9a-azalides with anti-inflammatory activity
Macrolides with anti-inflammatory activity are described. Particularly described are 9a-azalides and their anti-inflammatory activity without cladinose in position 3, the pharmaceutically acceptable salts thereof and the pharmaceutical composition that contain them as active principle.
1. A compound of formula
in which
R is a hydrogen atom or a methyl
R 1 is a hydrogen atom, an N,N-di-(C 1 -C 3 )-alkylamino group, an N,N-di-(C 1 -C 3 )-alkylamino-N-oxide group, an N—(C 1 -C 4 )-acyl-N—(C 1 -C 3 )-alkylamino group or together with R 2 forms a bond between the carbon atoms at 3′ and 4′;
R 2 is a hydrogen atom or together with R 1 forms a bond between the carbon atoms at 3′ and 4′;
R 3 is a linear or branched C 1 -C 5 alkyl, a benzyl optionally substituted with one or two substituents selected from nitro, hydroxy, carboxy, amino, linear or branched C 1 -C 5 alkyl, C 1 -C 4 alkoxy groups, C 1 -C 4 alkoxycarbonyl groups, aminocarbonyl groups or cyano or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl with five or six members containing from one to three atoms selected from nitrogen, oxygen and sulfur;
X represents O, S, SO, SO 2 , NR 6 and R 6 is a hydrogen atom, a linear or branched C 1 -C 3 alkyl, a C 1 -C 3 alkoxycarbonyl group, a benzyloxycarbonyl group;
Y is a C 6 H 4 group, a heteroaryl with five or six members containing from one to three atoms selected from nitrogen, oxygen and sulfur or represents O, S, SO, SO 2 , NR 6 where R 6 has the meanings given above;
r is an integer of from 1 to 3;
m is an integer of from 1 to 6;
n is an integer of from 0 to 2;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form;
and their pharmaceutically acceptable salts;
provided that when R is a hydrogen atom and R 1 is a dimethylamino group, R 3 is different from a (C 1 -C 5 )-alkyl group.
2. A compound according to claim 1 in which R 1 is a hydrogen atom, an N-methyl-N—(C 1 -C 3 )-alkylamino group, an N-methyl-N—(C 1 -C 3 )-alkylamino-N-oxide group, an N—(C 1 -C 4 )-acyl-N-methylamino group or R 1 together with R 2 forms a bond between the carbon atoms at 3′ and 4′.
3. A compound according to claim 2 in which R 1 is a hydrogen atom, an N,N-dimethylamino group, an N,N-dimethylamino-N-oxide group, an N-acetyl-N-methylamino group or R 1 together with R 2 forms a bond between the carbon atoms at 3′ and 4′.
4. A compound according to claim 1 in which R 3 is a linear or branched (C 1 -C 3 ) alkyl, a benzyl optionally substituted with one or two substituents selected from nitro, hydroxy, carboxy, amino, linear or branched (C 1 -C 3 ) alkyl, C 1 -C 4 alkoxy and cyano groups or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl with five or six members containing from one to three atoms selected from nitrogen, oxygen and sulfur;
X is O or NR 6 and R 6 is a hydrogen atom, a linear or branched C 1 -C 3 alkyl;
Y, when n is 0, is a C 6 H 4 group or a heteroaryl with five or six members containing from one to three atoms selected from nitrogen, oxygen and sulfur; or, when n is different from 0, it is O or NR 6 and R 6 is a hydrogen atom, a linear or branched C 1 -C 3 alkyl;
r is an integer of from 1 to 3;
m is an integer selected from 1 and 2;
n is an integer of from 0 to 2;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form.
5. A compound according to claim 4 in which R 3 is a methyl, a benzyl or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl with five or six members selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;
X is O or NR 6 and R 6 is a hydrogen atom;
Y, when n is 0, is a C 6 H 4 group or a heteroaryl with five or six members selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole; or, when n is 1, it is NR 6 and R 6 is a hydrogen atom;
r is an integer of from 1 to 3;
m is an integer selected from 1 and 2;
n is an integer selected from 0 and 1;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form.
6. A compound according to claim 5 in which R 3 is a methyl, a benzyl or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl selected from thiophene, furan, imidazole, thiazole, pyridine and triazole;
X is NR 6 and R 6 is a hydrogen atom;
Y, when n is 0, is a C 6 H 4 group or a heteroaryl selected from thiophene, furan, imidazole, thiazole, pyridine and triazole; or, when n is 1, it is NR 6 and R 6 is a hydrogen atom;
r is 3;
m is an integer selected from 1 and 2;
n is an integer selected from 0 and 1;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form.
7. A compound according to claim 1 , in which R 1 is a hydrogen atom, an N-methyl-N—(C 1 -C 3 )-alkylamino group, an N-methyl-N—(C 1 -C 3 )-alkylamino-N-oxide group, an N—(C 1 -C 4 )-acyl-N-methylamino group or R 1 together with R 2 forms a bond between the carbon atoms at 3′ and 4′;
at the same time R 3 is a linear or branched (C 1 -C 3 ) alkyl, a benzyl optionally substituted with one or two substituents selected from nitro, hydroxy, carboxy, amino, linear or branched (C 1 -C 3 ) alkyl, C 1 -C 4 alkoxy and cyano groups or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl with five or six members containing from one to three atoms selected from nitrogen, oxygen and sulfur;
X is O or NR 6 and R 6 is a hydrogen atom, a linear or branched C 1 -C 3 alkyl;
Y, when n is 0, is a C 6 H 4 group or a heteroaryl with five or six members containing from one to three atoms selected from nitrogen, oxygen and sulfur; or, when n is different from 0, it is O or NR 6 and R 6 is a hydrogen atom, a linear or branched C 1 -C 3 alkyl;
r is an integer of from 1 to 3;
m is an integer selected from 1 and 2;
n is an integer of from 0 to 2;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form.
8. A compound according to claim 7 in which R 3 is a methyl, a benzyl or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl with five or six members selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;
X is O or NR 6 and R 6 is a hydrogen atom;
Y, when n is 0, is a C 6 H 4 group or a heteroaryl with five or six members selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole; or, when n is 1, it is NR 6 and R 6 is a hydrogen atom;
r is an integer of from 1 to 3;
m is an integer selected from 1 and 2;
n is an integer selected from 0 and 1;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form.
9. A compound according to claim 8 in which R 3 is a methyl, a benzyl or a chain of formula
—(CH 2 )r-X—(CH 2 )m-Y—(CH 2 )n-A
in which
A is a hydrogen atom, a phenyl or a heteroaryl selected from thiophene, furan, imidazole, thiazole, pyridine and triazole;
X is NR 6 and R 6 is a hydrogen atom;
Y, when n is 0, is a C 6 H 4 group or a heteroaryl selected from thiophene, furan, imidazole, thiazole, pyridine and triazole; or, when n is 1, it is NR 6 and R 6 is a hydrogen atom;
r is 3;
m is an integer selected from 1 and 2;
n is an integer selected from 0 and 1;
moreover the nitrogen atom to which R 3 is bound can be present in the N-oxide form.
10. A compound according to claim 9 in which R 1 is a hydrogen atom, an N,N-dimethylamino group, an N,N-dimethylamino-N-oxide group, an N-acetyl-N-methylamino group or R 1 together with R 2 forms a bond between the carbon atoms at 3′ and 4′.
11. A process for preparing a compound according to claim 1 that comprises the removal of the L-cladinose at position 3, through a reaction of hydrolysis, from the azithromycin derivatives of formula
in which
R, R 1 , R 2 and R 3 are defined as in claim 1 .
12. A process according to claim 11 in which, in formula II, the substituent R 3 is a methyl.
13. A process according to claim 11 in which the removal of cladinose is effected through a reaction of catalyzed acid hydrolysis in the presence of an inorganic acid and a protic organic solvent.
14. A pharmaceutical composition containing a therapeutically effective quantity of a compound according to claim 1 mixed with a pharmaceutically acceptable vehicle.
15. A pharmaceutical composition according to claim 14 that can be used for treating inflammatory pathologies.