Channel modulators

Patent metadata

Field	Value
Publication number	US-10465188-B2
Application number	US-201514833041-A
Country	US
Kind code	B2
Filing date	Aug 21, 2015
Priority date	Aug 22, 2014
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

The inventions relate to compositions and articles of manufacture comprising connexin modulators, pannexin modulators, gap junction modulators, hemichannel modulators, and pannexin channel modulators and their use, alone or in combination, in treating ocular and other disorders.

First claim

We claim:

1. A method for treating a subject for an ocular disorder selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, ocular fibrosis, retinal perfusion impairment, geographic atrophy, ocular inflammation, ocular vessel leak, ocular edema and ocular hypoxia, comprising administering to said subject a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator, wherein said modulator is a compound according to Formula I:

wherein Y is C—R 1 ;
R 1 is acetyl;
R 2 is hydrogen, C 3-8 cycloalkyl, C 1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C 1-6 alkoxy or substituted aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF 3 S; or a group CF 3 -A-, where A is —CF 2 —,
—CO—, —CH 2 —, CH(OH), SO 2 , SO, CH 2 —O, or CONH; or a group CF 2 H-A′- where A′ is oxygen, sulphur, SO, SO 2 , CF 2 or CFH; trifluoromethoxy, C 1-6 alkylsulphinyl, perfluoro C 2-6 alkylsulphonyl, C 1-6 alkylsulphonyl, C 1-6 alkoxysulphinyl, C 1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, or heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, 1-mercapto C 2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, in which any amino moiety is optionally substituted by one or two C 1-6 alkyl groups, or C 1-6 alkylsulphinylamino, C 1-6 alkylsulphonylamino, C 1-6 alkoxysulphinylamino or C 1-6 alkoxysulphonylamino, or ethylenyl terminally substituted by C 1-6 alkylcarbonyl, nitro or cyano, or —C(C 1-6 alkyl)NOH or —C(C 1-6 alkyl)NNH 2 ; or amino optionally substituted by one or two C 1-6 alkyl or by C 2-7 alkanoyl; one of R 3 and R 4 is hydrogen or C 1-4 alkyl and the other is C 1-4 alkyl, CF 3 or CH 2 X a is fluoro, chloro, bromo, iodo, C 1-4 alkoxy, hydroxy, C 1-4 alkylcarbonyloxy, —S—C 1-4 alkyl, nitro, amino optionally substituted by one or two C 1-4 alkyl groups, cyano or C 1-4 alkoxycarbonyl; or R 3 and R 4 together are C 2-5 polymethylene optionally substituted by C 1-4 alkyl;
R 5 is C 1-6 alkylcarbonyloxy, benzoyloxy, ONO 2 , benzyloxy, phenyloxy or C 1-6 alkoxy and R 6 and R 9 are hydrogen or R 5 is hydroxy and R 6 is hydrogen or C 1-2 alkyl and R 9 is hydrogen;
R 7 is heteroaryl or phenyl, both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C 1-4 alkyl, cyano, azido, C 1-4 alkoxy, trifluoromethoxy and trifluoromethyl;
R 8 is hydrogen, C 1-6 alkyl, OR or NHCOR 10 wherein R 11 is hydrogen, C 1-6 alkyl, formyl, C 1-6 alkanoyl, aroyl or aryl-C 1-6 alkyl and R 10 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, mono or di C 1-6 alkyl amino, amino, amino-C 1-6 alkyl, hydroxyl-C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 acyloxy-C 1-6 alkyl, C 1-6 alkoxycarbonyl-C 1-6 -alkyl, aryl or heteroaryl; the R 8 —N—CO—R 7 group being cis to the R 5 group; and X is oxygen or NR 12 where R 12 is hydrogen or C 1-6 alkyl;

or Formula II

wherein
Q is O or an oxime,
R 2 is H or B—R 21 ,
A is a direct bond, —C(O)O*—, —C(R 3 )(R 4 )O*—, —C(O)O—C(R 3 )(R 4 )O*—, or —C(R 3 )(R 4 )OC(O)O*— wherein the atom marked * is directly connected to R 1 , R 3 and R 4 are selected independently from H, fluoro, C 1-4 alkyl, or C 1-4 fluoroalkyl, or R 3 and R 4 together with the atom to which they are attached form a cyclopropyl group,
R 1 is selected from groups [1], [2], [2A], [3], [4], [5] and [6] wherein the atom marked ** is directly connected to A:

R 5 and R 6 are each independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, and benzyl;
R 7 is independently selected from H, C 1-4 alkyl, and C 1-4 fluoroalkyl;
R 8 is selected from:
(i) H, C 1-4 alkyl, or C 1-4 fluoroalkyl,
(ii) the side chain of a natural or unnatural alpha-amino acid, or a peptide as described herein, and
(iii) biotin or chemically linked to biotin;
R 9 is selected from H, —N(R)(R 12 ), —N + (R 1 )(R 12 )(R 13 )X − , and —N(R 11 )C(O)R 14
wherein R 11 , R 12 , and R 13 are independently selected from H, C 1-4 alkyl, and C 1-4 fluoroalkyl,
R 14 is H, C 1-4 alkyl, or C 1-4 fluoroalkyl,
R 10 and R 15 are independently selected from C 1-4 alkyl and C 1-4 fluoroalkyl,
X is a pharmaceutically acceptable anion,
wherein,
B is a direct bond, —C(O)O*—, —C(R 23 )(R 24 )O*, C(O)O C(R 23 )(R 24 )*, or
C(R 23 )(R 24 )OC(O)O* wherein the atom marked * is directly connected to R 21 ,
R 23 and R 24 are selected independently from H, fluoro, C 1-4 alkyl, and C 1-4 fluoroalkyl,
R 21 is selected from groups [21], [22], [22A], [23], [24], [25] and [26] wherein the atom marked ** is directly connected to B:

R 25 and R 26 are each independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl and benzyl;
R 27 is independently selected from H, C 1-4 alkyl, and C 1-4 fluoroalkyl;
R 28 is selected from:
(i) H, C 1-4 alkyl, or C 1-4 fluoroalkyl,
(ii) the side chain of a natural or unnatural alpha-amino acid or a peptide as described herein, and
(iii) biotin or chemically linked to biotin;
R 29 is selected from H, —N(R 31 )(R 32 ), or —N*(R 31 )(R 32 )(R 33 )X—, and —N(R 31 )C(O)R 34
wherein R 31 , R 32 , and R 33 are independently selected from H, C 1-4 alkyl, and C 1-4 fluoroalkyl,
R 34 is H, C 1-4 alkyl, or C 1-4 fluoroalkyl,
X is a pharmaceutically acceptable anion,
R 30 and R 35 are independently C 1-4 alkyl and C 1-4 fluoroalkyl.

2. A method for treating a subject for inflammation of the choroid or the inner retina, comprising administering to said subject a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator, wherein said modulator is a compound according to Formula I or Formula II and inflammation in the choroid or inner retina is reduced:

wherein Y is C—R 1 ;
R 1 is acetyl;
R 2 is hydrogen, C 3-8 cycloalkyl, C 1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C 1-6 alkoxy or substituted aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF 3 S; or a group CF 3 -A-, where A is —CF 2 —,
—CO—, —CH 2 —, CH(OH), SO 2 , SO, CH 2 —O, or CONH; or a group CF 2 H-A′- where A′ is oxygen, sulphur, SO, SO 2 , CF 2 or CFH; trifluoromethoxy, C 1-6 alkylsulphinyl, perfluoro C 2-6 alkylsulphonyl, C 1-6 alkylsulphonyl, C 1-6 alkoxysulphinyl, C 1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, or h

Assignees

• Auckland Uniservices Ltd
• Coda Therapeutics Inc
• Ocunexus Therapeutics Inc

Inventors

• Green Colin Richard
• Kim Yeri
• Phillips Anthony
• Duft Bradford James

Classifications

• A61K9/0048

  Eye, e.g. artificial tears · CPC title

• A61K38/39

  Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG] · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• A61K31/557

  Eicosanoids, e.g. leukotrienes {or prostaglandins} · CPC title

• A61K31/5575

  having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha · CPC title