Non-hallucinogenic tryptamine compounds, preparation, pharmaceutical compositions and uses thereof

Abstract

The present invention relates to novel non-hallucinogenic tryptamine compounds of formula I and / or formula II:. Compounds of formula I or II can be obtained by a process comprising a conjugation step of a non-hydrolysable chemical moiety with tryptamine precursors, which can be obtained synthetically, and which are analogue to tryptamines naturally occurring in psilocybin containing mushrooms, preferably in psilocybin containing mushrooms belonging to the Psilocybe genus. The conjugated non-hydrolysable chemical moiety allows to reduce or to prevent the crossing of the blood brain barrier (BBB). The invention also relates to a composition comprising at least one of said non-hallucinogenic tryptamine compounds of formula I and / or formula II, optionally in combination with at least one monoamine oxidase inhibitor (MAOI) compound and / or with at least one antioxidant selected from carotenoids. Lastly, the invention relates to the pharmaceutical uses of the compounds according to formula I and / or II and to the pharmaceutical uses of the composition of the invention.

Description

[0001] DESCRIPTION TITLE “Non-hallucinogenic tryptamine compounds, preparation, pharmaceutical compositions and uses thereof”

[0002] FIELD OF INVENTION

[0003] The present invention relates to non-hallucinogenic tryptamine compounds, preparation, pharmaceutical compositions and uses thereof. BACKGROUND OF THE INVENTION

[0004] Psilocybin, a tryptamine alkaloid isolated from various genera of fungi including the genus Psilocybe, and its active metabolite Psilocin, are known to bind to the 5-hydroxy tryptamine (serotonin) receptor 5-HT2A in the Central Nervous System (CNS) causing hallucinogenic, anxiolytic, and psychoactive activities. Although psilocybin and its derivatives are currently under investigation among others for the treatment of major depression, anxiety, alcoholism and nicotine addiction, the psychedelic activity of these molecules represents a serious side effect for the development of new therapeutic agents. Recently, it has been proposed that psychedelics could be helpful in the treatment of neuroinflammation and chronic pain providing relief where conventional analgesics cannot (“The psychedelic remedy for chronic pain”, Clare Watson, Nature (2022) vol. 609, S100-S102 (DOI: 10.1038 / d41586-022-02878-3); “From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders”, Urszula Kozlowska, Charles Nichols, Kalina Wiatr and Maciej Figiel, Journal of Neurochemistry (2022), vol. 162, p. 89- 108 (DOI: 10.1 111 / jnc.15509).

[0005] Apart from CNS, high levels of 5-HT2A receptor expression in other body areas such as the intestine, platelets and endothelial cells suggest that 5- HT2A receptor play crucial roles in other aspects of physiology. This makes peripheral 5-HT2A receptors promising targets for the development of new molecules with powerful anti-inflammatory properties. Recent findings demonstrated that activation of 5-HT2A receptors determined an anti-inflammatory response in rat model of asthma (“Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore”, Thomas W. Flanagan, Gerald B. Billac, Alexus N. Landry, Melaine N. Sebastian, Stephania A. Cormier and Charles D. Nichols ACS Pharmacol. Transl. Sci. (2021 ), vol. 4, p. 488-502 (DOI: 10.1021 / acsptsci.0c00063) and tumor necrosis factor alpha (TNF-oc) mediated inflammation (Serotonin 5-HT2A Receptor Activation Blocks TNF-a Mediated Inflammation In Vivo, Felix Nau Jr, Bangning Yu, David Martin, Charles D. Nichols, PLoS ONE (2013), vol. 8(10): e75426 https: / / journals.plos.org / plosone / article?id=10.1371 / journal. pone.0075426) . In addition, it has been found that activation of 5-HT2A receptors reduces neuropathic pain after spinal cord injury (Activation of 5-HT2A Receptors Restores KCC2 Function and Reduces Neuropathic Pain after Spinal Cord Injury, Irene Sanchez-Brualla, Pascale Boulenguez, Cecile Brocard, Sylvie Liabeuf, Annelise Viallat-Lieutaud, Xavier Navarro, Esther Udina, Frederic Brocard, Neuroscience (2018), vol. 387, p. 48-57, https: / / www.sciencedirect.com / science / article / pii / S0306452217305997).

[0006] Some attempt have been done in order to reducing the rate of transport of small molecules across the BBB (W02005058367, describing the covalent attachment of a water-soluble polymer to small molecule drugs; W02003032990, disclosing polymer conjugates of opioid antagonists with a polymer, such as polyethylene glycol).

[0007] In this context, tryptamine derivatives which are unable to cross the BBB in order to modulate the activity of peripheral 5-HT2A receptors are needed, representing ideal molecules for the development of non-hallucinogenic anti-inflammatory drugs.

[0008] DEFINITIONS

[0009] Unless otherwise defined, all the terms of the art, notations and other scientific terms used herein are intended to have the meanings commonly understood by those who are experts in the technique to which this description belongs. In some cases, terms with commonly understood meanings are defined here for clarity and I or for ready reference; the inclusion of these definitions in this description should therefore not be interpreted as representing a substantial difference with respect to what is generally understood in the art.

[0010] The terms "comprise", "have", "include", "contain", "comprising", "having", "including" and "containing" are to be understood as open terms (i.e. the meaning "comprising, but not limited to") and are to be considered as a support also for terms such as "essentially consist of”, “consisting essentially of”, “consist of” or “consisting of”.

[0011] For all the ranges indicated in the text and in the claims of the present patent application, it is understood that the extremes of these ranges are included.

[0012] The tryptamine precursors used as starting points in the present invention can be obtained synthetically and are analogue to the tryptamines naturally occurring in psilocybin containing mushrooms, preferably in psychedelic psilocybin containing mushrooms belonging to the Psilocybe genus.

[0013] The psychedelic psilocybin containing mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject.

[0014] Preferred tryptamines naturally occurring in psilocybin containing mushrooms which can be used in the present are non-phosphorylated tryptamines, like psilocin, norpsilocin, 4-hydroxytriptamine and / or 4- hydroxy-N,N,N-trimethyltryptamine, and combinations thereof.

[0015] The pharmaceutically acceptable salts, derivatives, hydrate, or solvate of the above cited tryptamines naturally occurring in psilocybin containing mushrooms are comprised in the definition too. The term “Psilocybe genus” may refer to the following non-limiting examples of suitable mushrooms containing psilocybin-like psychedelic compounds: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and combinations thereof.

[0016] The term “pharmaceutically acceptable salts or derivatives” herein refers to those salts or derivatives which possess the biological effectiveness and properties of the salified or derivatized compound and which and which do not produce adverse reactions when administered to a mammal, preferably a human. The pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include but are not limited to: carbonate, hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and para-toluenesulphonate. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, (2008), herein incorporated by reference. The pharmaceutically acceptable derivatives include the esters, the ethers and the N-oxides.

[0017] “Psilocybin” is the common name of 4-phosphoryloxy-N,N- dimethyltryptamine.

[0018] “Psilocin” is the common name of 4-hydroxy-N,N-dimethyltryptamine. “Norpsilocin” is the common name of 4-hydroxy-N-methyltryptamine.

[0019] The term “MAOIs” means monoamine oxidases inhibitors. The MAOIs used in the present invention belong to the p-carboline class of inhibitors and are selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8- hydroxymanzamine A, 8-methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A , ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and / or salts, derivatives, hydrate, or solvate and / or combinations thereof.

[0020] The “carotenoids” also called “tetraterpenoids”, are yellow, orange, and red organic pigments that are produced by plants and algae, as well as several bacteria, and fungi. Carotenoids can be further categorized into two classes, xanthophylls (which contain oxygen) and carotenes (which are purely hydrocarbons and contain no oxygen). Examples of carotenes are a-carotene, p-carotene, lycopene, astaxantin and zeaxanthin. All carotenoids are derivatives of tetraterpenes, meaning that they are produced from 8 isoprene molecules and contain 40 carbon atoms. In general, carotenoids absorb wavelengths ranging from 400 to 550 nanometers (violet to green light).

[0021] Carotenoids that contain unsubstituted beta-ionone rings (including p- carotene, a-carotene, p-cryptoxanthin, and y-carotene) have vitamin A activity (meaning that they can be converted to retinol).

[0022] Preferably, the carotenoids used in the present invention are obtained by plants extraction and / or microbial fermentation. SUMMARY OF INVENTION

[0023] The present invention relates to novel non-hallucinogenic tryptamine compounds of formula I and / or formula II:

[0024] The invention relates also to a process for the preparation of compounds of formula I or II comprising a conjugation step of a non-hydrolysable chemical moiety with tryptamine precursors, which can be obtained synthetically, and which are analogue to tryptamines naturally occurring in psilocybin containing mushrooms, preferably in psilocybin containing mushrooms belonging to the Psilocybe genus.

[0025] Further, the invention relates to a composition comprising at least one of said non-hallucinogenic tryptamine compounds of formula I and / or formula II, optionally in combination with at least one monoamine oxidase inhibitor (MAOI) compound and / or with at least one antioxidant selected from carotenoids.

[0026] A further object of the invention are the compounds of formula I and / or formula II of claim 1 for use as a medicament.

[0027] Lastly, the invention relates to the compounds according to formula I and / or II and to the composition containing them, for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, chronic musculoskeletal pain, pain from chemotherapy associated neuropathy and / or a TNF-a-induced inflammatory disease. According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, pathological ocular neovascularization, reducing scarring in the eye, macular degeneration, neovascularization, retinochoroidal, corneal neovascularization, keratitis, and / or irritable bowel syndrome.

[0028] DETAILED DESCRIPTION

[0029] The present invention relates to novel non-hallucinogenic tryptamine compounds of formula I and / or formula II: wherein:

[0030] - A is -NR1 R2 or -N+RI R2RS;

[0031] - R1, R2 and R3 are each independently selected from the group consisting of H, CH3 or an alkyl group, preferably selected from C2H5, C3H7 and (CH3)2CH, more preferably R1, R2 and R3 are each CH3;

[0032] - the group (OCH2CH2)n is oligo-ethylene glycol, wherein preferably n is selected from 1 and 50, more preferably n is selected from 3 and 12;

[0033] - X is selected from the group consisting of H, CH3, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, halogen or CH2CH2PO(OH)2, with the proviso that X cannot be H in formula I;

[0034] - Y is a Ci- C30 alkyl spacer, optionally substituted with one or more hydroxy group, preferably a C2-C18 alkyl spacer, preferably a C4-C16 alkyl spacer, wherein the alkyl spacer optionally contains oxygen, nitrogen, sulfur, 1 ,2,3-triazole and / or a further oligo- or polyethylene glycol chain; and / or pharmaceutically acceptable salts, derivatives, hydrate, or solvate and / or combinations thereof, with the proviso that when Ri, R2 and X are each CH3 in formula I, n is not 4 or 6.

[0035] Particularly preferred are the compounds according to the above formula II, wherein Y is selected from

[0036] -(OCH2CHOHCHOHCH2O)-(CH2)P- or -O-(CH2)m-(OCH2CHOHCHOHCH2O)-(CH2)P-, and wherein m and p are each independently selected from 2 and 8, preferably between 4 and 6.

[0037] The compounds according to the above formula II, wherein n is selected from 3 and 12, preferably from 4 and 6, and more preferably wherein n is 6, and / or X is CH3, are particularly preferred.

[0038] According to a further embodiment, the following compounds according to the above formula II are particularly preferred: wherein n is 6, and p is selected from 4 and 6; and / or wherein n is 6, m and p are each independently selected from 4 and 6.

[0039] The compounds of formula I or formula II and / or pharmaceutically acceptable salts, derivatives, hydrate, or solvate and / or combinations thereof, with the proviso that when Ri, R2 and X are each CH3 in formula I, n is not 4 or 6 can be obtained using a process comprising a conjugation step of a non-hydrolysable chemical moiety with tryptamine precursors, which can be obtained synthetically, and which are analogue to tryptamines naturally occurring in psilocybin containing mushrooms, preferably in psilocybin containing mushrooms belonging to the Psilocybe genus. The non-hydrolysable chemical moiety is selected from: wherein:

[0040] - the group (OCH2CH2)n is oligo-ethylene glycol, wherein preferably n is selected from 1 and 50, more preferably n is selected from 3 and 12;

[0041] - X is selected from the group consisting of H, CH3, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, halogen or CH2CH2PO(OH)2, with the proviso that X cannot be H in formula I; and

[0042] - Y is a C1-C30 alkyl spacer, optionally substituted with one or more hydroxy group, preferably a C2-C18 alkyl spacer, preferably a C4-C16 alkyl spacer, wherein the alkyl spacer optionally contains oxygen, nitrogen, sulfur, 1 ,2,3-triazole and / or a further oligo- or polyethylene glycol chain. According to a preferred embodiment, psilocybin containing mushrooms belonging to the Psilocybe genus comprise Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and combinations thereof.

[0043] The above-described non-hydrolysable chemical moiety, namely oligo- or polyethylene glycol optionally functionalized and optionally containing a spacer, makes the tryptamine compounds of formula I and / or II unable to cross the blood brain barrier (BBB). Hence, the pharmacological activity of tryptamine compounds of formula I and / or II takes place only at a peripheral level, namely on peripheral 5-HT2A receptors, thus avoiding secondary undesired effect on central nervous systems, such as hallucinations.

[0044] In view of the above, compounds of formula I and / or formula II of claim 1 can be used as a medicament, in particular they are non-hallucinogenic anti-inflammatory drugs, useful in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain, pain from chemotherapy associated neuropathy and / or a TNF-a-induced inflammatory disease.

[0045] According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, pathological ocular neovascularization, reducing scarring in the eye, macular degeneration, neovascularization, retinochoroidal, corneal neovascularization, keratitis, and / or irritable bowel syndrome.

[0046] It is an object of the present invention also a composition comprising at least one non-hallucinogenic tryptamine compound of formula I and / or formula II above described.

[0047] According to a preferred embodiment, the composition of the invention further comprises at least one MAOI compound, to inhibit the metabolic breakdown and clearance of the non-hallucinogenic tryptamine compounds of formula I and / or formula II.

[0048] Monoamine oxidases (MAOs) are metabolic enzymes attached to cytosolic side of the outer membrane of mitochondria of neuronal, glial and several cell types. Specifically, they catalyze the oxidative deamination of neuroactive and vasoactive biogenic compounds (including serotonin and tryptamines) and xenobiotic amines into the corresponding aldehyde and ammonia, both in the central nervous system and peripheral tissues. Several monoamine oxidase inhibitors (MAOIs) have been extensive employed as antidepressants and neuroprotective agents in Parkinson’s disease, as well as in the treatment of anxiety. There are two main isoforms, MAO-A and MAO-B. Monoamine oxidase A is predominantly responsible for the metabolism of psilocin (Reniers et al., “Synthesis and evaluation of [3-carboline derivatives as potential monoamine oxidase inhibitors”, Bioorg. Med. Chem. (2011 ) v. 19(1 ), p. 134-44).

[0049] According to a preferred embodiment, the at least one MAOI compound which can be optionally added to the composition of the invention is selected from the group consisting of norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DH[3C), tetrahydro-[3-carboline (TH[3C), methyl-tetrahydro-[3-carboline MTH[3C, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3- carboline-3-carboxylate ([3CCE), [3-carboline-3-carboxylate ([3CCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8- hydroxymanzamine A, 8-methoxymanzamine A, 6-hydroxymanzamine A,

[0050] 3.4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine or fascaplysin and / or salts, derivatives, hydrate, or solvate and / or combinations thereof.

[0051] According to a further preferred embodiment, the at least one MAOI is selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine and / or salts, derivatives, hydrate, or solvate and / or combinations thereof.

[0052] Moreover, the composition of the invention can also comprise at least one antioxidant selected from carotenoids, preferably selected from carotenoids obtained by plants extraction and / or microbial fermentation.

[0053] According to a further preferred embodiment, the at least one antioxidant selected from carotenoids is a-carotene, [3-carotene, lycopene, astaxantin and / or zeaxanthin.

[0054] The molar ratio between the at least one non-hallucinogenic tryptamine compound of formula I and / or formula II of the invention and the at least one MAOI compound, preferably selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DH[3C), tetrahydro-[3-carboline (TH[3C), methyl-tetrahydro-[3-carboline MTH[3C, pinoline, 1 -trichloromethyl-

[0055] 1 .2.3.4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3-carboline-3-carboxylate ([3CCE), [3-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymanzamine A, 6- hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8- hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and / or salts, derivatives, hydrate, or solvate and / or combinations thereof is comprised between about 10 : 1 to about 1 : 10, preferably comprised between about 100 : 1 to about 1 : 100, more preferably comprised between about 1 ,000 : 1 to about 1 : 1 ,000 and further more preferably comprised between 10,000: 1 to about 1 : 10,000. According to a further preferred embodiment, the composition of the invention comprises also at least one antioxidant selected from carotenoids, preferably selected from carotenoids obtained by plants extraction and / or microbial fermentation. More preferably, the at least one antioxidant selected from carotenoids is a-carotene, [3-carotene, lycopene, astaxantin and / or zeaxanthin.

[0056] The composition of the invention can be used in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, chronic musculoskeletal pain, pain from chemotherapy associated neuropathy and / or a TNF-a-induced inflammatory disease.

[0057] According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, pathological ocular neovascularization, reducing scarring in the eye, macular degeneration, neovascularization, retinochoroidal, corneal neovascularization, keratitis, and / or irritable bowel syndrome.

Claims

CLAIMS1 . A compound of the formula I or II:wherein:- - A is -NR1R2 or -N+RI R2RS;- R1, R2 and R3 are each independently selected from the group consisting of H, CH3 or an alkyl group, preferably selected from C2H5, C3H7 and (CH3)2CH, more preferably R1, R2 and R3 are each CH3;- the group (OCH2CH2)n is oligo-ethylene glycol, wherein preferably n is selected from 1 and 50, more preferably n is selected from 3 and 12;- X is selected from the group consisting of H, CH3, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, halogen or CH2CH2PO(OH)2, with the proviso that X cannot be H in formula I;- Y is a Ci- C30 alkyl spacer, optionally substituted with one or more hydroxy group, preferably a C2-C18 alkyl spacer, preferably a C4-C16 alkyl spacer, wherein the alkyl spacer optionally contains oxygen, nitrogen, sulfur, 1 ,2,3-triazole and / or a further oligo- or polyethylene glycol chain; and / or pharmaceutically acceptable salts, derivatives, hydrate, or solvate and / or combinations thereof, with the proviso that when R1, R2 and X are each CH3 in formula I, n is not 4 or 6.

2. The compound according to claim 1 , wherein Y of formula II is selected from-(OCH2CHOHCHOHCH2O)-(CH2)p- or -O-(CH2)m-(OCH2CHOHCHOHCH2O)-(CH2)P-, and wherein m and p are each independently selected from 2 and 8, preferably between 4 and 6.

3. The compound according to claim 2, wherein n is selected from 3 and 12, preferably from 4 and 6, and more preferably n is 6, and / or X is CH3.

4. The compound according to any one of claims 2 to 3, having the following formula:wherein n is 6, and p is selected from 4 and 6.

5. The compound according to any one of claims 2 to 3, having the following formula:wherein n is 6, m and p are each independently selected from 4 and 6.

6. A process for the preparation of compounds of formula I or II of claim 1 and / or pharmaceutically acceptable salts, derivatives, hydrate, or solvate and / or combinations thereof, with the proviso that when Ri, R2 and X are each CH3 in formula I, n is not 4 or 6, comprising a conjugation step of tryptamine precursors, which are analogue to tryptamines naturally occurring in psilocybin containing mushrooms, preferably in psilocybin containing mushrooms belonging to the Psilocybe genus, with a non- hydrolysable chemical moiety selected from:wherein:- the group (OCH2CH2)n is oligo-ethylene glycol, wherein preferably n is selected from 1 and 50, more preferably n is selected from 3 and 12;- X is selected from the group consisting of H, CH3, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, halogen or CH2CH2PO(OH)2, with the proviso that X cannot be H in formula I; and- Y is a Ci- C30 alkyl spacer, , optionally substituted with one or more hydroxy group, preferably a C2-C18 alkyl spacer, preferably a C4-C16 alkyl spacer, wherein the alkyl spacer optionally contains oxygen, nitrogen, sulfur, 1 ,2,3-triazole and / or a further oligo- or polyethylene glycol chain.

7. Process according to claim 6, wherein Y of formula II is selected from -(OCH2CHOHCHOHCH2O)-(CH2)P- or -O-(CH2)m-(OCH2CHOHCHOHCH2O)-(CH2)P-, and wherein m and p are each independently selected from 2 and 8, preferably between 4 and 6.

8. Compounds of formula I and / or formula II of claim 1 , for use as a medicament.

9. Compounds of formula I and / or formula II of claim 1 , for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain, pain from chemotherapy associated neuropathy and / or a TNF-a-induced inflammatory disease.

10. The compounds according to claim 9, wherein the TNF-a-induced inflammatory disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, pathological ocular neovascularization, reducing scarring in the eye, macular degeneration, neovascularization, retinochoroidal, corneal neovascularization, keratitis, and / or irritable bowel syndrome.

11. A composition comprising at least one non-hallucinogenic tryptamine compound of formula I and / or formula II according to claim 1 .

12. The composition according to claim 11 , further comprising at least one MAOI compound, preferably selected from the group consisting of norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6- methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-[3-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8- methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A,plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine or fascaplysin and / or salts, derivatives, hydrate, or solvate and / or combinations thereof.

13. The composition according to claim 12, wherein the at least one MAOI is selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine and / or salts, derivatives, hydrate, or solvate and / or combinations thereof.

14. The composition according to any one of claims 12 to 13, wherein the molar ratio between the at least one non-hallucinogenic tryptamine compound of formula I and / or formula II according to claim 1 and the at least one MAOI compound, is comprised between about 10 : 1 to about 1 : 10, preferably comprised between about 100 : 1 to about 1 OO, more preferably comprised between about 1 ,000 : 1 to about 1 : 1 ,000 and further more preferably comprised between 10,000: 1 to about 1 : 10,000.

15. The composition according to any one of claims 6 to 9, further comprising at least one antioxidant selected from carotenoids, preferably selected from carotenoids obtained by plants extraction and / or microbial fermentation.

16. The composition according to claim 15, wherein the at least one antioxidant selected from carotenoids is a-carotene, [3-carotene, lycopene, astaxantin and / or zeaxanthin.

17. A composition according to any one of claims 11 to 16, for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain, pain fromchemotherapy associated neuropathy and / or a TNF-a-induced inflammatory disease.

18. The composition according to claim 17, wherein the TNF-a-induced inflammatory disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, pathological ocular neovascularization, reducing scarring in the eye, macular degeneration, neovascularization, retinochoroidal, corneal neovascularization, keratitis, and / or irritable bowel syndrome.

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