US 9,499,464 B2 · Opsin-binding ligands, compositions and methods of use

Abstract

Compounds are disclosed that are useful for treating ophthalmic conditions caused by or related to production of toxic is visual cycle products that accumulate in the eye, such as dry adult macular degeneration, as well as conditions caused by or related to the misfolding of mutant opsin proteins and/or the mis-localization of opsin proteins. Compositions of these compounds alone or in combination with other therapeutic agents are also described, along with therapeutic methods of using such compounds and/or compositions. Methods of synthesizing such agents are also disclosed.

Claims16

Dependent claims

A compound of Formula I,

wherein R1 and R2 are independently:
1) hydrogen,
2) —CH3, or
1) —CH2CH3,
Ra and Rb, are each independently:
1) hydrogen,
2) —CH3, or
3) —CH2CH3;
R3′ and R5 are each independently:
1) hydrogen, or
2) lower alkyl;
and
R4 is
1) hydrogen,
2) cycloalkyl, or
3) phenyl;
wherein if either R1 or R2 is hydrogen then each of Ra and Rb is selected from methyl and ethyl, including pharmaceutically acceptable salts, solvates and hydrates thereof.

14 more elements

A method of inhibiting the formation or accumulation of a visual cycle product, comprising contacting an opsin protein with a compound selected from the group consisting of:

(±)-(3aS,7aS)-methyl 3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-indene-2-carboxylate (Compound 8);
2,7,7-trimethyl-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one (Compound 13);
(±)-(3aR,7aS)-3,3a,7,7-tetramethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one oxime (Compound 14);
(±)-(3R,3aS,7aS)-3,3a,7,7-tetramethyloctahydro-1H-inden-1-one oxime (Compound 16);
(±)-(1R,7aS)-1,4,4,7a-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 20);
(±)-((3aS,7aS)-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-2-yl)methanol (Compound 22);
(±)-((3aS,7aS)-3a,7,7-trimethyloctahydro-1H-inden-2-yl)methanol (Compound 26);
7,7-dimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 27);
(±)-(3aR,7aS)-3-isopropyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 29);
4,4,7a-trimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one oxime (Compound 30);
(±)-(3aS,7aR)-4,4,7a-trimethyloctahydro-1H-inden-1-one oxime (Compound 33);
(±)-(3aR,7aS)-3-ethyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 34);
(±)-(1S,3aS,7aS)-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-ol (Compound 36);
(±)-(1R,3aS,7aS)-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-ol (Compound 37);
4,4,7,7-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 41);
(±)-(3aR,7aS)-3-cyclopropyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 44);
(±)-(3aR,7aS)-3-isopropyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one oxime (Compound 45);
(±)-(3S,3aS,7aS)-3-isopropyl-3a,7,7-trimethyloctahydro-1H-inden-1-one (Compound 46);
4,4-dimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 53);
4,4-dimethylhexahydro-1H-inden-2(3H)-one oxime (Compound 55);
(±)-(1S,3S,3aS,7aS)-3-isopropyl-3a,7,7-trimethyloctahydro-1H-inden-1-ol (Compound 58);
(±)-(1S,3aS,7aS)-3a,7,7-trimethyloctahydro-1H-inden-1-ol (Compound 60);
(±)-(3aS,7aS)-3a,7,7-trimethylhexahydro-1H-inden-2(3H)-one oxime (Compound 62);
(±)-(3aS,7aS)-3a,7,7-trimethyloctahydro-1H-inden-2-ol (Compound 63);
(±)-(3aS,7aS)-2,3,4,4-tetramethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 64);
(±)-(1R,3aR,7aS)-2,3,3a,7,7-pentamethyl-3a,4,5,6,7,7a-hexahydro 1H inden-1-ol (Compound 66);
(±)-(1R,7aS)-1,4,4-trimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 67);
(+)-4,4,7,7-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 69a);
(3aR,7aS) and (3aS,7aR)-4,4,7,7-tetramethylhexahydro-1H-inden-2(3H)-one (Compound 70);
(±)-(1S,3aS,7aS)-2,3,4,4-tetramethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-ol (Compound 72);
(±)-(3aS,7aS)-2,3,4,4-tetramethyloctahydro-1H-inden-1-one (Compound 73);
(±)-(3R,3aS,7aR)-3,7,7-trimethyloctahydro-1H-inden-1-one (Compound 74);
7a-ethyl-4,4-dimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 75);
(±)-(1R,7aS)-1-ethyl-4,4,7a-trimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 76);
(±)-(3aR,7aS)-4,4,7,7-tetramethyloctahydro-1H-inden-2-ol (Compound 77);
4,4,7,7-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one oxime (Compound 78);
and
(±)-(3aR,7aS)-4,4,7,7-tetramethylhexahydro-1H-inden-2(3H)-one oxime (Compound 79),
or a pharmaceutically acceptable salt thereof.

36 more elements

A compound selected from the group consisting of:

(±)-(3aS,7aS)-methyl 3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-indene-2-carboxylate (Compound 8);
2,7,7-trimethyl-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one (Compound 13);
(±)-(3aR,7aS)-3,3a,7,7-tetramethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one oxime (Compound 14);
(±)-(3R,3aS,7aS)-3,3a,7,7-tetramethyloctahydro-1H-inden-1-one oxime (Compound 16);
(±)-(1R,7aS)-1,4,4,7a-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 20);
(±)-((3aS,7aS)-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-2-yl)methanol (Compound 22);
(±)-((3aS,7aS)-3a,7,7-trimethyloctahydro-1H-inden-2-yl)methanol (Compound 26);
7,7-dimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 27);
(±)-(3aR,7aS)-3-isopropyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 29);
4,4,7a-trimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one oxime (Compound 30);
(±)-(3aS,7aR)-4,4,7a-trimethyloctahydro-1H-inden-1-one oxime (Compound 33);
(±)-(3aR,7aS)-3-ethyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 34);
(±)-(1S,3aS,7aS)-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-ol (Compound 36);
(±)-(1R,3aS,7aS)-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-ol (Compound 37);
4,4,7,7-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 41);
(±)-(3aR,7aS)-3-cyclopropyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 44);
(±)-(3aR,7aS)-3-isopropyl-3a,7,7-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one oxime (Compound 45);
(±)-(3S,3aS,7aS)-3-isopropyl-3a,7,7-trimethyloctahydro-1H-inden-1-one (Compound 46);
4,4-dimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 53);
4,4-dimethylhexahydro-1H-inden-2(3H)-one oxime (Compound 55);
(±)-(1S,3S,3aS,7aS)-3-isopropyl-3a,7,7-trimethyloctahydro-1H-inden-1-ol (Compound 58);
(±)-(1S,3aS,7aS)-3a,7,7-trimethyloctahydro-1H-inden-1-ol (Compound 60);
(±)-(3aS,7aS)-3a,7,7-trimethylhexahydro-1H-inden-2(3H)-one oxime (Compound 62);
(±)-(3aS,7aS)-3a,7,7-trimethyloctahydro-1H-inden-2-ol (Compound 63);
(±)-(3aS,7aS)-2,3,4,4-tetramethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound 64);
(±)-(1R,3aR,7aS)-2,3,3a,7,7-pentamethyl-3a,4,5,6,7,7a-hexahydro 1H inden-1-ol (Compound 66);
(±)-(1R,7aS)-1,4,4-trimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 67);
(+)-4,4,7,7-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 69a);
(3aR,7aS) and (3aS,7aR)-4,4,7,7-tetramethylhexahydro-1H-inden-2(3H)-one (Compound 70);
(±)-(1S,3aS,7aS)-2,3,4,4-tetramethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-ol (Compound 72);
(±)-(3aS,7aS)-2,3,4,4-tetramethyloctahydro-1H-inden-1-one (Compound 73);
(±)-(3R,3aS,7aR)-3,7,7-trimethyloctahydro-1H-inden-1-one (Compound 74);
7a-ethyl-4,4-dimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 75);
(±)-(1R,7aS)-1-ethyl-4,4,7a-trimethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one (Compound 76);
(±)-(3aR,7aS)-4,4,7,7-tetramethyloctahydro-1H-inden-2-ol (Compound 77);
4,4,7,7-tetramethyl-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one oxime (Compound 78);
and
(±)-(3aR,7aS)-4,4,7,7-tetramethylhexahydro-1H-inden-2(3H)-one oxime (Compound 79),
or a pharmaceutically acceptable salt thereof.

36 more elements

Dependencies are inferred from the claim text.

Facts

Application

14/352,178Filed 19 Oct 2012 · us provisional application

Priority

19 Oct 2011

Published

US 2014/0256782 A111 Sep 2014

Granted

22 Nov 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 307/83
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents
C07C 35/32
With hydroxy on a condensed ring system having two rings: the condensed ring system being a system, e.g. indenols
C07C 49/443
Having two rings: the condensed ring system containing eight or nine carbon atoms

Family

Application61/627,855Us provisional application · filed 19 Oct 2011

Application61/561,434Us provisional application · filed 18 Nov 2011

Application61/564,401Us provisional application · filed 29 Nov 2011

US 2014/0256782 A1Pre-grant publication · published 11 Sep 2014

US 9,499,464 B2This patent

From the US filing history. Foreign family members aren’t listed.

Opsin-binding ligands, compositions and methods of use

Life of this patent

Opsin-binding ligands, compositions and methods of use

Life of this patent

Abstract

Claims16