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EP-4172145-B1 - TRYPTAMINE PRODRUGS AS SEROTONIN RECEPTOR ACTIVATORS FOR THE TREATMENT OF E.G. DEPRESSION

EP4172145B1EP 4172145 B1EP4172145 B1EP 4172145B1EP-4172145-B1

Inventors

  • BRYSON, NATHAN

Dates

Publication Date
20260513
Application Date
20210630

Claims (15)

  1. A compound selected from the group consisting of: (1) psilocin-4-succinate (2) N,N diisopropyltryptamine-4-succinate (3) N,N diisopropyltryptamine -4-Fumarate (4) Psilocin-4-Methyl-5-succinate (5) Iso- N,N dimethyltryptamine-6-succinate (6) N,N diisopropyltryptamine-4-glutarate (7) N-methyl N-isopropyltryptamine-4-glutarate (8) Psilocin-4-glutarate (9) N,N diethyltryptamine-4-glutarate (10) N,N diethyltryptamine-4-succinate and (11) N,N diisopropyltryptamine-4-(3,3-dimethylglutarate) or a pharmaceutically acceptable salt or zwitterion thereof.
  2. The compound of claim 1, wherein the compound is N,N diisopropyltryptamine-4-glutarate.
  3. The compound of claim 1, wherein the compound is the HCI salt of N,N diisopropyltryptamine-4-glutarate.
  4. The compound of claim 1, wherein the HCI salt of N,N diisopropyltryptamine-4-glutarate exhibits a DSC endotherm at 174°C.
  5. A composition comprising the compound of any one of claims 1 to 4, and a pharmaceutically acceptable excipient.
  6. The composition of claim 5 comprising an oral dosage formulation or an injectable formulation.
  7. The composition of claim 6, which is a solution for injection.
  8. The composition of claim 7, wherein the solution has a pH of between about 3.0 and 7.0, preferably 4.0 to 6.0, and more preferably 4.0 to 5.0.
  9. The compound of any one of claims 1 to 4 for use in a method of treatment of a mental disorder.
  10. The compound for use according to claim 9, wherein the mental disorder is depression.
  11. The compound for use according to claim 10, wherein the depression is postpartum depression.
  12. A method of making a compound according to any one of claims 1 to 4 comprising reacting a tryptamine comprising hydroxytryptamine or hydroxyisotryptamine with a cyclic anhydride in a suitable anhydrous solvent.
  13. The method of claim 12, wherein the solvent contains a base with pKa greater than 4 and less than about 9, and the resulting compound is isolated as a zwitterion.
  14. The method of claim 13, wherein the solvent is pyridine.
  15. The method of any one of claims 12 to 14, wherein the tryptamine is 4-hydroxy-isopropyltrytamine or psilocin, and the cyclic anhydride is succinic anhydride or glutaric anhydride.

Description

Field of the Invention The present invention relates to novel tryptamine compounds, methods of making such compounds, such compounds for use in a method of treatment of a mental disorder, and compositions comprising such compounds. Background Tryptamines are a class of 3-aminoethyl-indoles that bind and activate the serotonin receptor, also called the 5HT receptor. A psychedelic state may be achieved by activation of the 2A form of the serotonin receptor by 5HT2A receptor agonist compounds. The endogenous substance for this receptor is 5-hydroxy-tryptamine (serotonin). The tryptamine 3-(2-aminoethyl)-indole is also an endogenous neurotransmitter. The serotonin receptor system is implicated in depression and depressive states which are commonly treated with 5HT1A antagonists (Affective Disorders: Depression in Neuropsychopharmacology and Therapeutics, Chapter 6, First Edition. Ivor S. Ebenezer, 2015). More recently, 5HT2A agonists have shown potential as medicines for depression (Carhart-Harris 2018 Psychopharmacology). Tryptamine molecules which produce a psychedelic state and which have been used in traditional medicine, may have therapeutic potential for the treatment of mood disorders, distress, depression and others. For example, ayahuasca is a natural form of dimethyltryptamine (DMT) which when combined with a monoamine oxidase inhibitor can be ingested and produces a variable, but prolonged psychedelic state that can last for 6 to 15 hours. DMT is also naturally found to occur in small amounts in the brain and may act as a neurotransmitter. Lysergic acid diethylamide (LSD), is a diethylamide derivative of a naturally occurring substance from fungus found in rye grain, which also produces a prolonged psychedelic state up to 8 to 12 hours long. Psilocybin is a naturally occurring plant-based tryptamine found in Psilocybe mushrooms, and produces a prolonged psychedelic state of about 6 to 8 hours. Psilocybin was first synthesized in 1958 and is currently being investigated as a treatment for depression. Psilocybin is a prodrug, with psilocin being the active species in vivo. Psilocybin contains a phosphate bound to the 4-hydroxy group of psilocin, which is cleaved in the gut when Psilcybe mushrooms or the drug substance is taken orally: Simple mono-functional organic esters of psilocin have been reported. Lower alkoxy radical modified psilocins have also been described. Sulfate-bound psilocin has been produced and other mono- and di-basic mineral acid modified psilocins have been described. Psilocin acetate is known and has been used in underground psychedelic subculture. Psychedelic substances have been shown to be effective for treating depression, and even more effective for treating depression when associated with psychotherapy (Watts 2020 J Contextual Behavioral Science). A limited number of synthetic tryptamine substances have been prepared since perhaps the earliest recorded work of Albert Hoffman. Structure-activity relationships have been described for a variety of tryptamine substances (Claire 1988). Succinate and other diacid functions have been explored as components of a prodrug delivery system toward water-soluble, injectable forms of hydrophobic or poorly water soluble drug substances, such as testosterone, haloperidol, chloramphenicol or estradiol (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in The Organic Chemistry of Drug Design and Drug Action (3rd Ed), 2014). Tetrahydrocannabinol ester of succinic acid has been patented to treat glaucoma. However, ester cleavage is not consistently rapid, is not predictable and can depend on the structure of the moiety attached to the drug and therefore must be investigated (Anderson 1984 JPharmaSci). Esterase enzymes are responsible for active cleavage of the prodrug ester group in vivo and species differences in esterase quantities and specificity in various tissues complicate investigations and optimizations (Bahar 2012 JPharmSci). WO 2006/047032 A2 discloses indole compounds useful as serotonin selective agents. This background information is believed to be relevant to a basic understanding of the present invention. It is not an admission that any of the foregoing is prior art against any aspect of the claimed invention. Summary of the Invention The subject matter of the invention is as set out in the appended claims. One aspect of the invention relates to a compound selected from the group consisting of: (1) psilocin-4-succinate (2) N,N diisopropyltryptamine-4-succinate (3) N,N diisopropyltryptamine -4-Fumarate (4) Psilocin-4-Methyl-5-succinate (5) Iso- N,N dimethyltryptamine-6-succinate (6) N,N diisopropyltryptamine-4-glutarate (7) N-methyl N-isopropyltryptamine-4-glutarate (8) Psilocin-4-glutarate (9) N,N diethyltryptamine-4-glutarate (10) N,N diethyltryptamine-4-succinate and(11) N,N diisopropyltryptamine-4-(3,3-dimethylglutarate) or a pharmaceutically acceptable salt or zwitterion thereof. A further aspect of the