5-LIPOXYGENASE-ACTIVATING PROTEIN INHIBITOR
A pharmaceutically acceptable salt comprising 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate as the anion and a cation selected from Na + , K + , Li + , Ca 2+ , NH 4 + , the protonated form of dicyclohexylamine, the protonated form of N-methyl-D-glucamine, the protonated form of tris(hydroxymethyl)methylamine, the protonated form of arginine, and the protonated form of lysine is disclosed, along with formulations and methods of using the same.
1 . A pharmaceutically acceptable salt comprising 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate as the anion and a cation selected from Na + , K + , Ca 2+ , NH 4 + , the protonated form of dicyclohexylamine, the protonated form of N-methyl-D-glucamine, the protonated form of tris(hydroxymethyl)methylamine, the protonated form of arginine, and the protonated form of lysine.
2 . The pharmaceutically acceptable salt according to claim 1 , which is sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate (Compound 2):
3 . The pharmaceutically acceptable salt according to claim 1 , wherein the pharmaceutically acceptable salt is desolvated.
4 . The pharmaceutically acceptable salt according to claim 1 , wherein the pharmaceutically acceptable salt is solvated.
5 . The pharmaceutically acceptable salt according to claim 1 , wherein the pharmaceutically acceptable salt is solvated with a solvent selected from ethyl acetate, isopropyl acetate, methyl tert-butylether, heptane, isopropanol, and ethanol.
6 . The pharmaceutically acceptable salt according to claim 1 , wherein the pharmaceutically acceptable salt is solvated with methyl tert-butylether.
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12 . The pharmaceutically acceptable salt according to claim 1 , wherein the pharmaceutically acceptable salt is crystalline.
13 . The pharmaceutically acceptable salt according to claim 1 , which is sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate (Compound 2), wherein Compound 2 is crystalline polymorph Form C.
14 . The pharmaceutically acceptable salt according to claim 1 which is sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate (Compound 2), wherein Compound 2 is crystalline and was formed using methyl tert-butyl ether.
15 . The pharmaceutically acceptable salt according to claim 1 which is sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate (Compound 2), wherein Compound 2 has at least one of the following properties:
(1c) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in FIG. 1 ;
(2c) an XRPD pattern with peaks at about 17.2°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta;
(3c) a single melting point at about 290° C. to about 295° C. as measured by differential scanning calorimetry (DSC);
(4c) a DSC or a thermo-gravimetric analysis (TGA) substantially similar to the ones set forth in FIG. 15 ;
(5c) physical and chemical stability (at 5° C., 25° C./60% relative humidity (RH), and/or 40° C./75% RH for at least one month in a humidity chamber);
(6c) non-hygroscopicity;
(7c) IR spectrum substantially similar to the one set forth in FIG. 19 ; and/or
(8c) an X-ray powder diffraction (XRPD) pattern substantially similar to an XRPD pattern obtained for crystals of Compound 2 obtained from methyl tert-butyl ether (MTBE) or acetonitrile.
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23 . A pharmaceutical composition comprising:
a. a pharmaceutically acceptable salt according to claim 1 ; and
b. at least one pharmaceutically acceptable inactive ingredient selected from among excipients, diluents, and carriers.
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31 . A pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1 , wherein the pharmaceutical composition is in a form suitable for oral administration to a mammal.
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33 . An oral pharmaceutical composition comprising:
(a) a pharmaceutically acceptable salt according to claim 1 , wherein the cation is selected from Na + , K + , and Li + ;
(b) an aqueous buffer solution; and optionally
(c) ethanol or Poloxamer 124.
34 . An oral pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1 , wherein:
the cation is Na + .
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82 . A method of treating asthma in a human comprising administering to the human an oral pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1 .
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84 . A method of treating allergic rhinitis in a human comprising administering to the human an oral pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1 .
85 . A method of preventing allergic rhinitis in a human comprising administering to the human an oral pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1 .
86 . A method of treating chronic obstructive pulmonary disease in a human comprising administering to the human an oral pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1 .
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91 . A method of treating cardiovascular disease in a human comprising administering to the human a pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim 1
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