon atoms, with the proviso that R 3 is then hydrogen,

R 4 is a hydroxy or cladinosyl group represented by the structure

or R 4 and R 5 together form a carbonyl group, with the proviso that R 1 is then a methyl group;

iv)

wherein

R 1 is hydrogen or methyl group,

R 2 and R 3 are both hydrogen or together form a bond or

R 2 is an amino group represented by the substructure -NR′R″;

wherein R′ and R″ independently represent hydrogen, alkyl or cycloalkyl group having 1-6 carbon atoms, with the proviso that R 3 is then hydrogen,

R 4 is a hydroxy or cladinosyl group represented by the structure

v)

wherein

R 1 is hydrogen or a methyl group,

R 2 and R 3 are both hydrogen or together form a bond, or

R 2 is an amino group represented by the substructure -NR′R″,

wherein R′and R″independently represent hydrogen, alkyl or cycloalkyl group having 1-6 carbon atoms, with the proviso that R 3 is then hydrogen.

R 4 is hydroxy or cladinosyl group represented by the structure:

R 5 represents alkyl group having 1-4 carbon atoms;

vi)

wherein

R 1 is hydrogen or an acetyl group,

R 2 and R 3 are both hydrogen or together form a bond, or

R 2 is an amino group represented by the substructure —NR′R″,

wherein R′ and R″ independently represent hydrogen, alkyl or cycloalkyl group having 1-6 carbon atoms, with the proviso that R 3 is then hydrogen,

R 4 is hydroxy or cladinosyl group represented by the structure

R 5 represents alkyl group having 1-4 carbon atoms;

A is an anti-inflammatory steroid subunit selected from the group consisting of A1, A2, A3,

A4, A5 and A6 stereoisomeric forms thereof:

i)

wherein

1,2-position represents a double or single carbon-carbon bond,

Z represents oxygen or NH group,

R 1 represents hydrogen, hydroxy, O-acyl or O-alkyl group,

R 2 represents hydrogen or methyl group oriented in α- or β-position,

X 1 represents hydrogen, fluorine, chlorine or bromine,

X 2 represents hydrogen, fluorine, chlorine or bromine;

ii)

wherein

Z represents oxygen or NH group,

R 1 represents hydrogen, hydroxy, O-acyl or O-alkyl group,

R 2 represents hydrogen or an acyl group,

X 1 represents hydrogen. fluorine, chlorine or bromine,

X 2 represents hydrogen, fluorine, chlorine or bromine;

iii)

wherein

the 1,2-position represents a double or single carbon-carbon bond,

Z represents oxygen or NH group,

R 1 represents hydrogen, a straight or branched hydrocarbon chain having 1-4 carbon atoms,

R 2 represents hydrogen, a straight or branched hydrocarbon chain having 1-10 carbon atoms, with the proviso that R, and R 2 are not simultaneously hydrogen,

X 1 represents hydrogen, fluorine, chlorine or bromine,

X 2 represents hydrogen, fluorine, chlorine or bromine;

iv)

wherein

the 1,2-position represents a double or single carbon-carbon bond,

Z represents oxygen or NH group,

R 1 represents hydrogen, a straight or branched hydrocarbon chain having 1-4 carbon atoms,

R 2 represents hydrogen, a straight or branched hydrocarbon chain having 1-10 carbon atoms, with the proviso that R 1 and R 2 are not simultaneously hydrogen,

X 1 represents hydrogen, fluorine, chlorine or bromine,

X 2 represents hydrogen, fluorine, chlorine or bromine;

v)

wherein

the 1,2-position represents a double or single carbon-carbon bond,

R 1 represents hydrogen, a straight or branched hydrocarbon chain having 1-4 carbon atoms,

R 2 represents hydrogen, a straight or branched hydrocarbon chain having 1-10 carbon atoms, with the proviso that R 1 and R 2 are not simultaneously hydrogen,

X 1 represents hydrogen, fluorine, chlorine or bromine,

X 2 represents hydrogen, fluorine, chlorine or bromine;

vi)

wherein

1,2-position represents a double or single carbon-carbon bond,

Z represents oxygen or NH group,

R 1 represents hydrogen or hydroxy group, O-acyl or O-alkyl group,

R 2 represents hydrogen or a methyl group oriented in α- or β-position,

R 3 represents hydrogen or a radical of an acid having 1-4 carbon atoms,

X 1 is hydrogen, fluorine, chlorine or bromine,

X 2 is hydrogen, fluorine, chlorine or bromine;

L is a chain linking subunit M with A of the formula: —CR 1 R 2 (CR 3 R 4 ) n CR 5 R 6 —,

wherein

n is 1-10,

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 represent hydrogen, C 1 -C 4 alkyl, aryl, metoxy, halogen,

hydroxy or mercapto group, and one or more —CR 3 R 4 - groups is optionally substituted with oxygen, sulphur, an aromatic nucleus or an amino group additionally bearing hydrogen or a C 1 -C 4 alkyl or aryl group with the proviso that at least one methylene group is situated at the end of the linking L group, or

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 together form one or more double or triple bonds in a chain, thus forming alkenyl or alkinyl, with the proviso that at least one methylene group is situated at the end of linking L group;

or a salt or solvate thereof.

2. The compound according to claim 1 , characterized in that:

M is M1, wherein R 1 is a methyl group. R 2 is a dimethylamino group, R 3 is hydrogen, R 4 is cladinose, or R 4 and R 5 together form a carbonyl group;

A is selected from:

i) A1, wherein Z represents oxygen or NH group, R 1 , is hydroxy group, or O-alkyl group having 1-4 carbon atoms, R 2 is hydrogen or methyl group, X 1 is hydrogen or fluorine and X 2 is hydrogen;

ii) A2, wherein Z represents oxygen or NH group, R 1 is hydrogen, R 2 is hydrogen, X 1 is fluorine and X 2 is hydrogen;

iii) A3, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine;

iv) A4, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine; and

v) A6, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 is hydroxy group, R 2 is hydrogen or a methyl group in α- or β- position, R 3 is hydrogen, X 1 is hydrogen, fluorine or chlorine and X 2 is hydrogen or fluorine; and

L is —CR 1 R 2 (CR 3 R 4 ) n CR 5 R 6 —, wherein n is 1-10 and R 1 , R 2 , R 3 and R 4 are each hydrogen.

3. The compound according to claim 1 , characterized in that: M is M2, wherein R 1 is hydrogen, R 2 is a dimethylamino group, R 3 is hydrogen, R 4 is methyl;

A is selected from:

i) A1, wherein Z represents oxygen or NH group, R 1 is hydroxy group, or O-alkyl group having 1-4 carbon atoms, R 2 is hydrogen or methyl group, X 1 is hydrogen or fluorine and X 2 is hydrogen;

ii) A2, wherein Z represents oxygen or NH group, R 1 is hydrogen, R 2 is hydrogen, X 1 is fluorine and X 2 is hydrogen;

iii) A3, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R2 are methyl groups, X 1 is fluorine and X 2 is fluorine;

iv) A4, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine; and

v) A6 , wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 is hydroxy group, R 2 is hydrogen or a methyl group in α- or β-position, R 3 is hydrogen, X 1 is hydrogen, fluorine or chlorine and X 2 is hydrogen or fluorine; and

L is —CR 1 R 2 (CR 3 R 4 CR 5 R 6 —, wherein n is 1-10 and R 1 , R 2 , R 3 and R 4 are each hydrogen.

4. The compound according to claim 1 , characterized in that:

M is M3, wherein R 1 is hydrogen, R 2 is a dimethylamino group, R 3 is hydrogen, R 4 and R 5 together form a carbonyl group;

A is selected from:

i) A1, wherein Z represents oxygen or NH group, R 1 is hydroxy group, or O-alkyl group having 1-4 carbon atoms, R 2 is hydrogen or methyl group, X 1 is hydrogen or fluorine and X 2 is hydrogen;

ii) A2, wherein Z represents oxygen or NH group, R 1 is hydrogen, R 2 is hydrogen, X 1 is fluorine and X 2 is hydrogen;

iii) A3, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine;

iv) A4, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and K are methyl groups, X 1 is fluorine and X 2 is fluorine; and

v) A6, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 is hydroxy group, R 2 is hydrogen or a methyl group in α- or β-position, R 3 is hydrogen, X 1 is hydrogen, fluorine or chlorine and X 2 is hydrogen or fluorine; and

L is —CR 1 R 2 (CR 3 R 4 ) n CR 5 R 6 —, wherein n is 1-10 and R 1 , R 2 , R 3 and R 4 are each hydrogen.

5. The compound according to claim 1 , characterized in that:

M is M4, wherein R 1 is hydrogen, R 2 is a dimethylamino group, R 3 is hydrogen, R 4 is cladinose or hydroxy group;

A is selected from:

i) A1, wherein Z represents oxygen or NH group, R 1 is hydroxy group, or O-alkyl group having 1-4 carbon atoms, R 2 is hydrogen or methyl group, X 1 is hydrogen or fluorine and X 2 is hydrogen;

ii) A2, wherein Z represents oxygen or NH group, R 1 is hydrogen, R 2 is hydrogen, X 1 is fluorine and X 2 is hydrogen;

iii) A3, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine;

iv) A4, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine; and

v) A6, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 is hydroxy group, R 2 is hydrogen or a methyl group in α- or β-position, R 3 is hydrogen, X 1 is hydrogen, fluorine or chlorine and X 2 is hydrogen or fluorine; and

L is —CR 1 R 2 (CR 3 R 4 ) n CR 5 R 6 —, wherein n is 2-10 and R 1 , R 2 , R 3 and R 4 are each hydrogen.

6. The compound according to claim 1 , characterized in that:

M is M5, wherein R 1 is hydrogen, R 2 is a dimethylamino group, R 3 is hydrogen, R 4 is a cladinose or hydroxy group and R 5 is a methyl group;

A is selected from:

i) A1, wherein Z represents oxygen or NH group, R 1 is hydroxy group, or O-alkyl group having 1-4 carbon atoms, R 2 is hydrogen or methyl group, X 1 is hydrogen or fluorine and X 2 is hydrogen;

ii) A2, wherein Z represents oxygen or NH group, R 1 is hydrogen, R 2 is hydrogen, X 1 is fluorine and X 2 is hydrogen;

iii) A3, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine;

iv) A4, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine; and

v) A6, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 is hydroxy group, R 2 is hydrogen or a methyl group in α- or β-position, R 3 is hydrogen, X 1 is hydrogen, fluorine or chlorine and X 2 is hydrogen or fluorine; and

L is —CR 1 R 2 (CR 3 R 4 ) n CR 5 R 6 —, wherein n is 2-10 and R 1 , R 2 , R 3 and R 4 are each hydrogen.

7. The compound according to claim 1 , characterized in that:

M is M6, wherein R 1 is hydrogen, R 2 is a dimethylamino group, R 3 is hydrogen, R 4 is cladinose or hydroxy group and R 5 is a methyl group;

A is selected from:

i) A1, wherein Z represents oxygen or NH group, R 1 is hydroxy group, or O-alkyl group having 1-4 carbon atoms, R 2 is hydrogen or methyl group, X 1 is hydrogen or fluorine and X 2 is hydrogen;

ii) A2, wherein Z represents oxygen or NH group, R 1 is hydrogen, R 2 is hydrogen, X 1 is fluorine and X 2 is hydrogen;

iii) A3, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine;

iv) A4, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 and R 2 are methyl groups, X 1 is fluorine and X 2 is fluorine; and

v) A6, wherein Z represents oxygen or NH group, 1,2-position is a double carbon-carbon bond, R 1 is hydroxy group, R 2 is hydrogen or a methyl group in α- or β-position, R 3 is hydrogen, X 1 is hydrogen, fluorine or chlorine and X 2 is hydrogen or fluorine; and

L is —CR 1 R 2 (CR 3 R 4 ) n CR 5 R 6 —, wherein n is 2-10 and R 1 , R 2 , R 3 and R 4 are each hydrogen.

8. The compound according to claim 1 having the formula (1):

9. The compound according to claim 1 having the formula (2):

10. The compound according to claim 1 having the formula (3):

11. The compound according to claim 1 having the formula (4):

12. The compound according to claim 1 having the formula (5):

13. The oompound according to claim 1 having the formula (6):

14. The compound according to claim 1 having the formula (7):

15. The compound according to claim 1 having the formula (8):

16. The compound according to claim 1 having the formula (9):

17. The compound according to claim 1 having the formula (10):

18. The compound according to claim 1 having the formula (11):

19. The compound according to claim 1 having the formula (12):

20. The compound according to claim 1 having the formula (13):

21. The compound according to claim 1 having the formula (14):

22. The compound according to claim 1 having the formula (15):

23. The compound according to claim 1 having the formula (16):

24. The compound according to claim 1 having the formula (17):

25. The compound according to claim 1 having the formula (18):

26. The compound according to claim 1 having the formula (19):

27. The compound according to claim 1 having the formula (20):

28. The compound according to claim 1 having the formula (21):

29. The compound according to claim 1 having the formula (22):

30. The compound according to claim 1 having the formula (23):

31. The compound according to claim 1 having the formula (24):

32. The compound according to claim 1 having the formula (25):

33. The compound according to claim 1 having the formula (26):

34. The compound according to claim 1 having the formula (27):

35. The compound according to claim 1 having the formula (28):

36. A method for the treatment of an inflammatory condition or disease induced by excessive nonregulated production of cytokines and inflammation mediators comprising administration to a human or animal body in need of such treatment an effective amount of a compound according to claim 1 .

37. The method according to claim 36 wherein said inflammatory condition or disease is selected from asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, Crohn′ s disease, colitis, ulcerative colitis, eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis, conjunctivitis and rheumatoid arthritis.

38. The compound according to claim 1 , characterized in that: M is M1.

39. The compound according to claim 1 , characterized in that: M is M2.

40. The compound according to claim 1 , characterized in that: M is M3.

41. The compound according to claim 1 , characterized in that: M is M4.

42. The compound according to claim 1 , characterized in that: M is M5.

43. The compound according to claim 1 , characterized in that: M is M6.