EP-4734978-A2 - COMBINATION THERAPIES USING PSILOCYBIN

Abstract

Methods of therapy using compounds of formula (I) in combination with or as adjunctive to a GLP-1 receptor agonist, metformin, a PPARγ-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, acarbose or pramlintide or one or more amino acids, one or more vitamins, or one or more hormones are described.

Inventors

• DE MARTIN, Sara
• Mattarei, Andrea
• PAPPAGALLO, MARCO
• FOLLI, FRANCO
• PASUT, GIANFRANCO
• COMAI, Stefano
• MANFREDI, PAOLO L.
• INTURRISI, CHARLES E.

Assignees

• University of Padova
• Manfredi, Paolo L.
• Inturrisi, Charles, E.

Dates

Publication Date

20260506

Application Date

20240627

Claims (20)

1. 1. A method for treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising: administering a non-psychedelic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a GLP- 1 receptor agonist to the patient, wherein: Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R3 is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino; Rs-Rg are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may he optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.
2. 2. The method of claim 1, wherein the compound of formula (I) is administered as an adjunctive therapy to the GLP- 1 receptor agonist.
3. 3. The method of claim 1, wherein the compound of formula (I) is administered in combination with the GLP-1 receptor agonist.
4. 4. The method of any of claims 1-3, wherein the GLP-1 receptor agonist comprises dulaglutide, exenatide, semaglutide, liraglutide, or lixisenatide.
5. 5. The method of claim 4, wherein the GLP- 1 receptor agonist is semaglutide.
6. 6. The method of claim 5, wherein about 0.125 mg, 0.25 mg, about 0.5 mg, about 1 mg, about 2.4 mg, or about 3 mg of semaglutide is administered parenterally to the patient.
7. 7. The method of claim 5, wherein 1-21 mg of oral semaglutide is administered to the patient.
8. 8. The method of any of claim 4, wherein the GLP-1 receptor agonist is dulaglutide.
9. 9. The method of claim 8, wherein about 0.75 mg, about 1.5 mg, about 3 mg, or about 4.5 mg of dulaglutide is administered parentally to the patient.
10. 10. The method of claim 4, wherein the GLP-1 receptor agonist is exenatide.
11. 11. The method of claim 10, wherein about 5 mcg or about 10 mcg of exenatide is administered to the patient, or wherein 1-2 mg of slow release exenatide is administered to the patient.
12. 12. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of the compound according to formula (1), or a pharmaceutically acceptable salt thereof, and a biguanide to the patient, wherein: Ri and Ry are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, Cy-Cs alkenyl, Cy-Cs alkynyl, Ci-Cs cycloalkyl, Cy-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; Rs is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cr-Cs cycloalkyl, Cr-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino; Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.
13. 13. The method of claim 12, wherein the compound of formula (I) is administered as an adjunctive therapy to the biguanide.
14. 14. The method of claim 12, wherein the compound of formula (I) is administered in combination with the biguanide.
15. 15. The method of cl ai ms 12-14, wherei n the bi guanide i s metformin .
16. 16. The method of any of claim 15, wherein about 850 mg to about 2550 mg of metformin hydrochloride is administered to the patient per day.
17. 17. The method of claim 15, wherein about 500 mg of metformin hydrochloride is administered twice a day.
18. 18. The method of claim 15, wherein about 850 mg of metformin hydrochloride is administered once a day.
19. 19. The method of claim 15, wherein about 500 mg, about 1000 mg, about 1500 mg, or about 2000 mg of metformin hydrochloride is administered to the patient a day in an extended- release tablet.
20. 20. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a PPARy- agonist to the patient, wherein: Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R3 is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R4 is hydrogen, deuterium, Ci-C» alkyl, C2-C8 alkenyl, Cz-Cs alkynyl, Cs-Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino; Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R5-R8 are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

Description

COMBINATION THERAPIES USING PSILOCYBIN BACKGROUND [0001] Psilocybin produces alterations in consciousness and emotion, including various psychedelic effects. Psychedelic substances are presently under investigation for the treatment of several diseases and symptoms, including depression, PTSD, OCD, and addiction. In clinical studies to date, the psychedelic experience and central nervous system (CNS) psychoactive effects are integral parts of the intended treatment. However, the effect of these substances on other biological processes, including lipid and sugar metabolism, the dysregulation of which leads to metabolic disorders, is poorly understood. [0002] Sarcopenia is often present in patients with metabolic disorders. Sarcopenia is a medical term describing the loss of skeletal muscle mass, in particular with metabolic disorders, aging, cancer or as a consequence of other diseases and their treatments, including treatments for obesity and metabolic disorders, that can impact overall health and quality of life. [0003] Accordingly, there is a need to develop new compositions, formulations, and methods for treating metabolic disorders and sarcopenia and/or to treat metabolic disorders without causing/worsening sarcopenia. SUMMARY OF THE DISCLOSURE [0004] The present disclosure provides methods of treating a metabolic disorder and or sarcopenia in a patient in need thereof, comprising administering psilocybin or other molecules with a similar pharmacodynamic profile (e.g., as reported in Example 1, agonism to 5-HT2A and 5-HT2C and antagonism to 5-HT2B), for example as an adjunctive therapy to another therapeutic or even in combination with another therapeutic. [0005] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising: administering a non-psychedelic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a GLP- 1 receptor agonist to the patient, wherein: Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R3 is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino; Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-R are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5. [0006] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of the compound according to formula (I), or a pharmaceutically