Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
The invention provides α-amino esters of a hydroxypropylthiazolidine carboxamide derivative, (2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide, as well as salts and crystal polymorph s thereof, that can be used to inhibit prostaglandin F receptor. The invention further encompasses methods of treating disorders such as pre-term labor at the early gestational stage by the administration of these substances to a patient in need of treatment.
1. A compound represented by formula (I)
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein said compound binds human prostaglandin F2α receptor with an affinity of about 1 nM.
3. The compound of claim 1 , wherein said compound is soluble in aqueous solution at a concentration of from about 300 μg/mL to about 500 μg/mL.
4. The compound of claim 3 , wherein said compound is soluble in aqueous solution at a concentration of about 380 μg/mL.
5. The compound of claim 1 , wherein said compound inhibits production of inositol trisphosphate in a uterine myocyte.
6. The compound of claim 1 , wherein said compound induces a reduction in the amplitude of uterine contractions in a mammalian subject following administration of said compound to said mammalian subject.
7. The compound of claim 6 , wherein said mammalian subject is a human.
8. The compound of claim 1 , wherein said compound is in a crystalline state.
9. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
10. The pharmaceutical composition of claim 9 , wherein said pharmaceutical composition is formulated for oral administration to a human subject.
11. The pharmaceutical composition of claim 10 , wherein said pharmaceutical composition is a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.
12. The pharmaceutical composition of claim 9 , wherein said pharmaceutical composition is formulated for intravenous administration to a human subject.
13. A method of synthesizing a compound represented by formula (I)
or a pharmaceutically acceptable salt thereof, said method comprising reacting a precursor represented by formula (IV)
with a precursor represented by formula (V)
to form an amino ester, wherein X is a protecting group, and wherein said method comprises deprotecting said amino ester.
14. The method of claim 13 , said method comprising reacting said amino ester with a reagent capable of deprotecting said amino ester.
15. The method of claim 14 , wherein said protecting group is selected from the group consisting of tert-butoxycarbonyl, trityl, 4-monomethoxytrityl, 4-methyltrityl, 3,5-dimethoxyphenylisopropoxycarbonyl, 2-(4-biphenyl)isopropoxycarbonyl, 2-nitrophenylsulfenyl, 9-fluorenylmethoxycarbonyl, 2-(4-nitrophenylsulfonyl)ethoxycarbonyl, (1,1-dioxobenzo[b]thiophene-2-yl)methoxycarbonyl, 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl, 2,7-di-tert-butyl-9-fluorenylmethoxycarbonyl, 2-fluoro-9-fluorenylmethoxycarbonyl, 2-monoisooctyl-9-fluorenylmethoxycarbonyl, 2,7-diisooctyl-9-fluorenylmethoxycarbonyl, tetrachlorophthaloyl, 2-[phenyl(methyl)sulfonio]ethyloxycarbonyl tetrafluoroborate, ethanesulfonylethoxycarbonyl, 2-(4-sulfophenylsulfonyl)ethoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, o-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, benzothiazole-2-sulfonyl, 2,2,2-trichloroethyloxycarbonyl, dithiasuccinoyl, p-nitrobenzyloxycarbonyl, an α-azidoacid, propargyloxycarbonyl, 9-(4-bromophenyl)-9-fluorenyl, azidomethoxycarbonyl, hexafluoroacetone, 2-chlorobenzyloxycarbonyl, trifluoroacetyl, 2-(methylsulfonyl)ethoxycarbonyl, phenyldisulfanylethyloxycarbonyl, and 2-pyridyldisulfanylethyloxycarbonyl.
16. The method of claim 14 , wherein said reagent is selected from the group consisting of methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, acetic acid, piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, morpholine, hexamethyleneimine, ammonia, diethylamine, piperazine, tris(2-aminoethyl)amine, hydrazine, 1-methylpyrrolidine, sodium hydrogen carbonate, sodium hydroxide, barium hydroxide, sodium carbonate, molecular hydrogen, hydrobromic acid, boron tribromide, tetrakis(triphenylphosphine)palladium, thiophenol, β-mercaptoethanol, 2-mercaptoacetic acid, aluminum amalgam, zinc, hypophosphorous acid, sodium borohydride, N-mercaptoacetamide, tin(II) chloride, trimethylphosphine, tributylphosphine, triphenylphosphine, benzyltriethylammonium tetrathiomolybdate, palladium(II) acetate, hydrofluoric acid, trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, and trifluoromethanesulfonic acid.
17. The method of claim 14 , wherein said protecting group is tert-butoxycarbonyl and said reagent is methanesulfonic acid.
18. The method of claim 13 , said method comprising exposing said amino ester to electromagnetic radiation, thereby deprotecting said amino ester.
19. The method of claim 18 , wherein said protecting group is selected from the group consisting of o-nitrobenzyloxycarbonyl, 4-nitroveratryloxycarbonyl, 2-(2-nitrophenyl)propyloxycarbonyl, and 2-(3,4-methylenedioxy-6-nitrophenyl)propyloxycarbonyl.
20. The method of claim 18 , wherein said electromagnetic radiation is characterized by a wavelength of from about 300 to about 400 nm.
21. The method of claim 13 , said method comprising reacting said precursor represented by formula (IV) with said precursor represented by formula (V) and a diimide.
22. The method of claim 21 , wherein said diimide is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-diisopropylcarbodiimide, and N,N′-diisopropylcarbodiimide.
23. The method of claim 22 , wherein said diimide is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
24. The method of claim 13 , said method comprising reacting said precursor represented by formula (IV) with said precursor represented by formula (V) and a benzotriazole derivative.
25. The method of claim 24 , wherein said benzotriazole derivative is selected from the group consisting of 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.
26. The method of claim 25 , wherein said benzotriazole derivative is 1-hydroxybenzotriazole.
27. The method of claim 13 , said method comprising reacting said precursor represented by formula (IV) with said precursor represented by formula (V) and a base.
28. The method of claim 27 , wherein said base is N,N-dimethylaminopyridine.
29. The method of claim 13 , said method comprising synthesizing said precursor represented by formula (IV) by reacting a precursor represented by formula (VI)
with a precursor represented by formula (VII)
30. The method of claim 29 , said method comprising reacting said precursor represented by formula (VI) with said precursor represented by formula (VII), diisopropylethylamine, and N,N-dimethylaminopyridine.
31. A method of treating or preventing preterm labor in a human subject, said method comprising administering to said human subject a therapeutically effective amount of a compound represented by formula (I)
or a pharmaceutically acceptable salt thereof.
32. The method of claim 31 , wherein said human subject is characterized by a gestational age of from about 24 to about 34 weeks.
33. The method of claim 31 , wherein said human subject exhibits a reduction in the amplitude of uterine contractions following said administering.
34. The method of claim 31 , said method comprising orally administering said compound to said human subject.
35. The method of claim 31 , said method comprising intravenously administering said compound to said human subject.
36. A method of preventing labor prior to cesarean delivery in a human subject, said method comprising administering to said human subject a therapeutically effective amount of a compound represented by formula (I)
or a pharmaceutically acceptable salt thereof.
37. The method of claim 36 , wherein said human subject is characterized by a gestational age of from about 24 to about 34 weeks.
38. The method of claim 36 , wherein said human subject exhibits a reduction in the amplitude of uterine contractions following said administering.
39. The method of claim 36 , said method comprising orally administering said compound to said human subject.
40. The method of claim 36 , said method comprising intravenously administering said compound to said human subject.
41. A kit comprising a compound represented by formula (I)
or a pharmaceutically acceptable salt thereof and a package insert, wherein said package insert instructs a user of said kit to administer said compound to a human subject experiencing or at risk of undergoing preterm labor.
42. The kit of claim 41 , wherein said human subject is characterized by a gestational age of from about 24 to about 34 weeks.
43. The kit of claim 41 , wherein said package insert instructs a user of said kit to orally administer said compound to said human subject.
44. The kit of claim 41 , wherein said package insert instructs a user of said kit to intravenously administer said compound to said human subject.