Dendrimer like amino amides possessing sodium channel blocker activity for the treatment of dry eye and other mucosal diseases
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/4965
C07D-241/02
C07D-241/32
C07D-241/34
A61K-045/06
A61K-031/497
출원번호
US-0988540
(2016-01-05)
등록번호
US-9878988
(2018-01-30)
발명자
/ 주소
Johnson, Michael Ross
Thelin, William Robert
Boucher, Richard C.
출원인 / 주소
PARION SCIENCES, INC.
대리인 / 주소
Choate, Hall & Stewart LLP
인용정보
피인용 횟수 :
0인용 특허 :
96
초록
Sodium channel blockers represented by the formula: are provided where the structural variables are defined herein. The invention also includes a variety of compositions, combinations and methods of treatment using these inventive sodium channel blockers.
대표청구항▼
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-l
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(R2)2,R1 is hydrogen or lower alkyl;each R2 is, independently, —R7, —(CH2)m—OR8, —(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —(CH2)n—(Z)g—R7, —(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, or R3 and R4 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 R3 and R4 is a group represented by formula A or formula B: —(C(RL)2)o-x-(C(RL)2)pA1 formula A:—(C(RL)2)o-x-(C(RL)2)pA2; formula B:A1 is a C6-C15-membered aromatic carbocycle substituted with at least one R5 and the remaining substituents are R6;A2 is a six to fifteen-membered aromatic heterocycle substituted with at least one R5 and the remaining substituents are R6, wherein the aromatic heterocycle comprises 1-4 heteroatoms selected from the group consisting of O, N, and S;each RL is, independently, —R7, —(CH2)n—OR8, —O—(CH2)m—OR8, —(CH2)n—NR7R10, —O—(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —O—(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —O—(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —O—(CH2)m—C(═O)NR7R10, —(CH2)n—(Z)g-R7, —O—(CH2)m—(Z)g-R7, —(CH2)—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —O—(CH2)m—CO2R7, ˜OSO3H, ˜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 pin each contiguous chain is from 1 to 10;each x is, independently, O, NR10, C(═O), CHOH, C(═N—R10), CHNR7R10, or a single bond;each R5 is, independently, -Link-(CH2)m-CAP, -Link-(CH2)n(CHOR8)(CHOR8)n-CAP, -Link-(CH2CH2O)m—CH2-CAP, -Link-(CH2CH2O)m—CH2CH2-CAP, -Link-(CH2)m—(Z)g-CAP, -Link-(CH2)n(Z)g—(CH2)m-CAP, -Link-(CH2)n—NR13—CH2(CHOR8)(CHOR8)n-CAP, -Link-(CH2)n-(CHOR8)mCH2—NR13—(Z)g-CAP, -Link-(CH2)nNR13—(CH2)(CHOR8)nCH2NR13—(Z)g-CAP, -Link-(CH2)m—(Z)g—(CH2)m-CAP, -Link-NH—C(═O)—NH—(CH2)m-CAP, -Link-(CH2)m—C(═O)NR13—(CH2)m-CAP, -Link-(CH2)n—(Z)g—(CH2)m—(Z)g-CAP, -Link-Zg—(CH2)m-Het-(CH2)m-CAP, each R6 is, independently, R5, —R7, —OR11, —N(R7)2, —(CH2)m-OR8, —O—(CH2)m—OR8, —(CH2)n—NR7R10, ˜O—(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m(CHOR8)(CHOR8)n-CH2OR8, —(CH2CH2O)m—R8, —O—(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —O—(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —O—(CH2)m—C(═O)NR7R10, —(CH2)n—(Z)g—R7, —O—(CH2)m—(Z)g—R7, —(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, ˜O—(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —(CH2)m—CO2R7, ˜OSO3H, ˜O-glucuronide, ˜O-glucose, wherein when two R6 are -OR11 and are located adjacent to each other on the aromatic carbocycle or aromatic heterocycle, the two OR11 may form a methylenedioxy group;each R7 is, independently, hydrogen, lower alkyl, phenyl, substituted phenyl, or —CH2(CHOR8)mCH2OR8,each R8 is, independently, hydrogen, lower alkyl, —C(═O)—R11, glucuronide, 2-tetrahydropyranyl, or each R10 is, independently, —H, —SO2CH3, —CO2R7, —C(═O)R7, or —CH2-(CHOH)n-CH2OH;each Z is, independently, —(CHOH)—, —C(═O)—, —(CHNR7R10)—, —(C═NR10)—, —NR10—, —(CH2)n—, —(CHNR13R13)—, —(C═NR13)—, or —NR13—;each R11 is, independently, hydrogen, lower alkyl, phenyl lower alkyl, or substituted phenyl lower alkyl;each R12 is, independently, —SO2CH3, —CH2(CHOH)n—CH2OH, —CO2R7, —C(═O)NR7R7, or —C(═O)R7;each R13 is, independently, hydrogen, —OR7, R10, R11, or R12;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(R7)—, —N(R10)—, —S—, —SO—, —SO2—; —O—, —SO2NH—, —NHSO2—, —NR7CO—, —CONR7—, —N(R13)—, —SO2NR13—, —NR13CO—, or —CONR13—;each Link is, independently, —O—, —(CH2)n—, —O(CH2)m—, —NR13—C(═O)—NR13—, —NR13—C(═O)-(CH2)m—, —C(═O)NR13—(CH2)m—, —(CH2)n—(Z)g—(CH2)n—, —S—, —SO—, —SO2—, —SO2NR7—, —SO2NR10—, or -Het-;each CAP is 2. The compound of claim 1, which is represented by formula II or formula III: 3. The compound of claim 1, wherein at least one of R3 and R4 is a group represented by formula A; andthe C6-C15-membered aromatic carbocycle of A1 is selected from the group consisting of -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl. 4. The compound of claim 1, wherein at least one of R3 and R4 is a group represented by formula A; andA1 is 5. The compound of claim 1, wherein R5 is 6. The compound of claim 1, which is represented by one of the following formulas: or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein at least one of R3 and R4 is hydrogen. 8. The compound of claim 1, wherein R3 is a group represented by formula A; andR4 is hydrogen. 9. The compound of claim 1, wherein R3 is a group represented by formula A;the C6-C15-membered aromatic carbocycle of A1 is selected from the group consisting of -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl; andR4 is hydrogen. 10. The compound of claim 1, wherein R3 is a group represented by formula A:A1 is and R4 is hydrogen. 11. The compound of claim 1, wherein R3 is a group represented by formula A;A1 is and R4 is hydrogen. 12. The compound of claim 1, wherein each CAP is 13. The compound of claim 1, wherein each CAP is and each R13 is hydrogen. 14. The compound of claim 1, wherein R3 is a group represented by formula A;the C6-C15-membered aromatic carbocycle of A1 is selected from the group consisting of -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl;R4 is hydrogen; andCAP is 15. The compound of claim 1, wherein R3 is a group represented by formula A;the C6-C15-membered aromatic carbocycle of A1 is selected from the group consisting of -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl;R4 is hydrogen; andCAP is and each R13 is hydrogen. 16. The compound of claim 1, wherein R3 is a group represented by formula A;A1 is substituted with one R5 and the remaining substituents are R6; andR4 is hydrogen. 17. The compound of claim 1, wherein R3 is a group represented by formula A;A1 is substituted with one R5 and the remaining substituents are R6;each R6 is hydrogen; andR4 is hydrogen. 18. The compound of claim 1, wherein R3 is a group represented by formula A;the C6-C15-membered aromatic carbocycle of A1 is selected from the group consisting of -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl;A1 is substituted with one R5 and the remaining substituents are R6;each R6 is hydrogen;R4 is hydrogen; andCAP is 19. The compound of claim 1, wherein R3 is a group represented by formula A;the C6-C15-membered aromatic carbocycle of A1 is selected from the group consisting of -phenyl, napthalenyl, 1,2-dihydronapthalenyl, and 1,2,3,4-tetrahydronapthalenyl;A1 is substituted with one R5 and the remaining substituents are R6;each R6 is hydrogen;R4 is hydrogen;CAP is and each R13 is hydrogen. 20. The compound of claim 1, which is or a pharmaceutically acceptable salt thereof. 21. The compound of claim 1, which is a hydrochloride salt of 22. A pharmaceutical composition, comprising a pharmaceutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 23. The pharmaceutical composition of claim 22, wherein the compound is or a pharmaceutically acceptable salt thereof. 24. The pharmaceutical composition of claim 22, wherein the compound is a hydrochloride salt of 25. The pharmaceutical composition of claim 22, further comprising a pharmaceutically effective amount of a therapeutically active agent selected from the group consisting of anti-inflammatory agents, anticholinergic agents, β-agonists, P2Y2 receptor agonists, peroxisome proliferator-activated receptor agonists, kinase inhibitors, antiinfective agents, and antihistamines. 26. The pharmaceutical composition according of claim 22, which is a solution suitable for administration by eye drops. 27. A composition, comprising: (a) the compound or a pharmaceutically acceptable salt thereof of claim 1; and(b) an osmolotically active compound. 28. The composition of claim 27, wherein the compound is or a pharmaceutically acceptable salt thereof. 29. The composition of claim 27, wherein the compound is a hydrochloride salt of 30. A method for blocking sodium channels in a human comprising administering to a human in need thereof an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. 31. The method of claim 30, wherein the compound is or a pharmaceutically acceptable salt thereof. 32. The method of claim 30, wherein the compound is a hydrochloride salt of 33. A method for promoting hydration of mucosal surfaces or restoring mucosal defense in a human comprising administering to a human in need thereof an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. 34. The method of claim 33, wherein the compound is or a pharmaceutically acceptable salt thereof. 35. The method of claim 33, wherein the compound is a hydrochloride salt of 36. 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 of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 37. The method of claim 36, wherein the compound is or a pharmaceutically acceptable salt thereof. 38. The method of claim 36, wherein the compound is a hydrochloride salt of 39. 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 of claim 1, or a pharmaceutically acceptable salt thereof. 40. The method of claim 39, wherein the compound is or a pharmaceutically acceptable salt thereof. 41. The method of claim 39, wherein the compound is a hydrochloride salt of 42. The method of claim 39, 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 (xerostomia), nasal dehydration, asthma, primary ciliary dyskinesia, otitis media, chronic obstructive pulmonary disease, emphysema, pneumonia, diverticulitis, rhinosinusitis, and airborne infections. 43. The method of claim 42, wherein the compound is or a pharmaceutically acceptable salt thereof. 44. The method of claim 42, wherein the compound is a hydrochloride salt of 45. A method of treating dry eye comprising administering to a human in need thereof an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. 46. The method of claim 45, wherein the compound is or a pharmaceutically acceptable salt thereof. 47. The method of claim 45, wherein the compound is a hydrochloride salt of
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