Centrally-active ghrelin agonist and medical uses thereof
The new compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt has a high capability to permeate through the blood-brain barrier and to display, at central nervous system level, a consistent ghrelin agonist activity; the compound is effective in the treatment and/or prevention of a medical condition mediated by the ghrelin receptor in the central nervous system. In particular, in experimental tests, the compound has shown high efficacy in the treatment of neurotoxic damage, with a useful combined pattern of neuroprotective effects both at central and peripheral level. The compound is further useful in the treatment of conditions which require a reduction of the heart rate. The compound is pharmacologically active at low to moderate doses, thus showing a favourable therapeutic index.
1. A compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt in a crystalline form, wherein said compound has an Xray Powder Diffraction (XRPD) pattern comprising peaks at about 4.1° 2θ, about 8.2° 2θ, about 12.3° 2θ, about 23.7° 2θ, and about 25.2° 2θ.
2. The compound of claim 1 , wherein said compound has an XRPD pattern further comprising at least two peaks chosen from about 14.8° 2θ, about 17.5° 2θ, about 27.5° 2θ, and about 28.2° 2θ.
3. The compound of claim 1 , wherein said compound has an XRPD pattern comprising peaks at 4.1° 2θ, 8.2° 2θ, 12.3° 2θ, 23.7° 2θ, and 25.2° 2θ.
4. The compound of claim 3 , wherein said compound has an XRPD pattern further comprising at least two peaks chosen from 14.8° 2θ, 17.5° 2θ, 27.5° 2θ, and 28.2° 2θ.
5. A compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt in a crystalline form, wherein said compound has an Xray Powder Diffraction (XRPD) pattern substantially as shown in FIG. 9 .
6. A pharmaceutical composition comprising the compound of claim 1 , and one or more pharmaceutically acceptable excipients.
7. The pharmaceutical composition of claim 6 , wherein said compound has an XRPD pattern comprising peaks at 4.1° 2θ, 8.2° 2θ, 12.3° 2θ, 23.7° 2θ, and 25.2° 2θ.
8. The pharmaceutical composition of claim 6 , wherein at least one pharmaceutically acceptable excipient is starch or lactose.
9. The pharmaceutical composition of claim 6 , wherein said pharmaceutical composition is a tablet, a pill, troche, chewing gum, a capsule, a microcapsule, a powder, a lyophilizate, pellets, micropellets, granules, microgranules, a gel, a cream, an ointment, a film, a patch, a suppository, a solution, a suspension, a syrup, an elixir or a wafer.
10. A method of treating a medical condition mediated by the ghrelin receptor in the central nervous system of a subject in need thereof, the method comprising administering compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt in a crystalline form to the subject, wherein said compound has an XRPD pattern comprising peaks at about 4.1° 2θ, about 8.2° 2θ, about 12.3° 2θ, about 23.7° 2θ, and about 25.2° 2θ.
11. The method of claim 10 , wherein said compound has an XRPD pattern comprising peaks at 4.1° 2θ, 8.2° 2θ, 12.3° 2θ, 23.7° 2θ, and 25.2° 2θ.
12. The method of claim 10 , wherein said compound is administered in a dose amount ranging from about 0.03 to about 10 mg, expressed as free base.
13. The method of claim 10 , wherein said compound is administered externally to the central nervous system.
14. The method of claim 10 , wherein said compound is administered by an oral, peroral, buccal, sublingual, ocular, percutaneous, transcutaneous, intravenous, intramuscular, inhalatory or rectal route.
15. The method of claim 10 , wherein said medical condition is neurodegeneration, neuropathy, neuropathic pain, encephalomyelitis, Parkinson's Disease, Alzheimer's Disease, cognitive disorders, vagal hyperstimulation, or tachycardia.
16. The method of claim 15 , wherein said neuropathy is a chemotherapy-induced neuropathy.
17. The method of claim 16 , wherein said chemotherapy-induced neuropathy is induced by a proteasome inhibitor or an alkylating agent.
18. The method of claim 15 , wherein said tachycardia is a chemotherapy-induced tachycardia.
19. A method of preventing a medical condition mediated by the ghrelin receptor in the central nervous system of a subject in need thereof, the method comprising administering compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt in a crystalline form to the subject, wherein said compound has an XRPD pattern comprising peaks at about 4.1° 2θ, about 8.2° 2θ, about 12.3° 2θ, about 23.7° 2θ, and about 25.2° 2θ, and wherein the medical condition is chemotherapy-induced neuropathy.
20. The method of claim 19 , wherein said compound has an XRPD pattern comprising peaks at 4.1° 2θ, 8.2° 2θ, 12.3° 2θ, 23.7° 2θ, and 25.2° 2θ.
21. The method of claim 19 , wherein said chemotherapy-induced neuropathy is induced by a proteasome inhibitor or an alkylating agent.
22. A process of producing a compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt in a crystalline form, the process comprising:
dissolving 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl) urea in acetone;
adding aqueous hydrochloric acid to the 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea dissolved in the solvent to form a reaction mixture;
stirring the reaction mixture at about room temperature for about 2 hours;
isolating the compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt in a crystalline form; and
wherein said compound has an XRPD pattern comprising peaks at about 4.1° 2θ, about 8.2° 2θ, about 12.3° 2θ, about 23.7° 2θ, and about 25.2° 2θ.
23. The process of claim 22 , wherein the compound has an XRPD pattern comprising peaks at 4.1° 2θ, 8.2° 2θ, 12.3° 2θ, 23.7° 2θ, and 25.2° 2θ.
24. The process of claim 22 , wherein the aqueous hydrochloric acid is a 4 M solution; and/or wherein the isolation step comprises centrifugation.
25. The pharmaceutical composition of claim 6 , wherein said compound has an XRPD pattern further comprising at least two peaks chosen from about 14.8° 2θ, about 17.5° 2θ, about 27.5° 2θ, and about 28.2° 2θ.
26. The method of claim 10 , wherein said compound has an XRPD pattern further comprising at least two peaks chosen from about 14.8° 2θ, about 17.5° 2θ, about 27.5° 2θ, and about 28.2° 2θ.
27. The method of claim 19 , wherein said compound has an XRPD pattern further comprising at least two peaks chosen from about 14.8° 2θ, about 17.5° 2θ, about 27.5° 2θ, and about 28.2° 2θ.
28. The process of claim 22 , wherein said compound has an XRPD pattern further comprising at least two peaks chosen from about 14.8° 2θ, about 17.5° 2θ, about 27.5° 2θ, and about 28.2° 2θ.