Compounds and methods for the treatment of asthma
Compounds and methods for the treatment of asthma are disclosed. The methods involve mast cell stabilization together with selective inhibition of iNOS. The compounds are combinations of a mast cell inhibiting moiety and an inhibitor of iNOS. An example is:
1. A compound of formula I
wherein
R 1 and R 2 are chosen from hydroxy, C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 straight and branched alkoxy, -G-O(C═O)R 4 , R 5 , —NHR 6 , —OR 7 and —O − X + , wherein X + is a pharmaceutically acceptable cation;
R 3 is chosen from hydrogen, —(C═O)R 4 , —(C═O)-G-O(C═O)R 4 , —(C═O)R 5 , —(C═O)NHR 6 and —(C═O)OR 7 ;
—O(C═O)R 4 is the deshydrogen residue of a carboxylic acid, the parent of which, R 4 COOH, is chosen from the group consisting of:
—(C═O)R 4 is the deshydroxy residue of a carboxylic acid, the parent of which, R 4 COOH, is chosen from the group consisting of:
R 5 is —O—R 20 —U, wherein U is chosen from hydrogen, (1,2-dithiolan-3-yl) and phenyl, and R 20 is a divalent C 1 to C 20 alkane or oxaalkane residue;
—NHR 6 is the deshydrogen residue of an amine, the parent of which, R 6 NH 2 , is chosen from the group consisting of:
—OR 7 is
G is chosen from —OCH 2 — and —OCH(CH 3 )—;
at least one of R 1 , R 2 and R 3 must be -G-O(C═O)R 4 , —NHR 6 , —OR 7 , —(C═O)R 4 , —(C═O)-G-O(C═O)R 4 , —(C═O)R 5 , —(C═O)NHR 6 or —(C═O)OR 7
R 50 is chosen from C 1 to C 4 alkyl, C 3 to C 4 cycloalkyl, C 1 to C 4 hydroxyalkyl and C 1 to C 4 haloalkyl;
Q is chosen from —CH 2 CH═CHCH 2 —, —(CH 2 ) p X(CH 2 ) q —, —O—, —NR 51 — and —(CH 2 ) r A(CH 2 ) s —;
p is 2 or 3;
q is 1 or 2;
X is S(O) x
x is 0, 1 or 2;
R 51 is H or C 1-6 alkyl;
r is 1 or 2;
s is 1 or 2; and
A is cyclobutyl, phenyl or pyridyl.
2. A compound according to claim 1 wherein R 4 COOH and R 6 NH 2 are chosen from:
3. A compound according to claim 1 wherein R 4 COOH and R 6 NH 2 are chosen from compounds of structure:
wherein R 50 is chosen from C 1 to C 4 alkyl, C 3 to C 4 cycloalkyl, C 1 to C 4 hydroxyalkyl and C 1 to C 4 haloalkyl.
4. A compound according to claim 1 wherein R 4 COOH and R 6 NH 2 are chosen from compounds of structure:
wherein Q is chosen from —CH 2 CH═CHCH 2 —, —(CH 2 ) p X(CH 2 ) q —, —O—, —NR 51 — and —(CH 2 ) r A(CH 2 ) s —;
p is 2 or 3;
q is 1 or 2;
X is S(O) x ;
x is 0, 1 or 2;
R 51 is H or C 1-6 alkyl;
r is 1 or 2;
s is 1 or 2; and
A is cyclobutyl, phenyl or pyridyl.
5. A compound according to claim 1 wherein R 6 NH 2 is chosen from compounds of structure:
6. A compound according to claim 1 wherein
R 1 and R 2 are chosen from hydroxy, C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 straight and branched alkoxy, —R 5 , —NHR 6 , —OR 7 and —O − X + ; and
R 3 is chosen from hydrogen, —(C═O)R 4 , —(C═O)R 5 , —(C═O)NHR 6 and —(C═O)OR 7 .
7. A compound according to claim 1 wherein at least one of
R 1 , R 2 and R 3 is -G-O(C═O)R 4 or —(C═O)-G-O(C═O)R 4 ; and
G is chosen from —OCH 2 — and —OCH(CH 3 )—.
8. A compound according to claim 1 wherein R 5 is
9. A compound according to claim 1 wherein R 5 is
10. A compound according to claim 1 of formula
wherein
R 1 and R 2 are chosen from hydroxy, C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 straight and branched alkoxy and —O − X + .
11. A compound according to claim 1 of formula:
12. A compound according to claim 1 of formula:
wherein
R 1 is chosen from -G-O(C═O)R 4 , —NHR 6 and OR 7 ; and
R 2 is chosen from hydroxy, C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 straight and branched alkoxy, R 5 and —O − X.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .
14. An aerosol pharmaceutical composition according to claim 13 .
15. An oral pharmaceutical composition according to claim 13 .
16. An oral pharmaceutical composition according to claim 15 in the form of a tablet, capsule or syrup.