Dendrimer like amino amides possessing sodium channel blocker activity for the treatment of dry eye and other mucosal diseases

1. A compound represented by formula (I):

and racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and pharmaceutically acceptable salts, thereof,

wherein:

X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl;

Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R 2 ) 2 ;

R 1 is hydrogen or lower alkyl;

each R 2 is, independently, —R 7 , —(CH 2 ) m —OR 8 , —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , or

R 3 and R 4 are each, independently, hydrogen, lower alkyl, hydroxyl-lower alkyl, phenyl, (phenyl)-lower alkyl, (halophenyl)-lower alkyl, ((lower-alkyl)phenyl)-lower-alkyl, ((lower-alkoxy)phenyl)-lower-alkyl, (naphthyl)-lower-alkyl, or (pyridyl)-lower-alkyl, or a group represented by formula A or formula B, with the proviso that at least one of R 3 and R 4 is a group represented by the formula A or formula B;

—(C(R L ) 2 ) o - x -(C(R L ) 2 ) p A 1   formula A:

—(C(R L ) 2 ) o - x -(C(R L ) 2 ) p A 2   formula B:

A 1 is a C 6 -C 15 -membered aromatic carbocycle substituted with at least one R 5 and the remaining substituents are R 6 ;

A 2 is a six to fifteen-membered aromatic heterocycle substituted with at least one R 5 and the remaining substituents are R 6 wherein said aromatic heterocycle comprises 1-4 heteroatoms selected from the group consisting of O, N, and S;

each R L is, independently, —R 7 , —(CH 2 ) n —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m —(Z) g —R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose,

each o is, independently, an integer from 0 to 10;

each p is, independently, an integer from 0 to 10;

with the proviso that the sum of o and p in each contiguous chain is from 1 to 10;

each x is, independently, O, NR 10 , C(═O), CHOH, C(═N—R 10 ), CHNR 7 R 10 , or a single bond;

each R 5 is, independently, -Link-(CH 2 ) m -CAP, -Link-(CH 2 ) n (CHOR 8 )(CHOR 8 ) n -CAP, -Link-(CH 2 CH 2 O) m —CH 2 -CAP, -Link-(CH 2 CH 2 O) m —CH 2 CH 2 -CAP, -Link-(CH 2 ) m —(Z) g -CAP, -Link-(CH 2 ) n (Z) g —(CH 2 ) m -CAP, -Link-(CH 2 ) n —NR 13 —CH 2 (CHOR 8 )(CHOR 8 ) n -CAP, -Link-(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 13 —(Z) g -CAP, -Link-(CH 2 ) n NR 13 —(CH 2 ) m (CHOR 8 ) m CH 2 NR 13 —(Z) g -CAP, -Link-(CH 2 ) m —(Z) g —(CH 2 ) m -CAP, -Link-NH—C(═O)—NH—(CH 2 ) m -CAP, -Link-(CH 2 ) m —C(═O)NR 13 —(CH 2 ) m -CAP, -Link-(CH 2 ) n —(Z) g —(CH 2 ) m —(Z) g -CAP, or -Link-Z g —(CH 2 ) m -Het-(CH 2 ) m -CAP;

each R 6 is, independently, R 5 , —R 7 , —OR 11 , —N(R 7 ) 2 , —(CH 2 ) m —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m —(Z) g —R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose,

wherein when two R 6 are —OR 11 and are located adjacent to each other on the aromatic carbocycle or aromatic heterocycle, the two OR 11 may form a methylenedioxy group;

each R 7 is, independently, hydrogen, lower alkyl, phenyl, substituted phenyl or —CH 2 (CHOR 8 ) m —CH 2 OR 8 ;

each R 8 is, independently, hydrogen, lower alkyl, —C(═O)—R 11 , glucuronide, 2-tetrahydropyranyl, or

each R 9 is, independently, —CO 2 R 7 , —CON(R 7 ) 2 , —SO 2 CH 3 , —C(═O)R 7 , —CO 2 R 13 , —CON(R 13 ) 2 , —SO 2 CH 2 R 13 , or —C(═O)R 13 ;

each R 10 is, independently, —H, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —CH 2 —(CHOH) n —CH 2 OH;

each Z is, independently, —(CHOH)—, —C(═O)—, —(CHNR 7 R 10 )—, —(C═NR 10 )—, —NR 10 —, —(CH 2 ) n —, —(CHNR 13 R 13 )—, —(C═NR 13 )—, or —NR 13 —;

each R 11 is, independently, hydrogen, lower alkyl, phenyl lower alkyl or substituted phenyl lower alkyl;

each R 12 is, independently, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , —CH 2 (CHOH) n —CH 2 OH, —CO 2 R 7 , —C(═O)NR 7 R 7 , or —C(═O)R 7 ;

each R 13 is, independently, hydrogen, —OR 7 , R 10 , R 11 or R 12 ;

each g is, independently, an integer from 1 to 6;

each m is, independently, an integer from 1 to 7;

each n is, independently, an integer from 0 to 7;

each -Het- is, independently, —N(R 7 )—, —N(R 10 )—, —S—, —SO—, —SO 2 —; —O—, —SO 2 NH—, —NHSO 2 —, —NR 7 CO—, —CONR 7 —, —N(R 13 )—, —SO 2 NR 13 —, —NR 13 CO—, or —CONR 13 —;

each Link is, independently, —O—, —(CH 2 ) n —, —O(CH 2 ) m —, —NR 13 —C(═O)—NR 13 —, —NR 13 —C(═O)—(CH 2 ) m —, —C(═O)NR 13 —(CH 2 ) m − , —(CH 2 ) n —(Z) g —(CH 2 ) n —, —S—, —SO—, —SO 2 —, —SO 2 NR 7 —, —SO 2 NR 10 —, or -Het-;

each CAP is

2. The compound according to claim 1 , which is represented by formula II or formula III:

and racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and pharmaceutically acceptable salts, thereof.

3. The compound according to claim 1 , wherein the C 6 -C 15 -membered aromatic carbocycle of A 1 is selected from -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl.

4. The compound according to claim 1 , wherein A 1 is

5. The compound according to claim 1 , wherein R 5 is represented by one of the following formulas:

6. A compound represented by one of the following formulas:

or a pharmaceutically active salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition according to claim 7 , wherein the compound is

(2R,2′R)—N,N′-(3,3′-(2-(4-(4-(3-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino)butyl)phenoxy)ethylazanediyl)bis(propane-3,1-diyl))bis(2-amino-6-guanidinohexanamide), or a pharmaceutically acceptable salt thereof.

9. The composition according to claim 7 , wherein said composition is a solution for administration by eye drops.

10. A method for blocking sodium channels in a human comprising administering to said human an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

11. A method for promoting hydration of mucosal surfaces or restoring mucosal defense in a human comprising administering to said human an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

12. A method of treating dry eye, treating Sjogren's disease-associated dry eye, treating eye inflammation caused by dry eye, promoting ocular hydration, promoting corneal hydration, treating chronic bronchitis, treating bronchiectasis, treating cystic fibrosis, treating sinusitis, treating vaginal dryness, promoting mucus clearance in mucosal surfaces, treating Sjogren's disease, treating distal intestinal obstruction syndrome, treating dry skin, treating esophagitis, treating dry mouth, treating nasal dehydration, treating ventilator-induced pneumonia, treating asthma, treating primary ciliary dyskinesia, treating otitis media, inducing sputum for diagnostic purposes, treating chronic obstructive pulmonary disease, treating emphysema, treating pneumonia, treating constipation, treating chronic diverticulitis, treating rhinosinusitis, comprising:

administering an effective amount of the compound according to claim 1 to a subject in need thereof.

13. A method of treating a disease ameliorated by increased mucociliary clearance and mucosal hydration comprising administering to a subject in need of increased mucociliary clearance and mucosal hydration an effective amount of an osmolyte and the compound according to claim 1 .

14. The method according to claim 12 , wherein the disease is one or more conditions selected from the group consisting of dry eye, chronic bronchitis, bronchiectasis, cystic fibrosis, sinusitis, vaginal dryness, Sjogren's disease, distal intestinal obstruction syndrome, dry skin, esophagitis, dry mouth, nasal dehydration, asthma, primary ciliary dyskinesia, otitis media, chronic obstructive pulmonary disease, emphysema, pneumonia, diverticulitis, rhinosinusitis, and airborne infections.

15. A composition, comprising:

(a) a compound or a pharmaceutically acceptable salt thereof according to claim 1 and

(b) an osmolotically active compound.

16. The composition according to claim 7 , further comprising a pharmaceutically effective amount of a therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, β-agonists, P2Y2 receptor agonists, peroxisome proliferator-activated receptor agonists, kinase inhibitors, antiinfective agents and antihistamines.

17. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in treating dry eye, treating Sjogren's disease-associated dry eye, treating eye inflammation caused by dry eye, promoting ocular hydration, promoting corneal hydration, treating chronic bronchitis, treating bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), treating cystic fibrosis, treating sinusitis, treating vaginal dryness, promoting mucus clearance in mucosal surfaces, treating Sjogren's disease, treating distal intestinal obstruction syndrome, treating dry skin, treating esophagitis, treating dry mouth, treating nasal dehydration (including nasal dehydration is brought on by administering dry oxygen to the subject), treating ventilator-induced pneumonia, treating asthma, treating primary ciliary dyskinesia, treating otitis media, inducing sputum for diagnostic purposes, treating chronic obstructive pulmonary disease, treating emphysema, treating pneumonia, treating constipation, treating chronic diverticulitis, or treating rhinosinusitis in a human in need thereof.

18. The method according to claim 10 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

19. The hydrochloride salt of: