Formulations of rbp4 inhibitors and methods of use

Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for the treatment of retinal binding protein (RBP4) related diseases, such as macular degeneration and the like.

We claim: 
     
         1 . A pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises:
 (i) a compound of Formula (I), a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof:   
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently halogen, haloalkyl, or alkyl; 
 R 2  is —H, —OH, or halogen; 
 p is 0, 1, 2, 3, 4, or 5; 
 A has the structure: 
 
       
         
           
           
               
               
           
         
         wherein:
 α, β, χ, and δ are each independently absent or present, and when present each is a bond; 
 X is C; 
 Z 1  is S, O, or N; 
 Z 2  is S, O, N, or NR 3 ; 
 R 3  is H, C 1 -C 4  alkyl, or oxetane; and 
 B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure; and 
 (ii) a dispersion polymer. 
 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein A has the structure 
       
         
           
           
               
               
           
         
         wherein:
 n is 0, 1, or 2; 
 α, χ, δ, ε, and ϕ are each independently absent or present, and when present each is a bond; 
 Z 1  is S, O, or N; 
 Z 2  is S, O, N or NR 3 ,
 wherein R 3  is H, C 1 -C 4  alkyl, or oxetane; 
 
 X is C; 
 Y 1 , Y 2 , Y 3  and each occurrence of Y 4  are each independently CR 4 , C(R 5 ) 2 , NR 6 , O, N, SO 2 , or —(C═O)—, wherein:
 R 4  is H, halogen, C 1 -C 10  alkyl, C 1 -C 10  cycloalkyl, —O(C 1 -C 10  alkyl), —C(O)OH, —C(O)O(C 1 -C 10  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4  alkyl), —C(O)N(C 1 -C 4  alkyl) 2 , —NHC(O)NH(C 1 -C 10  alkyl), —NHC(O)N(C 1 -C 4  alkyl) 2 , —SO 2 NH(C 1 -C 10  alkyl), —SO 2 N(C 1 -C 10  alkyl) 2 , —CN, or —CF 3 ; 
 R 5  is H or C 1 -C 10  alkyl; and 
 R 6  is H, C 1 -C 10  alkyl, C 3 -C 6  cycloalkyl, —(C 1 -C 10  alkylene)CF 3 , —(C 1 -C 10  alkylene)OCH 3 , —(C 1 -C 10  alkylene)-halogen, —SO 2 (C 1 -C 10  alkyl), —SO 2 (C 1 -C 10  alkylene)—CF 3 , —SO 2 (C 1 -C 10  alkylene)OCH 3 , —SO 2 (C 1 -C 10  alkylene)-halogen, —C(O)(C 1 -C 10  alkyl), —C(O)(C 1 -C 10  alkylene)CF 3 , —C(O)(C 1 -C 10  alkylene)OCH 3 , —C(O)(C 1 -C 10  alkylene)-halogen, —C(O)NH(C 1 -C 10  alkyl), —C(O)N(C 1 -C 10  alkyl) 2 , —(C 1 -C 10  alkyl)C(O)OH, —C(O)NH 2 , or oxetane. 
 
 
       
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein A has the structure 
       
         
           
           
               
               
           
         
         wherein:
 n is 0; 
 R 3  is H, C 1 -C 4  alkyl, or oxetane; 
 Y 1  and Y 3  are each CH 2  or C(CH 3 ) 2 ; 
 Y 2  is O, SO 2 , or NR 6 ; and
 R 6  is H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —(C 1 -C 4  alkylene)CF 3 , —(C 1 -C 4  alkylene)OCH 3 , —(C 1 -C 4  alkylene)-halogen, —SO 2 (C 1 -C 4  alkyl), —SO 2 (C 1 -C 4  alkylene)CF 3 , —SO 2 (C 1 -C 4  alkylene)OCH 3 , —S02(C 1 -C 4  alkylene)-halogen, —C(O)(C 1 -C 4  alkyl), —C(O)(C 1 —C 4  alkylene)CF 3 , —C(O)(C 1 -C 4  alkylene)OCH 3 , —C(O)(C 1 -C 4  alkylene)-halogen, —C(O)NH(C 1 -C 4  alkyl), —C(O)N(C 1 -C 4  alkyl) 2 , —(C 1 -C 4  alkylene)C(O)OH, —C(O)NH 2 , or oxetane. 
 
 
       
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (I) has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. 
       
     
     
         5 . The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is effective to reduce RBP4 concentrations in dosages forms of 1 to 200 mg or 5 to 25 mg. 
     
     
         6 . The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is a micronized crystalline. 
     
     
         7 . The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is a polymorph exhibiting an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/−0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. 
     
     
         8 . The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is amorphous and molecularly dispersed in the dispersion polymer. 
     
     
         9 . The pharmaceutical composition of any one of the preceding claims, wherein the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, and combinations thereof. 
     
     
         10 . The pharmaceutical composition of any one of the preceding claims, wherein the dispersion polymer comprises HPMC. 
     
     
         11 . The pharmaceutical composition of any one of  claims 1 - 6 , wherein the dispersion polymer comprises HPMC-AS. 
     
     
         12 . The pharmaceutical composition of any one of the preceding claims, wherein the dispersion polymer comprises about 1-99% by weight, 20-80% by weight, or 40-60% by weight of the solid dispersion. 
     
     
         13 . The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) comprises about 1-99% by weight, about 20-80% by weight, or about 40-60% by weight of the solid dispersion. 
     
     
         14 . The pharmaceutical composition of any one of the preceding claims, wherein the ratio of the compound of Formula (I):dispersion polymer is about 20:80 (w/w) in the solid dispersion. 
     
     
         15 . The pharmaceutical composition of any one of the preceding claims, wherein the ratio of the compound of Formula (I):dispersion polymer is about 40:60 (w/w) in the solid dispersion. 
     
     
         16 . The pharmaceutical composition of  claim 14  or  15 , wherein the compound of Formula (I) is 
       
         
           
           
               
               
           
         
         and the dispersion polymer is HPMC-AS. 
       
     
     
         17 . The pharmaceutical composition of any one of  claims 10 - 16 , wherein the dispersion polymer is HPMC-AS having an acetyl content from 7-11 wt %, a succinyl content from 10-14 wt %, a methoxyl content from 21-25 wt %, and a hydroxypropyl content from 5-9 wt %. 
     
     
         18 . The pharmaceutical composition of any one of  claims 10 - 16 , wherein the dispersion polymer is HPMC-AS having an acetyl content from 10-14 wt %, a succinyl content from 4-8 wt %, a methoxyl content from 22-26 wt %, and a hydroxypropyl content from 6-10 wt %. 
     
     
         19 . The pharmaceutical composition of any one of  claims 1 - 9 , wherein the dispersion polymer comprises polyvinylpyrrolidone (PVP). 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the PVP is present in a ratio with the compound of Formula (I) from about 10:1 to about 1:1. 
     
     
         21 . The pharmaceutical composition of  claim 19  or  20 , wherein the PVP is a present in a ratio with the compound of Formula (I) of about 2:1, about 3:1, or about 5:1. 
     
     
         22 . The pharmaceutical composition of any one of  claims 19 - 21 , wherein the PVP has a molecular weight average molecular weight from about 7,000 Daltons to about 11,000 Daltons. 
     
     
         23 . The pharmaceutical composition of any one of the preceding claims, further comprising a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof. 
     
     
         24 . The pharmaceutical composition of any one of the preceding claims, wherein the solid dispersion further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof. 
     
     
         25 . The pharmaceutical composition of any one of the preceding claims, wherein the solid dispersion has an average particle size of less than 10 μm or less than 20 μm. 
     
     
         26 . A nanosuspension pharmaceutical composition comprising:
 a compound of Formula (I), a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof:   
       
         
           
           
               
               
           
         
         wherein:
 each R 1  is independently halogen, haloalkyl, or alkyl; 
 R 2  is —H, —OH, or halogen; 
 p is 0, 1, 2, 3, 4, or 5; 
 A has the structure: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 α, β, χ, and δ are each independently absent or present, and when present each is a bond; 
 X is C; 
 Z 1  is S, O, or N; 
 Z 2  is S, O, N, or NR 3 ; 
 R 3  is H, C 1 -C 4  alkyl, or oxetane; and 
 B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure; 
 
         wherein the compound of Formula (I) is suspended in a pharmaceutically acceptable solvent. 
       
     
     
         27 . The nanosuspension pharmaceutical composition of  claim 26 , wherein the compound of Formula (I) is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. 
       
     
     
         28 . The nanosuspension pharmaceutical composition of  claim 27 , wherein the compound of Formula (I) is a polymorph exhibiting an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/−0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. 
     
     
         29 . The nanosuspension pharmaceutical formulation of any one of  claims 26 - 28 , wherein the concentration of the compound of Formula (I) is from about 1 mg/mL to about 50 mg/mL. 
     
     
         30 . The nanosuspension pharmaceutical formulation of any one of  claims 26 - 29 , wherein the compound of Formula (I) is micronized. 
     
     
         31 . The nanosuspension pharmaceutical formulation of any one of  claims 26 - 30 , wherein the compound of Formula (I) has an average particle size of less than 1000 nm. 
     
     
         32 . The nanosuspension pharmaceutical formulation of any one of  claims 26 - 31 , further comprising a surfactant. 
     
     
         33 . The nanosuspension pharmaceutical formulation of  claim 32 , wherein the surfacing is present at a concentration from about 0.01% to about 1%. 
     
     
         34 . The nanosuspension pharmaceutical formulation of  claim 32  or  33 , wherein the surfactant comprises sodium dodecyl sulfate, a poloxamer, or a polysorbate. 
     
     
         35 . The nanosuspension pharmaceutical formulation of any one of  claims 26 - 34 , further comprising an excipient. 
     
     
         36 . The nanosuspension pharmaceutical formulation of  claim 35 , wherein the excipient comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, or any combinations thereof. 
     
     
         37 . The nanosuspension pharmaceutical composition of  claim 35  or  36 , wherein the excipient is present at a concentration from about 0.1% to about 5%. 
     
     
         38 . The pharmaceutical composition of any one of  claims 1 - 25 , wherein the pharmaceutical composition is in the form of a tablet. 
     
     
         39 . The pharmaceutical composition of any one of  claims 1 - 38 , wherein the pharmaceutical composition is in the form of a capsule. 
     
     
         40 . A method of treating an eye disease comprising administering a therapeutically effective amount of a pharmaceutical composition of any one of the preceding claims to a subject in need thereof. 
     
     
         41 . The method of  claim 40 , wherein the eye disease is a disease characterized by excessive lipofuscin accumulation in the retina. 
     
     
         42 . The method of  claim 41 , wherein the disease characterized by excessive lipofuscin accumulation is Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Juvenile Macular Degeneration (Stargardt Disease), Best disease, adult vitelliform maculopathy, Geographic Atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or an ABCA4 gene associated retinal disease. 
     
     
         43 . A method for lowering the serum concentration of RBP4 in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of any one of  claims 1 - 35 . 
     
     
         44 . The method of any one of  claims 40 - 43 , wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg to about 400 mg of the compound of Formula (I). 
     
     
         45 . The method of any one of  claims 40 - 44 , wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.5 mg to about 50 mg of the compound of Formula (I). 
     
     
         46 . The method of any one of  claims 40 - 45 , wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg of the compound of Formula (I). 
     
     
         47 . The method of any one of  claims 40 - 46 , wherein the pharmaceutical composition is administered one, two, three, or four times daily. 
     
     
         48 . The method of any one of  claims 40 - 46 , wherein the pharmaceutical composition is administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. 
     
     
         49 . The method of any one of  claims 40 - 46 , wherein the pharmaceutical composition is administered once daily. 
     
     
         50 . The method of any one of  claims 40 - 49 , wherein the pharmaceutical composition is administered orally. 
     
     
         51 . The method of any one of  claims 40 - 50 , wherein the serum RBP4 concentration of the subject is reduced to below 1 μM after treatment. 
     
     
         52 . A method of manufacturing a solid dispersion comprising the steps of
 (i) adding a solvent to a vessel;   (ii) adding a compound of Formula (I) of any of  claims 1 - 4  or its pharmaceutically acceptable salt to the vessel;   (iii) adding a dispersion polymer to the vessel to obtain a first mixture;   (iv) mixing the first mixture until the compound of Formula (I) or its pharmaceutically acceptable salt and the dispersion polymer are dissolved in the solvent to obtain a first solution; and   (v) dry spraying the first solution to obtain a first solid.   
     
     
         53 . The method of  claim 52 , wherein the dispersion polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, and combinations thereof. 
     
     
         54 . The method of  claim 52  or  53 , wherein the dispersion polymer is HPMC-AS or polyvinyl pyrrolidine. 
     
     
         55 . The method of any of one of  claims 52 - 54 , wherein the compound of Formula (I) has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, crystalline solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. 
       
     
     
         56 . The method of any one of  claims 52 - 55 , wherein the solvent comprises acetic acid, acetone, acetonitrile, benzene, tert-butyl alcohol, tert-butyl methyl ether, carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, diglyme, 1,2,-dimethoxyethane, dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, dioxane, ethanol, ethyl acetate, ethyl methyl ketone, ethylene glycol, hexanes, hexamethylphosphoramide, methanol, nitromethane, pentanes, 2-proponal, pyridine, tetrahydrofuran, toluene, xylenes, or any combination thereof. 
     
     
         57 . A method for lowering the serum concentration of RBP4 in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, cystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof; 
         wherein the pharmaceutical composition is administered in an amount of about 10 mg; 
         wherein the pharmaceutical composition is administered daily; 
         wherein the serum or plasma levels of RBP4 of the subject are reduced to below 1 μM. 
       
     
     
         58 . A polymorph of a compound of Formula (I) having the structure 
       
         
           
           
               
               
           
         
         wherein the polymorph exhibits an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/−0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. 
       
     
     
         59 . The polymorph of  claim 54 , wherein the polymorph is crystalline. 
     
     
         60 . The polymorph of  claim 58  or  59 , wherein the polymorph exhibits an x-ray powder diffraction pattern having at least five characteristic peaks expressed in degrees two theta (+/−0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. 
     
     
         61 . The polymorph of  claim 58  or  59 , wherein the polymorph exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two theta (+/−0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. 
     
     
         62 . The polymorph of any one of  claims 58 - 61 , wherein the polymorph is micronized. 
     
     
         63 . The polymorph of any one of  claims 58 - 62 , wherein the polymorph has an average particle size of less than 20 μm, less than 10 μm, less than 1 μm, or less than 100 nm.