IP Library › Granted Patent US 9,499,464

Granted Patent B2

US 9,499,464 · App. 14/352,178 · Granted Nov 22, 2016

Opsin-binding ligands, compositions and methods of use

Inventors: David S. Garvey (Dover, MA); Gregory J. Larosa (Newton, MA); Jeremy R. Greenwood (Brooklyn, NY); Leah L. Frye (Portland, OR); Tan Quach (Scarborough, CA); Jamie B. Cote (Newmarket, CA); Judd Berman (Toronto, CA)

Assignee: BIKAM PHARMACEUTICALS, INC.

C07C49/443 C07C35/32 C07C49/553 C07C69/75 C07C233/58 C07D209/34 C07D307/83

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Quick Facts

Patent No.: US 9,499,464
App. No.: 14/352,178
Granted: Nov 22, 2016
Kind: B2

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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.

Claims (144)

1. A compound of Formula I,

wherein R 1 and R 2 are independently:

1) hydrogen,

2) —CH 3 , or

1) —CH 2 CH 3 ,

R a and R b , are each independently:

1) hydrogen,

2) —CH 3 , or

3) —CH 2 CH 3 ;

R 3′ and R 5 are each independently:

1) hydrogen, or

2) lower alkyl; and

R 4 is

1) hydrogen,

2) cycloalkyl, or

3) phenyl;

wherein if either R 1 or R 2 is hydrogen then each of R a and R b is selected from methyl and ethyl, including pharmaceutically acceptable salts, solvates and hydrates thereof.

2. The compound of claim 1 , wherein R 3′ is hydrogen and R 4 is hydrogen.

3. A method of inhibiting the formation or accumulation of a visual cycle product, comprising contacting an opsin protein with a compound of Formula I

wherein R 1 and R 2 are independently:

1) hydrogen,

2) —CH 3 , or

1) —CH 2 CH 3 ,

R a and R b are each independently:

1) hydrogen,

2) —CH 3 , or

3) —CH 2 CH 3 ;

R 3′ and R 5 are each independently:

1) hydrogen, or

2) lower alkyl; and

R 4 is:

1) hydrogen,

2) cycloalkyl, or

3) phenyl;

wherein if either R 1 or R 2 is hydrogen then each of R a and R b is selected from methyl and ethyl, including pharmaceutically acceptable salts, solvates and hydrates thereof.

4. The method of claim 3 , wherein said compound reduces mislocalization of said opsin protein.

5. The method of claim 3 , wherein said opsin protein is present in a cell.

6. The method of claim 3 , wherein said cell is a cone cell or rod cell.

7. The method of claim 3 , wherein said cell is present in a mammalian eye.

8. The method of claim 3 , wherein said visual cycle product is a toxic visual cycle product.

9. The method of claim 8 , wherein said toxic visual cycle product is lipofuscin or N-retinylidene-N-retinylethanolamine (A2E).

10. 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.

11. A composition, comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

12. A compound selected from the group consisting of: