WO2022236407A1 - Psilocybin and psilocin conjugates for treatment of mental illnesses - Google Patents

Psilocybin and psilocin conjugates for treatment of mental illnesses Download PDF

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WO2022236407A1
WO2022236407A1 PCT/CA2022/050733 CA2022050733W WO2022236407A1 WO 2022236407 A1 WO2022236407 A1 WO 2022236407A1 CA 2022050733 W CA2022050733 W CA 2022050733W WO 2022236407 A1 WO2022236407 A1 WO 2022236407A1
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acid
thc
delta
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Collin CLARKE
Mahmoud Mohamed Abdrabo MOUSTAFA
Abdelrahman S. MAYHOUB
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London Pharmaceuticals and Research Corp
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Priority to EP22806152.9A priority Critical patent/EP4337666A4/en
Priority to US18/560,206 priority patent/US20240261419A1/en
Priority to CA3218596A priority patent/CA3218596A1/en
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    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry and, in particular, to conjugates of psilocin and its pro-drug psilocybin, their salts and therapeutic uses for treating or preventing psychological or neurological disorders.
  • Psilocybin and its active form psilocin, can be classified as substituted dialkyl tryptamine derivatives and are the main chemical substances isolated from the genus Psilocybe (psychedelic mushrooms, which are an informal group including various species of mushrooms that contain psilocybin, psilocin or other related substances). They are emerging as an alternative therapy for mental illnesses such as post-traumatic stress disorder (PTSD), addiction, obsessive compulsive disorder (OCD), anxiety, Parkinson’s disease, dementia, and depression.
  • PTSD post-traumatic stress disorder
  • OCD obsessive compulsive disorder
  • psilocybin and/or psilocin in combinations with cannabinoids like cannabidiol (CBD) or tetrahydrocannbidivarin (THC-V) either by separate, sequential, or simultaneous administration.
  • CBD cannabidiol
  • THC-V tetrahydrocannbidivarin
  • WO2018/135943 A1 of Procare Beheer B.V. and US20180221396A1 of Caamtech LLC disclose a combination therapy and compositions comprising individual therapeutic agents including psilocybin, a cannabinoid and/or terpenes for regulating a neurotransmitter receptor (e.g., a serotonin receptor) and prevention or treatment of psychological or brain disorders.
  • a neurotransmitter receptor e.g., a serotonin receptor
  • the psilocybin and psilocin compounds are labile conjugates of psilocybin and psilocin derivatives and salts with other synergistic or additive therapeutic agents. These new conjugates aim to deliver multiple therapeutic benefits via more than one mechanism of action. This is achieved by combining a psilocybin derivative with a different therapeutic agent with synergistic or additive effects using a hydrolysable spacer.
  • the conjugates are sensitive to enzymatic or chemical hydrolysis within the animal or human body, to release the parent psilocybin derivative and the synergistic or additive therapeutic agent(s) thereby modulating their respective target receptors and tissues.
  • this invention pertains to a compound having one of formulas 1-6 or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein: spacer — PS
  • DR is an additive or synergistic drug
  • PS is psilocybin, a psilocin derivative, or another related phosphorylated mushroom alkaloid
  • each X is, independently, a linear, cyclic or branched alkyl carbon chain, with or without heteroatom(s), phosphate, phosphonate, substituted phosphate or phosphonate, oxygen, sulfur with any oxidation status, NH, or substituted nitrogen.
  • PS is any psilocybin psilocin derivative or metabolite or another related phosphorylated mushroom alkaloid, including natural, synthetic or semisynthetic derivatives, preferably psilocybin and psilocin, or other analogues baeocystin, norbaeocystin, bufotenine, and aeruginascin.
  • the natural phosphorylated mushroom alkaloids are: psilocybin baeocystin norbaeocystin [0010]
  • the synthetic or semisynthetic phosphorylated related mushrooms alkaloids are:
  • DR is an additive or synergistic drug or its metabolite selected from pregabalin, gabapentin, topiramate, morphine, levodopa, selective serotonin reuptake inhibitor (SSRI) (e.g., citalopram), amisulpride, lurasidone, paliperidone, paliperidone palmitate, tapentadol, pentazocine, carbidopa, nalbuphine, risperidone, ziprasidone, perospirone, doxorubicin, melperone, aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, fluoxetine, calcitonin, pseudoephedrine, piracetam, levetiracetam, sitagliptin, silodosin, hydrochlorothiazide, ezetimibe, propranol
  • SSRI selective se
  • DR is one or more cannabinoids selected from the group consisting of: delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerol (CBG), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), canabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerol monoethyl ether (CBGM), cannabigerolic acid monoethyl ether (CBGAM), cannabidiolic acid (CBDA), cannabigerovarinic (CBGV A), cann
  • X is, independently, a linear, cyclic or branched alkyl carbon chain, with or without heteroatom(s), phosphate, phosphonate, substituted phosphate or phosphonate, oxygen, sulfur with any oxidation status, NH, or substituted nitrogen.
  • the X moieties may be identical or not.
  • the spacer is a linear, branched, or cyclic alkane, alkene or alkyne, amino acid, acetal, ketal, peptide, aryl, heteroaryl, or heterocycloalkyl group, each of which is optionally substituted.
  • the compounds described herein may be used alone or in combination with other compounds that may be therapeutically effective by the same or different modes of action.
  • the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of psychiatric disorders, such as compounds administered to relieve pain, nausea, vomiting, and the like.
  • the psilocybin or psilocin conjugates or any of their derivatives or metabolites, according to the present invention, are two molecules connected directly through spacer(s) by covalent bond(s).
  • this invention pertains to compounds having formula 1, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • DR is an additive or synergistic drug
  • PS is psilocybin, a psilocin derivative or another related phosphorylated mushroom alkaloid.
  • this invention pertains to psilocin conjugates with formula la-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • DR is an additive or synergistic drug
  • PS is psilocybin, a psilocin derivative or another related phosphorylated mushroom alkaloid.
  • this invention pertains to psilocin conjugates with formula
  • this invention pertains to compounds having formula 3a-g, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • DR is an additive or synergistic drug
  • PS is psilocybin, a psilocin derivative or another phosphorylated mushroom alkaloid.
  • this invention pertains to psilocin conjugates with formula
  • this invention pertains to compounds having formula 4, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • DR is an additive or synergistic drug
  • PS is psilocybin, a psilocin derivative or another phosphorylated mushroom alkaloid.
  • this invention pertains to psilocin conjugates with formula 4a-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein: [0029] Psilocin conjugates with formula 4a-i are expected to be released after administration as illustrated in the following scheme 4:
  • this invention pertains to compounds having formula 5, in which the spacer is a therapeutic agent by itself, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • DR is an additive or synergistic drug
  • PS is psilocybin, a psilocin derivative or another phosphorylated mushroom alkaloid.
  • this invention pertains to psilocin conjugates with formula
  • this invention pertains to compounds having formula 6, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • DR is an additive or synergistic drug and PS is psilocybin, another psilocin derivative or another phosphorylated mushroom alkaloid.
  • this invention pertains to phosphorylated psilocin, or any other natural, synthetic, or semisynthetic derivatives, conjugates, in which the phosphate or its analogues or derivatives is (or are) part of the spacer or an “X” moiety with formula 6a-i, or both, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
  • the addition of one or more halogen, in particular fluorine atom(s) on the carbon backbone of the spacer may be used to modulate the enzymatic and chemical stabilities, or to control sequence of hydrolysis as shown in specific examples of formula 7 :
  • alkyl group(s), in particular methyl on the carbon backbone of the spacer may be used to modulate the enzymatic and chemical stabilities, to control the sequence of hydrolysis, or to reduce the toxicity as shown in specific examples of formula 8:
  • PS is any psilocybin, psilocin derivative or another related phosphorylated mushroom alkaloid or metabolite, including, natural, synthetic or semisynthetic derivatives.
  • PS is psilocybin, psilocin, or other analogues such as baeocystin, norbaeocystin, bufotenine, and aeruginascin.
  • Preferable examples of natural phosphorylated mushroom alkaloids are: psilocybin baeocystin norbaeocystin
  • DR is an additive or synergistic drug or its metabolite selected from pregababn, gabapentin, topiramate, morphine, levodopa, selective serotonin reuptake inhibitor (SSRI) (e.g., citalopram), amisulpride, lurasidone, pabperidone, paliperidone palmitate, risperidone, ziprasidone, perospirone, doxorubicin, melperone, aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, flouxetine, calcitonin, pseudoephedrine, piracetam, levetiracetam, sitagbptin, silodosin, hydrochlorothiazide, ezetimi
  • SSRI selective serotonin reuptake inhibitor
  • DR is one or more cannabinoid derivatives or metabolites, including, synthetic, or semisynthetic derivatives.
  • the one or more cannabinoids are taken from the group: delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerol (CBG), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), canabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerol monoethyl ether (CBGM), cannabigerolic acid monoethyl ether (C
  • X is linear, cyclic, or branched hydrocarbon chain, with or without heteroatom(s), oxygen, sulfur, with any oxidation status, NH or substituted nitrogen.
  • X is a phosphate, phosphonate, or a substituted phosphate or phosphonate.
  • Spacer is a linear, branched or cyclic alkane, alkene or alkyne, optionally halo substituted, amino acid, acetal, ketal, peptide, aryl, heteroaryl, or heterocycloalkyl each of which is optionally substituted.
  • any of Spacer , Spacer -X, or X-Spacer-X may be a hydroly sable peptide or protein.
  • each cannabinoid component can be the same or different, and, when spacers are used, each spacer can be the same or different.
  • the compounds described herein may be used alone or in combination with other psychiatric therapeutic(s) that may be therapeutically effective by the same or different modes of action.
  • the compounds described herein may be used in combination with other therapeutics that are administered to treat other symptoms of psychiatric diseases, such as compounds administered to relieve pain, allergy, swelling nausea/vomiting, and the like.
  • the term “about” can allow for a degree of variability in a value or range, for example, within 1%, within 5%, or within 10% of a stated value or of a stated limit of a range.
  • the term “substantially” can allow for a degree of variability in a value or range, for example, within 90%, within 95%, 99 %, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more of a stated value or of a stated limit of a range.
  • alkyl refers to a saturated monovalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkyl, illustrative variations of those embodiments include lower alkyl, such as Ci to C9 alkyl, methyl, ethyl, propyl, 3-methylbutyl, and the like.
  • cyclic alkane refers to a monovalent chain of carbon atoms, a portion of which forms a ring.
  • cyclic alkane refers to an unsaturated monovalent chain of carbon atoms, a portion of which forms a ring.
  • cyclic alkene moiety illustrative variations of those embodiments include a lower cyclic alkene moiety, such as C3 - CV, cycloalkenyl, cyclopentenyl, cyclohexenyl, and the like.
  • aryl used alone or as part of a phrase such as “aralkyl” or “alkylaryl” refer to monocyclic, bicyclic or fused ring systems, with at least one aromatic ring, having 5- to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring”. Examples of aryl rings include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • heteroaryl refers 4-, 5-, 6-, or 7-membered ring having 1 to
  • hetero-atom selected from O, N, and S, or 8-, 9-, or 10-memebered ring having 1 to 6 heteroatoms selected from O, N, and S, or a salt thereof.
  • heteroaryl groups include, pyridine, pyrimidine, pyridazine, quinazoline, quinoline, indole, pyrole, pyrazole, imidazole, furan, benzofuran, thiophene, and benzothiophene.
  • hetero-atom refers to non-carbon and non-hydrogen atoms such as N, O, S, Se, P, and the like, preferably N, O or S atoms.
  • the term “sulfer oxidation status” refers to sulfide, sulfone, sulfoxide, and sulfonamide.
  • heterocycloalkyl by itself or in combination with another term, refers to a saturated monovalent ring of carbon atoms, consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as 1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) have been independently replaced with the same or different heteroatoms, for example, nitrogen, oxygen or sulfur.
  • the carbon atom(s) being replace may be at any position of the ring.
  • heterocycloalkyl groups include tetrahydro-2H-pyran, tetrahydro-2H- thiopyran, -NH-alkyl, -alkylene-O-alkyl, and the like.
  • each of alkyl, cycloalkane, alkene, and cycloalkene moieties may be optionally substituted with independently selected groups such as halide, alkyl, alkoxy, hydroxy, hydroxyalkyl, carboxylic acid and derivatives thereof, including esters, nitrile, amides, and nitrites, acyloxy, aminoalkyl and dialkylamino, acylamino, thio, and the like, and combinations thereof.
  • halide refers to fluoride, chloride, bromide, or iodide.
  • the term “patient” includes human and non-human animals such as companion animals such as dogs and cats and the like, and livestock animals. Livestock animals are animals raised for food production.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • compositions or vehicles such as a liquid or solid filler, solvent or encapsulating material, involved in carrying or transporting any subj ect composition or component thereof.
  • carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include : (1) sugars, such as lactose and maltose; (2) starches, such as com starch and gelatinized starch; (3) cellulose, and its derivatives, such as carboxymethyl cellulose salt, and hydroxypropylmethyl cellulose; (4) thickening agents such as gelatin and tragacanth ; (5) disintegrants such as copovidone; (6 ) other excipients, such as cocoa butter and suppository waxes and pyrogen - free water for sterile products; and (7) other non-toxic compatible substances employed in pharmaceutical formulations.
  • subject in the present disclosure refers to human patients but is not limited to humans and may include animals.
  • administering includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, topical, oral, intravenous, intramuscular, transdermal, inhalation, buccal, ocular, vaginal, rectal, and the like.
  • the compounds and compositions described herein may be administered in unit dosage forms or formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • this invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable diluents, and excipients.
  • this invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, in combination with one or more other therapeutically active compounds by the same or different mode of action, and one or more pharmaceutically acceptable diluents, and excipients.
  • psilocybin and psilocin exerts its pharmacological effect via modulation of serotonin and dopaminergic receptors including 5HT 2 B, 5HTID, 5HTIE, 5HTI A , 5HT5A, 5HT7, 5HT6, 5HT2C, 5HTIB, 5HT2A, Dl, D3; while the DR moiety are modulators of cannabinoid receptor CB1, CB2 and other receptors.
  • modulators pertain to allosteric modulators, agonist, biased agonist, antagonist, biased antagonist or partial agonist of any opiate receptor(s), blocking the reuptake of serotonin, modulating the level of neurotransmitters in CNS or peripheral tissues, modulating the level of cellular secondary messengers or modulating the phosphorylated level of cellular enzymes or proteins.
  • this invention pertains to a method for treating a patient of psychological disorder(s), the method comprising the step of administering a therapeutically effective amount of a compound disclosed herein, together with one or more pharmaceutically acceptable diluents, and excipients, to the patient in need of relief from said psychological disorder(s).
  • the t-Bu-protected dicarboxylic acid (lequiv.) is activated using 1,1'- carbonyldiimidazole (CDI) (1 equiv.), and then the psilocin is added.
  • CDI 1,1'- carbonyldiimidazole
  • the reaction mixture is stirred at 80° C for 12 hours. Progress of reaction may be monitored by TLC. After complete conversion, the reaction is quenched with distilled water (50 mL), organic material is extracted with ethyl acetate (50 mL x 3), collected, dried over anhydrous MgSCft, and concentrated under reduced pressure.
  • the crude intermediate is dissolved in degassed absolute ethanol (20 mL), charged with Pd/C (10%, 20 mg), hydrogen gas is applied, and the reaction is stirred at room temperature for 8 hours. After completion of the reaction, as may be monitored by TLC, the reaction mixture is filtered through Celite 545, and the solvent is removed under vacuum. The free acid is then purified by partitioning between aqueous solution of sodium carbonate (1M, 50 mL), and DCM (25 mL). The aqueous layer is separated and acidified with ammonium hydrochloride to neutral pH. The precipitate is collected, washed thoroughly with distilled water and dried.
  • the I,G-carbonyldiimidazole (CDI) can be replaced by other coupling reagents including: phosgene, trichloroacetyl chloride, 1 , l'-carbonylbis(2- methylimidazole), /V/V'-disuccinimidyl carbonate, 4-nitrophenylchloroformate, and bis(4- nitrophenyl)carbonate, bis(pentafluorophenyl)carbonate.
  • synthesis of a carbamate moiety can be achieved by selecting reagents, including: phosgene, trichloroacetyl chloride, 1,1'- carbonyldiimidazole (CDI), l,r-carbonylbis(2-methylimidazole), /V,/V'-disuccinimidyl carbonate, 4-nitrophenylchloroformate, bis(4-nitrophenyl)carbonate, bis(pentafluorophenyl)carbonate, and then, optionally, treated with the second partner.
  • reagents including: phosgene, trichloroacetyl chloride, 1,1'- carbonyldiimidazole (CDI), l,r-carbonylbis(2-methylimidazole), /V,/V'-disuccinimidyl carbonate, 4-nitrophenylchloroformate, bis(4-nitrophenyl)carbonate, bis(pentafluorophen

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Abstract

New psilocybin and psilocin conjugates and their soluble salts with synergistic or additive therapeutic agents and stable formulations thereof, as well as their medical applications. The synergistic or additive conjugates may be used as drugs or prodrugs for treating various mental illness conditions related to the modulation or biased modulation of serotonin and related receptors, including but not limited to neurodegenerative disorders, depression, anxiety, obsessive compulsive disorder (OCD), cluster headaches, neuropathic pain and addiction.

Description

PSILOCYBIN AND PSILOCIN CONJUGATES FOR TREATMENT OF
MENTAL ILLNESSES
Field of the Invention [0001] The present invention relates to the field of medicinal chemistry and, in particular, to conjugates of psilocin and its pro-drug psilocybin, their salts and therapeutic uses for treating or preventing psychological or neurological disorders.
Background
[0002] Existing therapies for mental illness seldom lead to clinical remission and frequently yield significant side effects. Furthermore, they have a delay in therapeutic onset and typically require a trial of multiple drugs before one is deemed effective. The economic burden of mental illness in Canada is estimated at $51 billion per year. This is exemplified by the Lancet Commission report citing an estimate that psychiatric disorders will cost the world US $16 Trillion by 2030. Therefore, identifying novel therapeutic strategies is of paramount importance to public health. Ideally, the next generation of psychiatric medications will have a low number needed to treat, fast onset of therapeutic action and minimal acceptable side effects.
[0003] Psilocybin, and its active form psilocin, can be classified as substituted dialkyl tryptamine derivatives and are the main chemical substances isolated from the genus Psilocybe (psychedelic mushrooms, which are an informal group including various species of mushrooms that contain psilocybin, psilocin or other related substances). They are emerging as an alternative therapy for mental illnesses such as post-traumatic stress disorder (PTSD), addiction, obsessive compulsive disorder (OCD), anxiety, Parkinson’s disease, dementia, and depression. Aside from being a Schedule I substance and illegal to use since 1970, there are many fundamental challenges that prevented psilocybin from reaching the market as a medicinal product including: a) highly variable and subjective pharmacological actions; b) behavioral toxicity (e.g. psychosis); c) tachyphylaxis (loss of benefits after repeated doses); d) unknown dose-response relationship and duration of action.
Chemical structures of psilocybin and psilocin.
Figure imgf000003_0001
[0004] On the other hand, there are known clinical benefits of psilocybin and/or psilocin in combinations with cannabinoids like cannabidiol (CBD) or tetrahydrocannbidivarin (THC-V) either by separate, sequential, or simultaneous administration. For example, WO2018/135943 A1 of Procare Beheer B.V. and US20180221396A1 of Caamtech LLC, disclose a combination therapy and compositions comprising individual therapeutic agents including psilocybin, a cannabinoid and/or terpenes for regulating a neurotransmitter receptor (e.g., a serotonin receptor) and prevention or treatment of psychological or brain disorders. Although promising, this therapeutic approach is hampered by the fact that these drugs exhibit substantially different pharmacokinetic profiles, so they do not reach their target tissues at the same time. In particular, psilocybin reached its maximum plasma level after 90 mins, while it takes 4-6 hours for CBD to reach its maximum plasma level. The same remarkable difference was also observed in other PK parameters such as volume of distribution, rate of metabolism and elimination. Having two synergistically acting or additive molecules with different PK is a known major challenge in drug discovery and development. [0005] To minimize the limitations in the prior art, there exists a demand for new synergistic and effective therapies with optimized physicochemical, pharmacokinetic (PK) and pharmacodynamic (PD) properties to manage mental illnesses. Summary of the invention
[0006] The psilocybin and psilocin compounds, according to the present invention, are labile conjugates of psilocybin and psilocin derivatives and salts with other synergistic or additive therapeutic agents. These new conjugates aim to deliver multiple therapeutic benefits via more than one mechanism of action. This is achieved by combining a psilocybin derivative with a different therapeutic agent with synergistic or additive effects using a hydrolysable spacer. The conjugates are sensitive to enzymatic or chemical hydrolysis within the animal or human body, to release the parent psilocybin derivative and the synergistic or additive therapeutic agent(s) thereby modulating their respective target receptors and tissues. [0007] In some illustrative embodiments, this invention pertains to a compound having one of formulas 1-6 or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000004_0001
spacer — PS
Formula 1 Formula 2 Formula 3
PS
^X — spacer — DR DR— DR — PS DR — X — spacer
Figure imgf000004_0002
Formula 4 Formula 5 Formula 6
Formulas 1-6 and wherein: DR is an additive or synergistic drug; PS is psilocybin, a psilocin derivative, or another related phosphorylated mushroom alkaloid; and each X is, independently, a linear, cyclic or branched alkyl carbon chain, with or without heteroatom(s), phosphate, phosphonate, substituted phosphate or phosphonate, oxygen, sulfur with any oxidation status, NH, or substituted nitrogen.
[0008] In another embodiment, PS is any psilocybin psilocin derivative or metabolite or another related phosphorylated mushroom alkaloid, including natural, synthetic or semisynthetic derivatives, preferably psilocybin and psilocin, or other analogues baeocystin, norbaeocystin, bufotenine, and aeruginascin.
[0009] In another embodiment, the natural phosphorylated mushroom alkaloids are:
Figure imgf000005_0001
psilocybin baeocystin norbaeocystin [0010] In another embodiment, the synthetic or semisynthetic phosphorylated related mushrooms alkaloids:
Figure imgf000005_0002
[0011] In another embodiment, DR is an additive or synergistic drug or its metabolite selected from pregabalin, gabapentin, topiramate, morphine, levodopa, selective serotonin reuptake inhibitor (SSRI) (e.g., citalopram), amisulpride, lurasidone, paliperidone, paliperidone palmitate, tapentadol, pentazocine, carbidopa, nalbuphine, risperidone, ziprasidone, perospirone, doxorubicin, melperone, aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, fluoxetine, calcitonin, pseudoephedrine, piracetam, levetiracetam, sitagliptin, silodosin, hydrochlorothiazide, ezetimibe, propranolol, atenolol, nadolol, pindolol, sotalol, timolol, penbutolol, oxprenolol, carvedilol, carteolol, bucindolol, acebutanol, betaxolol, esmolol, nebivolol, bisoprolol, celiprolol, metoprolol, azelnidipine, bami dipine, mani dipine, lercandipine, efonidipine, benidipine, brimonidine, bortezomib, ledipasvir, daclatasvir, ombitasvir, elbasvir, lamivudine, dopamine, 5 -hydroxy try ptamine, levodopa, baclofen, pramipexole, ropinirole, rotigotine, apomorphine, tacrine, rivastigmine, donepezil, galantamine, vigabatrin, lamotrigine, tiagabine, amitriptyline, nortriptyline and histamine or a cannabinoid. Preferably, it is a cannabinoid.
[0012] In another embodiment, DR is one or more cannabinoids selected from the group consisting of: delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerol (CBG), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), canabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerol monoethyl ether (CBGM), cannabigerolic acid monoethyl ether (CBGAM), cannabidiolic acid (CBDA), cannabigerovarinic (CBGV A), cannabichromenic acid (CBCA), cannabichromenic acid (CBCA), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic (CBDV A), cannabidiorcol (CBD-C1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-8-tetrahydrocannabinolic acid (delta-8-THCA), delta-8-tetrahydrocannabinol (delta-8-THC), delta-9- tetrahydrocannabinol-C4 (THC-C4), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta- 9-tetrahydrocannabiorcol-Cl (THC-C1), tetrahydrocannabivarinic acid (THCVA), cannabicycolic acid (CBLA), cannbicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabivarin, cannabinol-C4 (CBN-C4), cannabinol methylether (CBNM), cannabiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), cannabitriolvarin (CBTV), dehydrocannabifuran (DCBF), cannabifuran, cannabicitran (CBT), cannabiripsol (CBR), ‘ll-hydroxytetrahydrocannabinoE (11-OH-THC), ‘ll-nor-9- carboxy -tetrahydrocannabinol’ (THC-COOH), and their derivatives, synthetic analogues, related chemical structures and salts, and mixtures and combinations thereof. Preferably, DR is CBD or THC-V. [0013] In another embodiment, DR is one or more cannabinoid derivatives or metabolites, including natural, synthetic, or semisynthetic derivatives.
[0014] In another embodiment, X is, independently, a linear, cyclic or branched alkyl carbon chain, with or without heteroatom(s), phosphate, phosphonate, substituted phosphate or phosphonate, oxygen, sulfur with any oxidation status, NH, or substituted nitrogen. The X moieties may be identical or not.
[0015] In another embedment the spacer is a linear, branched, or cyclic alkane, alkene or alkyne, amino acid, acetal, ketal, peptide, aryl, heteroaryl, or heterocycloalkyl group, each of which is optionally substituted.
[0016] It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of psychiatric disorders, such as compounds administered to relieve pain, nausea, vomiting, and the like.
Description of the Invention
[0017] The psilocybin or psilocin conjugates or any of their derivatives or metabolites, according to the present invention, are two molecules connected directly through spacer(s) by covalent bond(s).
[0018] In some illustrative embodiments, this invention pertains to compounds having formula 1, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000007_0001
Formula 1 and wherein: DR is an additive or synergistic drug, and PS is psilocybin, a psilocin derivative or another related phosphorylated mushroom alkaloid. [0019] In some specific examples this invention pertains to psilocin conjugates with formula la-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000008_0001
Figure imgf000009_0002
[0020] Psilocin conjugates with formula la-i are expected to be released after administration to a subject, as illustrated in scheme 1: Scheme 1
Figure imgf000009_0001
psilocin [0021] In some illustrative embodiments, this invention pertains to compounds having formula 2, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
D^X-space^S
Formula 2 and wherein: DR is an additive or synergistic drug, and PS is psilocybin, a psilocin derivative or another related phosphorylated mushroom alkaloid.
[0022] In some specific examples this invention pertains to psilocin conjugates with formula
2a-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000010_0001
Figure imgf000011_0002
[0023] Psilocin conjugates with formula 2a-i are expected to be released after administration as illustrated in the following scheme 2:
Scheme 2
Figure imgf000011_0001
[0024] In some illustrative embodiments, this invention pertains to compounds having formula 3a-g, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
DR . X — spacef — PS
Formula 3 and wherein: DR is an additive or synergistic drug, and PS is psilocybin, a psilocin derivative or another phosphorylated mushroom alkaloid.
[0025] In some specific examples this invention pertains to psilocin conjugates with formula
3a-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000012_0001
Figure imgf000013_0002
[0026] Psilocin conjugates with formula 3a-i are expected to be released after administration as illustrated in the following scheme 3:
Scheme 3
Figure imgf000013_0001
[0027] In some illustrative embodiments, this invention pertains to compounds having formula 4, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
P^x — spacer — DR
Formula 4 and wherein: DR is an additive or synergistic drug, and PS is psilocybin, a psilocin derivative or another phosphorylated mushroom alkaloid.
[0028] In some specific examples this invention pertains to psilocin conjugates with formula 4a-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000014_0001
[0029] Psilocin conjugates with formula 4a-i are expected to be released after administration as illustrated in the following scheme 4:
Scheme 4
Figure imgf000015_0001
[0030] In some illustrative embodiments, this invention pertains to compounds having formula 5, in which the spacer is a therapeutic agent by itself, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
DR— Drug - PS
Formula 5 and wherein: DR is an additive or synergistic drug, and PS is psilocybin, a psilocin derivative or another phosphorylated mushroom alkaloid.
[0031] In some specific examples this invention pertains to psilocin conjugates with formula
5a-i, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000015_0002
Figure imgf000016_0001
Figure imgf000017_0003
[0032] Psilocin conjugates with formula 5a-i are expected to be released after administration as illustrated in scheme 5:
Scheme 5
Figure imgf000017_0001
H psilocin gabapentin
[0033] In some illustrative embodiments, this invention pertains to compounds having formula 6, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000017_0002
Formula 6 and wherein: DR is an additive or synergistic drug and PS is psilocybin, another psilocin derivative or another phosphorylated mushroom alkaloid. [0034] In some specific examples this invention pertains to phosphorylated psilocin, or any other natural, synthetic, or semisynthetic derivatives, conjugates, in which the phosphate or its analogues or derivatives is (or are) part of the spacer or an “X” moiety with formula 6a-i, or both, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein:
Figure imgf000018_0001
Figure imgf000019_0001
[0035] Phosphorylated conjugates with formula 6a-i are expected to be released after two sequential steps of enzymatic hydrolysis or by an alkaline phosphatase activation followed by hydrolysis of the chemically unstable bond according to schemes 6 and 7: Scheme 6
[0036] In some other embodiments, the addition of one or more halogen, in particular fluorine atom(s) on the carbon backbone of the spacer may be used to modulate the enzymatic and chemical stabilities, or to control sequence of hydrolysis as shown in specific examples of formula 7 :
Figure imgf000020_0001
Formula 7
[0037] In some other embodiments, addition of alkyl group(s), in particular methyl on the carbon backbone of the spacer may be used to modulate the enzymatic and chemical stabilities, to control the sequence of hydrolysis, or to reduce the toxicity as shown in specific examples of formula 8:
Figure imgf000020_0002
Formula 8
[0038] In another embodiment, PS is any psilocybin, psilocin derivative or another related phosphorylated mushroom alkaloid or metabolite, including, natural, synthetic or semisynthetic derivatives. Preferably, PS is psilocybin, psilocin, or other analogues such as baeocystin, norbaeocystin, bufotenine, and aeruginascin.
[0039] Preferable examples of natural phosphorylated mushroom alkaloids are:
Figure imgf000021_0001
psilocybin baeocystin norbaeocystin
[0040] Preferable examples of synthetic or semisynthetic phosphorylated related mushrooms alkaloids are:
Figure imgf000021_0002
[0041] In another embodiment, DR is an additive or synergistic drug or its metabolite selected from pregababn, gabapentin, topiramate, morphine, levodopa, selective serotonin reuptake inhibitor (SSRI) (e.g., citalopram), amisulpride, lurasidone, pabperidone, paliperidone palmitate, risperidone, ziprasidone, perospirone, doxorubicin, melperone, aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, flouxetine, calcitonin, pseudoephedrine, piracetam, levetiracetam, sitagbptin, silodosin, hydrochlorothiazide, ezetimibe, propranolol, atenolol, nadolol, pindolol, sotalol, timolol, penbutolol, oxprenolol, carvedilol, carteolol, bucindolol, acebutanol, betaxolol, esmolol, nebivolol, bisoprolol, celiprolol, metoprolol, azelnidipine, bamidipine, manidipine, lercandipine, efonidipine, benidipine, brimonidine, bortezomib, ledipasvir, daclatasvir, ombitasvir, elbasvir, lamivudine, dopamine, 5 -hydroxy try ptamine, levodopa, pramipexole, ropinirole, rotigotine, apomorphine, tacrine, rivastigmine, donepezil, galantamine, vigabatrin, lamotrigine, tiagabine, amitriptyline, nortriptyline and histamine or cannabinoids. Preferably, DR is a cannabinoid.
[0042] In another embodiment, DR is one or more cannabinoid derivatives or metabolites, including, synthetic, or semisynthetic derivatives. Preferably the one or more cannabinoids are taken from the group: delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerol (CBG), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), canabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerol monoethyl ether (CBGM), cannabigerolic acid monoethyl ether (CBGAM), cannabidiolic acid (CBDA), cannabigerovarinic (CBGV A), cannabichromenic acid (CBCA), cannabichromenic acid (CBCA), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic (CBDV A), cannabidiorcol (CBD-C1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-8-tetrahydrocannabinolic acid (delta-8-THCA), delta-8-tetrahydrocannabinol (delta-8-THC), delta-9- tetrahydrocannabinol-C4 (THC-C4), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta- 9-tetrahydrocannabiorcol-Cl (THC-C1), tetrahydrocannabivarinic acid (THCVA), cannabicycolic acid (CBLA), cannbicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabivarin, cannabinol-C4 (CBN-C4), cannabinol methylether (CBNM), cannabiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), cannabitriolvarin (CBTV), dehydrocannabifuran (DCBF), cannabifuran, cannabicitran (CBT), cannabiripsol (CBR), ‘ll-hydroxytetrahydrocannabinoE (11-OH-THC), ‘ll-nor-9- carboxy -tetrahydrocannabinol’ (THC-COOH), and their derivatives, synthetic analogues, related chemical structures and salts, and mixtures and combinations thereof. Preferably, DR is CBD or THC-V.
[0043] In some illustrative embodiments, X is linear, cyclic, or branched hydrocarbon chain, with or without heteroatom(s), oxygen, sulfur, with any oxidation status, NH or substituted nitrogen. In other illustrative embodiments, preferably, X is a phosphate, phosphonate, or a substituted phosphate or phosphonate. [0044] In some illustrative embodiments, Spacer is a linear, branched or cyclic alkane, alkene or alkyne, optionally halo substituted, amino acid, acetal, ketal, peptide, aryl, heteroaryl, or heterocycloalkyl each of which is optionally substituted. In some illustrative embodiments, any of Spacer , Spacer -X, or X-Spacer-X may be a hydroly sable peptide or protein.
[0045] In any of the embodiments described above in which two or more cannabinoid components can be attached, each cannabinoid component can be the same or different, and, when spacers are used, each spacer can be the same or different.
[0046] It is appreciated herein that the compounds described herein may be used alone or in combination with other psychiatric therapeutic(s) that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other therapeutics that are administered to treat other symptoms of psychiatric diseases, such as compounds administered to relieve pain, allergy, swelling nausea/vomiting, and the like.
[0047] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.
[0048] In the present disclosure the term “about" can allow for a degree of variability in a value or range, for example, within 1%, within 5%, or within 10% of a stated value or of a stated limit of a range. In the present disclosure the term “substantially” can allow for a degree of variability in a value or range, for example, within 90%, within 95%, 99 %, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more of a stated value or of a stated limit of a range.
[0049] As used herein, the term “alkyl” refers to a saturated monovalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkyl, illustrative variations of those embodiments include lower alkyl, such as Ci to C9 alkyl, methyl, ethyl, propyl, 3-methylbutyl, and the like. [0050] As used herein, the terms “cyclic alkane” refers to a monovalent chain of carbon atoms, a portion of which forms a ring. It is understood that in embodiments that include a cyclic alkane moiety, illustrative variations of those embodiments include a lower cyclic alkane moiety, such as C3 - Ce cycloalkyl, cyclopropyl, cyclobutyl, 3-methylcyclohexyl, and the like. [0051] As used herein, the term “cyclic alkene” refers to an unsaturated monovalent chain of carbon atoms, a portion of which forms a ring. It is understood that in embodiments that include a cyclic alkene moiety, illustrative variations of those embodiments include a lower cyclic alkene moiety, such as C3 - CV, cycloalkenyl, cyclopentenyl, cyclohexenyl, and the like.
[0052] As used herein, the terms “aryl” used alone or as part of a phrase such as “aralkyl” or “alkylaryl” refer to monocyclic, bicyclic or fused ring systems, with at least one aromatic ring, having 5- to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". Examples of aryl rings include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. [0053] As used herein, the term “heteroaryl” refers 4-, 5-, 6-, or 7-membered ring having 1 to
4 heteroatom selected from O, N, and S, or 8-, 9-, or 10-memebered ring having 1 to 6 heteroatoms selected from O, N, and S, or a salt thereof. Examples of heteroaryl groups include, pyridine, pyrimidine, pyridazine, quinazoline, quinoline, indole, pyrole, pyrazole, imidazole, furan, benzofuran, thiophene, and benzothiophene. [0054] As used herein, the term “hetero-atom” refers to non-carbon and non-hydrogen atoms such as N, O, S, Se, P, and the like, preferably N, O or S atoms.
[0055] As used herein, the term “sulfer oxidation status” refers to sulfide, sulfone, sulfoxide, and sulfonamide.
[0056] As used herein, "heterocycloalkyl," by itself or in combination with another term, refers to a saturated monovalent ring of carbon atoms, consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as 1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) have been independently replaced with the same or different heteroatoms, for example, nitrogen, oxygen or sulfur. The carbon atom(s) being replace may be at any position of the ring. Examples of heterocycloalkyl groups include tetrahydro-2H-pyran, tetrahydro-2H- thiopyran, -NH-alkyl, -alkylene-O-alkyl, and the like. [0057] It is understood that each of alkyl, cycloalkane, alkene, and cycloalkene moieties may be optionally substituted with independently selected groups such as halide, alkyl, alkoxy, hydroxy, hydroxyalkyl, carboxylic acid and derivatives thereof, including esters, nitrile, amides, and nitrites, acyloxy, aminoalkyl and dialkylamino, acylamino, thio, and the like, and combinations thereof. [0058] The term “halide” refers to fluoride, chloride, bromide, or iodide.
[0059] The term "optionally substituted,” or “optional substituents," as used herein, means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. Moreover, when using the terms “independently,” means that the groups in question may be the same or different. Certain of the herein defined terms may occur more than once in the structure, and upon such occurrence each term shall be defined independently of the other.
[0060] The term “patient” includes human and non-human animals such as companion animals such as dogs and cats and the like, and livestock animals. Livestock animals are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human being.
[0061] The terms “pharmaceutically acceptable diluent" or “pharmaceutically acceptable excipient” are art - recognized and refer to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, solvent or encapsulating material, involved in carrying or transporting any subj ect composition or component thereof. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include : (1) sugars, such as lactose and maltose; (2) starches, such as com starch and gelatinized starch; (3) cellulose, and its derivatives, such as carboxymethyl cellulose salt, and hydroxypropylmethyl cellulose; (4) thickening agents such as gelatin and tragacanth ; (5) disintegrants such as copovidone; (6 ) other excipients, such as cocoa butter and suppository waxes and pyrogen - free water for sterile products; and (7) other non-toxic compatible substances employed in pharmaceutical formulations.
[0062] The term “subject” in the present disclosure refers to human patients but is not limited to humans and may include animals.
[0063] As used herein, the term “administering” includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, topical, oral, intravenous, intramuscular, transdermal, inhalation, buccal, ocular, vaginal, rectal, and the like. The compounds and compositions described herein may be administered in unit dosage forms or formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
[0064] In some other embodiments, this invention pertains to a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable diluents, and excipients.
[0065] In some embodiments, this invention pertains to a pharmaceutical composition comprising a compound disclosed herein, in combination with one or more other therapeutically active compounds by the same or different mode of action, and one or more pharmaceutically acceptable diluents, and excipients.
[0066] In some other embodiments, psilocybin and psilocin exerts its pharmacological effect via modulation of serotonin and dopaminergic receptors including 5HT2B, 5HTID, 5HTIE, 5HTIA, 5HT5A, 5HT7, 5HT6, 5HT2C, 5HTIB, 5HT2A, Dl, D3; while the DR moiety are modulators of cannabinoid receptor CB1, CB2 and other receptors. [0067] In some embodiments, modulators pertain to allosteric modulators, agonist, biased agonist, antagonist, biased antagonist or partial agonist of any opiate receptor(s), blocking the reuptake of serotonin, modulating the level of neurotransmitters in CNS or peripheral tissues, modulating the level of cellular secondary messengers or modulating the phosphorylated level of cellular enzymes or proteins. Several studies support the synergistic action of the dual modulating of CB1 and 5HT2A receptors in terms of blocking psychotropic/hallucination adverse effects. [0068] In some embodiments, this invention pertains to a method for treating a patient of psychological disorder(s), the method comprising the step of administering a therapeutically effective amount of a compound disclosed herein, together with one or more pharmaceutically acceptable diluents, and excipients, to the patient in need of relief from said psychological disorder(s).
Example 1: synthesis of psilocin-THC-V conjugate
[0069] The t-Bu-protected dicarboxylic acid (lequiv.) is activated using 1,1'- carbonyldiimidazole (CDI) (1 equiv.), and then the psilocin is added. The reaction mixture is stirred at 80° C for 12 hours. Progress of reaction may be monitored by TLC. After complete conversion, the reaction is quenched with distilled water (50 mL), organic material is extracted with ethyl acetate (50 mL x 3), collected, dried over anhydrous MgSCft, and concentrated under reduced pressure. The crude intermediate is dissolved in degassed absolute ethanol (20 mL), charged with Pd/C (10%, 20 mg), hydrogen gas is applied, and the reaction is stirred at room temperature for 8 hours. After completion of the reaction, as may be monitored by TLC, the reaction mixture is filtered through Celite 545, and the solvent is removed under vacuum. The free acid is then purified by partitioning between aqueous solution of sodium carbonate (1M, 50 mL), and DCM (25 mL). The aqueous layer is separated and acidified with ammonium hydrochloride to neutral pH. The precipitate is collected, washed thoroughly with distilled water and dried. The obtained solid material (1 equiv.) is then dissolved in dry DMF (10 mL), CDI (1 equiv.) is added, and the reaction mixture is stirred at room temperature for 2 hours. After that, THC-V (1 equiv.) is added, and the temperature is raised to 80° C. After completion or the reaction, 50 mL of cooled distilled water is added to the reaction mixture and solid flocculates are collected by filtration and purified by normal phase column chromatography using hexane: ethyl acetate (4:1) (scheme 8). Scheme 8
Figure imgf000028_0001
[0070] Expansion of synthetic protocol. The first discussed synthetic pathway (Scheme 8) is highly flexible and can be modified easily to cover all compounds belong to formula 1-5. As an illustrative example, Scheme 9 was designed to synthesize THC-V-Gabapentin-Psilocin. Scheme 9
Figure imgf000028_0002
THC-V.Gabapentin-Psilocin [0071] In another embodiment, the I,G-carbonyldiimidazole (CDI) can be replaced by other coupling reagents including: phosgene, trichloroacetyl chloride, 1 , l'-carbonylbis(2- methylimidazole), /V/V'-disuccinimidyl carbonate, 4-nitrophenylchloroformate, and bis(4- nitrophenyl)carbonate, bis(pentafluorophenyl)carbonate. [0072] In another embodiment, synthesis of a carbamate moiety (as in Scheme 9) can be achieved by selecting reagents, including: phosgene, trichloroacetyl chloride, 1,1'- carbonyldiimidazole (CDI), l,r-carbonylbis(2-methylimidazole), /V,/V'-disuccinimidyl carbonate, 4-nitrophenylchloroformate, bis(4-nitrophenyl)carbonate, bis(pentafluorophenyl)carbonate, and then, optionally, treated with the second partner. [0073] The present invention has been described and illustrated with reference to an exemplary embodiment; however, it will be understood by those skilled in the art that various changes may be made, and equivalents may be substituted for elements thereof without departing from the scope of the invention as set out in the following claims. Therefore, it is intended that the invention is not limited to the embodiments disclosed herein.

Claims

What is Claimed is:
1. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of formulas 1 to 6:
Figure imgf000030_0001
Formula 4 Formula 5 Formula 6 wherein:
PS is psilocybin, a psilocin derivative, or a relate phosphorylated mushroom alkaloid; each DR is, independently, an additive or synergistic compound; each X is, independently, a linear, cyclic or branched alkyl carbon chain, with or without heteroatom(s), phosphate, phosphonate, substituted, phosphate or phosphonate, oxygen, sulfur with any oxidation status, NH, or substituted nitrogen; and
SPACER is a substituted or unsubstituted linear, branched, or cyclic alkane, alkene, or alkyne, amino acid, acetal, ketal, peptide, aryl, heteroaryl, or heterocycloalkyl group. 2. The compound of claim 1, wherein the compound is a compound of formula 1; PS is psilocybin; and DR is selected from the group consisting of: CBD, THC-V, fluoxetine, quetiapine, paliperidone, tapentadol, pentazocine, galantamine, and pramipexole.
3. The compound of claim 2, wherein the compound is a compound of formula la.
Figure imgf000031_0001
the compound is a compound of formula lb. mpound of formula lc.
Figure imgf000031_0002
Formula lc the compound is a compound of formula Id.
Figure imgf000031_0003
Formula Id
7. The compound of claim 2, wherein the compound is a compound of formula le.
Figure imgf000032_0001
Formula le
8. The compound of claim 2, wherein the compound is a compound of formula If.
Figure imgf000032_0002
Formula If 9. The compound of claim 2, wherein the compound is a compound of formula lg.
Figure imgf000032_0003
10. The compound of claim 2, wherein the compound is a compound of formula lh.
Figure imgf000033_0001
Formula lh
11. The compound of claim 2, wherein the compound is a compound of formula li.
Figure imgf000033_0002
Formula li
12. The compound of claim 1, wherein the compound is a compound of formula 2; PS is psilocybin; and DR is selected from the group consisting of: CBD, THC-V, fluoxetine, quetiapine, paliperidone, tapentadol, pentazocine, galantamine, and pramipexole.
13. The compound of claim 12, wherein the compound is a compound of formula 2a.
Figure imgf000033_0003
14. The compound of claim 12, wherein the compound is a compound of formula 2b.
Figure imgf000034_0001
Formula 2b in the compound is a compound of formula 2c.
Figure imgf000034_0002
Formula 2c in the compound is a compound of formula 2d.
Figure imgf000034_0003
Formula 2d in the compound is a compound of formula 2e.
Figure imgf000034_0004
Formula 2e
18. The compound of claim 12, wherein the compound is a compound of formula 2f.
Figure imgf000035_0001
Formula 2f
19. The compound of claim 12, wherein the compound is a compound of formula 2g.
Figure imgf000035_0002
20. The compound of claim 12, wherein the compound is a compound of formula 2h.
Figure imgf000035_0003
Formula 2h
21. The compound of claim 12, wherein the compound is a compound of formula 2i.
Figure imgf000035_0004
Formula 2i
22. The compound of claim 1, wherein the compound is a compound of formula 3; PS is psilocybin; and DR is selected from the group consisting of: CBD, THC-V, fluoxetine, quetiapine, paliperidone, tapentadol, pentazocine, galantamine, and pramipexole. 23. The compound of claim 22, wherein the compound is a compound of formula 3a.
Figure imgf000036_0001
24. The compound of claim 22, wherein the compound is a compound of formula 3b.
Figure imgf000036_0002
Formula 3b
25. The compound of claim 22, wherein the compound is a compound of formula 3c.
Figure imgf000036_0003
Formula 3c
26. The compound of claim 22, wherein the compound is a compound of formula 3d.
Figure imgf000037_0004
Formula 3d in the compound is a compound of formula 3e.
Figure imgf000037_0001
Formula 3e in the compound is a compound of formula 3f.
Figure imgf000037_0002
Formula 3f in the compound is a compound of formula 3g.
Figure imgf000037_0003
Formula 3g in the compound is a compound of formula 3h.
Figure imgf000038_0001
31. The compound of claim 22, wherein the compound is a compound of formula 3i.
Figure imgf000038_0002
Formula 3i
32. The compound of claim 1, wherein the compound is a compound of formula 4; PS is psilocybin; and DR is selected from the group consisting of: CBD, THC-V, fluoxetine, quetiapine, paliperidone, tapentadol, pentazocine, galantamine, and pramipexole.
33. The compound of claim 32, wherein the compound is a compound of formula 4a.
Figure imgf000038_0003
34. The compound of claim 32, wherein the compound is a compound of formula 4b.
Figure imgf000038_0004
Formula 4b
35. The compound of claim 32, wherein the compound is a compound of formula 4c.
Figure imgf000039_0001
Formula 4c
36. The compound of claim 32, wherein the compound is a compound of formula 4d.
Figure imgf000039_0002
Formula 4d 37. The compound of claim 32, wherein the compound is a compound of formula 4e.
Figure imgf000039_0003
Formula 4e
38. The compound of claim 32, wherein the compound is a compound of formula 4f.
Figure imgf000039_0004
Formula 4f
39. The compound of claim 32, wherein the compound is a compound of formula 4g.
Figure imgf000040_0001
Formula 4g 40. The compound of claim 32, wherein the compound is a compound of formula 4h.
Figure imgf000040_0002
Formula 4h
41. The compound of claim 32, wherein the compound is a compound of formula 4i.
Figure imgf000040_0003
Formula 4i
42. The compound of claim 1, wherein the compound is a compound of formula 5; PS is psilocybin; and each DR is, independently, selected from the group consisting of: CBD, THC-V, fluoxetine, quetiapine, paliperidone, tapentadol, pentazocine, galantamine, carbidopa, gabapentin, nalbuphine, levodopa, and baclofen.
43. The compound of claim 42, wherein the compound is a compound of formula 5a.
Figure imgf000042_0001
in the compound is a compound of formula 5e.
Figure imgf000042_0002
in the compound is a compound of formula 5f.
Figure imgf000042_0003
Formula 5g
50. The compound of claim 42, wherein the compound is a compound of formula 5h.
Figure imgf000043_0001
Formula 5h 51. The compound of claim 42, wherein the compound is a compound of formula 5i.
Figure imgf000043_0002
52. The compound of claim 1, wherein the compound is a compound of formula 6; PS is psilocybin; and DR is selected from the group consisting of: CBD, THC-V, fluoxetine, quetiapine, paliperidone, tapentadol, pentazocine, galantamine, and pramipexole.
53. The compound of claim 52, wherein the compound is a compound of formula 6a.
Figure imgf000043_0003
54. The compound of claim 52, wherein the compound is a compound of formula 6b.
Figure imgf000044_0001
Formula 6b 55. The compound of claim 52, wherein the compound is a compound of formula 6c.
Figure imgf000044_0002
56. The compound of claim 52, wherein the compound is a compound of formula 6d.
Figure imgf000044_0003
Formula 6d
57. The compound of claim 52, wherein the compound is a compound of formula 6e.
Figure imgf000044_0004
58. The compound of claim 52, wherein the compound is a compound of formula 6f.
Figure imgf000045_0001
Formula 6f 59. The compound of claim 52, wherein the compound is a compound of formula 6g.
Figure imgf000045_0002
Formula 6g
60. The compound of claim 52, wherein the compound is a compound of formula 6h.
Figure imgf000045_0003
Formula 6h
61. The compound of claim 52, wherein the compound is a compound of formula 6i.
Figure imgf000045_0004
Formula 6i
62. The compound of claim 1, wherein each DR is, independently, selected from the group consisting of: pregabalin, gabapentin, topiramate, morphine, levodopa, selective serotonin reuptake inhibitor (SSRI), citalopram, amisulpride, lurasidone, paliperidone, paliperidone palmitate, tapentadol, pentazocine, carbidopa, nalbuphine, risperidone, ziprasidone, perospirone, doxorubicin, melperone, aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, fluoxetine, calcitonin, pseudoephedrine, piracetam, levetiracetam, sitagliptin, silodosin, hydrochlorothiazide, ezetimibe, propranolol, atenolol, nadolol, pindolol, sotalol, timolol, penbutolol, oxprenolol, carvedilol, carteolol, bucindolol, acebutanol, betaxolol, esmolol, nebivolol, bisoprolol, celiprolol, metoprolol, azelnidipine, bami dipine, mani dipine, lercandipine, efonidipine, benidipine, brimonidine, bortezomib, ledipasvir, daclatasvir, ombitasvir, elbasvir, lamivudine, dopamine, 5 -hydroxy try ptamine, levodopa, baclofen, pramipexole, ropinirole, rotigotine, apomorphine, tacrine, rivastigmine, donepezil, galantamine, vigabatrin, lamotrigine, tiagabine, amitriptyline, nortriptyline, histamine, and a cannabinoid. 63. The compound of claim 1, wherein each DR is, independently, a cannabinoid selected from the group consisting of: delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol
(THC), cannabidiol (CBD), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerol (CBG), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), canabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerol monoethyl ether (CBGM), cannabigerobc acid monoethyl ether (CBGAM), cannabidiobc acid (CBDA), cannabigerovarinic (CBGV A), cannabichromenic acid (CBCA), cannabichromenic acid (CBCA), cannabidiol monomethyl ether
(CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic (CBDV A), cannabidiorcol (CBD-C1), delta-9-tetrahydrocannabinobc acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinobc acid-C4 (THCA-C4), delta-8-tetrahydrocannabinobc acid (delta-8-THCA), delta-8-tetrahydrocannabinol (delta-8-THC), delta-9- tetrahydrocannabinol-C4 (THC-C4), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta- 9-tetrahydrocannabiorcol-Cl (THC-C1), tetrahydrocannabivarinic acid (THCVA), cannabicycobc acid (CBLA), cannbicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabivarin, cannabinol-C4 (CBN-C4), cannabinol methylether (CBNM), cannabiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), cannabitriolvarin (CBTV), dehydrocannabifuran (DCBF), cannabifuran, cannabicitran (CBT), cannabiripsol (CBR), ‘ll-hydroxytetrahydrocannabinoE (11-OH-THC), ‘ll-nor-9- carboxy -tetrahydrocannabinol’ (THC-COOH), and their derivatives, synthetic analogues, related chemical structures, and pharmaceutically acceptable salts.
64. The compound of claim 1, wherein each DR is, independently, CBD or THC-V.
65. The compound of claim 64, wherein PS is selected from the group consisting of: psilocin, psilocybin, baeocystin, norbaeocystin, bufotenine, aeruginascin, a liZ-indazole analogue, a 3- propyl-l //-indole analogue, and an azaindole analogue.
66. The compound of claim 65, wherein one or more halogen groups are added to the carbon backbone of the SPACER.
67. The compound of claim 65, wherein one ore more alkyl groups are added to the carbon backbone of the SPACER.
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