WO2023215335A1 - Functionalized psychoactive compounds - Google Patents
Functionalized psychoactive compounds Download PDFInfo
- Publication number
- WO2023215335A1 WO2023215335A1 PCT/US2023/020756 US2023020756W WO2023215335A1 WO 2023215335 A1 WO2023215335 A1 WO 2023215335A1 US 2023020756 W US2023020756 W US 2023020756W WO 2023215335 A1 WO2023215335 A1 WO 2023215335A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- psychoactive
- group
- psychoactive compound
- composition
- Prior art date
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- 235000019160 vitamin B3 Nutrition 0.000 description 1
- 239000011708 vitamin B3 Substances 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- CKWXDLJHOHJWOX-UHFFFAOYSA-N voacangine hydroxyindolenine Natural products CCC1CC2N3CCC4(O)C(=Nc5ccc(OC)cc45)C2(CC1C3)C(=O)OC CKWXDLJHOHJWOX-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
Definitions
- the invention relates to psychoactive drugs, derivatized to enhance properties thereof, for example, to facilitate manufacturing or to obtain beneficial pharmacologic properties.
- Psychoactive compounds also known as, for example, psychopharmaceutic, psychoactive agent, hallucinogen, psychedelic, psychostimulatory drug, psychotropic drug and so on relate to a chemical substance that alters nervous system function and results in alteration of, for example, perception, mood, consciousness, cognition, behavior and so on.
- Some substances have a propensity to cause increase in dendrite formation and some can cause neural plasticity (or neuroplasticity).
- Psychoactive compounds may initiate or trigger neural plasticity.
- the substances may be used medically, may be used recreationally, may improve performance, may alter consciousness, may be used as an entheogen for ritual, spiritual or shamanic purposes, may be used for research, and so on.
- Some psychoactive compounds with therapeutic value can be prescribed for a medical purpose.
- Examples include anti-inflammatories, anesthetics, analgesics, anticonvulsants and antiparkinson drugs, as well as medications used to treat neuropsychiatric disorders, such as, antidepressants, anxiolytics, antipsychotics, stimulants and so on.
- Some psychoactive substances may be used in detoxification and rehabilitation programs for persons dependent on or addicted to other psychoactive compounds.
- Psychiactive compounds may and could induce many, if not all psychologic, psychiatric, cognitive, sensory, behavioral and neural effects and observations,
- Functionalization, derivatization, conjugation, coupling, modifying and similar synonyms relate to changing a base compound, such as, a psychoactive compound, generally by adding a moiety thereto.
- the entity added is a functional group, any reagent that can be added to a base compound for a desired purpose.
- the joining can be by any known method and is a design choice. Modification also can occur by other means and does not necessarily require an addition, for example, can occur by ionization.
- modifying compounds can reduce cytotoxicity thereof.
- compounds can be modified to carry a sugar residue, for example, being converted to a glycoside. Glycosylation can occur, for example, with a glycosyltransferase using an appropriate sugar donor.
- the instant invention relates to modifying psychoactive compounds to attain beneficial properties.
- Any psychoactive compound aside from cannabinoids can be used in practice of the instant invention.
- the modification is a design choice, based on, for example, psychoactive compound chemistry and structure; desired property; starting reactant; method of modifying; and so on.
- Modification method is a design choice, such as, a known chemical reaction, which can occur, for example, in liquid phase, solid phase, gas phase or any combination thereof, which can, for example, facilitate or enhance reaction kinetics, progression and so on; use of an enzymic reaction (enzyme(s) can be in a liquid phase, immobilized on a solid phase, substrate or support); and so on.
- Desired properties include, for example, adding bulk or another property to enable or to assist physical separation; adding a functional group to enable or to assist separation, for example, a chemical property, such as, charge, for example, through formation of an ionic bond or a chemical bond, as one member of a binding pair and so on; instilling a new chemical property on a psychoactive compound, such as, hydrophilicity, hydrophobicity steric bulk, or lack thereof, and so on; instilling a desired pharmacologic property, such as, extended half-life, shortened half-life, facilitate organ or tissue uptake, facilitate cell uptake, enable and facilitate use as a prodrug and so on; and the like.
- a chemical property such as, charge, for example, through formation of an ionic bond or a chemical bond, as one member of a binding pair and so on
- a new chemical property on a psychoactive compound such as, hydrophilicity, hydrophobicity steric bulk, or lack thereof, and so on
- a first modification of a psychoactive compound provides a reaction site for a second modification and so on
- a psychoactive compound can comprise a plurality of modifications or modification groups, which can be added sequentially one on to another, concurrently, for example, at plural sites of a psychoactive compound, or combination thereof.
- a modified psychoactive compound of interest can comprise more than one modification at one or more sites of the base psychoactive compound.
- a modification can be a linking entity, linker and so on, which can be bifunctional, polyfunctional and so on, with one end of a linking moiety attached to a psychoactive compound and other end(s) serve as site(s) for modification.
- a psychoactive compound of interest can be, for example, an alkaloid, an opioid, a phenethylamine, a tryptamine, a psychoactive compound comprising an indole group, a 2C compound and so on.
- Examples include mescaline, psilocybin, psilocin and so on.
- a psychoactive compound of interest is one which binds to and activates a serotonin receptor, a dopamine receptor and so on.
- the moiety added to a psychoactive compound of interest includes an amino acid, a lipid, a nucleic acid, a carbohydrate and combinations thereof.
- An amino acid includes single amino acids and polymers thereof.
- a carbohydrate includes a single sugar and polymers thereof.
- a nucleic acid includes a nucleotide and polymers thereof.
- the added moiety can be one member of a binding pair.
- the added moiety can be a vitamin or a vitamer, such as, a biotin or a folate.
- one or more, or all of the added moiety or moi eties are removable from the modified psychoactive compound of interest to recover or to reform the original, based psychoactive compound.
- Alkyl refers to a linear, branched or cyclic saturated hydrocarbon group containing 1 to about 24 carbon atoms or more, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and so on, as well as, cycloalkyl groups, such as, cyclopentyl, cyclohexyl and the like.
- “Lower alkyl” can refer to an alkyl group of 1 to about 6 carbon atoms.
- Heteroatomcontaining alkyl and, “heteroalkyl,” refer to an alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, “alkyl,” and, “lower alkyl,” include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl or lower alkyl, respectively.
- Alkenyl refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms, or more, containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl and so on.
- Lower alkenyl can refer to an alkenyl group of 2 to about 6 carbon atoms.
- substituted alkenyl refers to alkenyl substituted with one or more substituent or functional groups
- heteroatom-containing alkenyl refers to alkenyl where at least one carbon atom is replaced with a heteroatom.
- alkenyl and, “lower alkenyl,” include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
- Alkynyl refers to a linear or branched hydrocarbon group of 2 to about 24 carbon atoms, or more, containing at least one triple bond, such as, ethynyl, n-propynyl and so on.
- Lower alkynyl can refer to an alkynyl group of 2 to about 6 carbon atoms.
- Substituted alkynyl refers to alkynyl substituted with one or more substituent groups, and, "heteroatom-containing alkynyl,” and, “heteroalkynyl,” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.
- alkynyl and, “lower alkynyl,” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
- Alkoxy refers to an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy,” group.
- A, “lower alkoxy,” group relates to an alkoxy group containing 1 to about 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy and so on.
- Substituents identified as, “C1-C6 alkoxy,” or, “lower alkoxy,” herein may, for example, contain 1 to about 3 carbon atoms.
- Alkylthio refers to a group with a sulfur atom attached to an alkyl.
- Aryl refers to an aromatic substituent generally, although not necessarily, containing 5 to about 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings, that may be fused together, directly linked or indirectly linked (such that the different aromatic rings are bound to a common group, such as, a methylene or ethylene moiety).
- Aryl groups may, for example, contain 5 to about 20 carbon atoms.
- aryl groups may contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl -substituted aryl and so on). Examples include phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and the like.
- Substituted aryl refers to an aryl moiety substituted with one or more substituent groups, and, “heteroatom-containing aryl,” and, “heteroaryl,” refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the term, "aryl,” includes unsubstituted, substituted, and/or heteroatomcontaining aromatic substituents.
- aralkyl refers to an alkyl group with an aryl substituent
- alkaryl refers to an aryl group with an alkyl substituent.
- aralkyl and alkaryl groups herein contain 6 to about 30 carbon atoms.
- Alkylene refers to a diradical alkyl group. Such groups include saturated hydrocarbon chains containing from 1 to about 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, may be heteroatom-containing. "Lower alkylene,” refers to alkylene linkages containing from 1 to about 6 carbon atoms. Examples include, for example, methylene (— CH2— ), ethylene (— CH2CH2— ), propylene (— CH2CH2CH2— ), 2-methylpropylene (— CH2— CH(CH3)— CH2— ) and so on.
- alkenylene alkynylene
- arylene aralkyl ene
- alkarylene alkarylene
- Amino refers to — NZ1Z2 wherein Z1 and Z2 are hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, substituted and/or heteroatom-containing variants thereof and so on.
- Halo and, “halogen,” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
- heteroatom-containing refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, for example, nitrogen, oxygen, sulfur, phosphorus, silicon and so on, for example.
- heteroalkyl refers to an alkyl substituent that is heteroatom-containing
- heterocyclic refers to a cyclic substituent that is heteroatom-containing
- heteroaryl refers to a cyclic substituent that is heteroatom-containing
- heteroaryl refers to a cyclic substituent that is heteroatom-containing
- heteroaryl refers to a cyclic substituent that is heteroatom-containing
- heteroaryl refers to aryl
- aromatic substituents that are heteroatom-containing and the like.
- heteroalkyl groups include alkoxyaryl, alkyl sulfanyl -substituted alkyl, N-alkylated amino alkyl and so on.
- heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl and so on.
- heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl and so on.
- Hydrocarbyl refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as, alkyl groups, alkenyl groups, aryl groups and the like.
- Substituted hydrocarbyl refers to hydrocarbyl substituted with one or more substituent groups
- heteroatom-containing hydrocarbyl refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom.
- hydrocarbyl is to be interpreted as including substituted, unsubstituted and/or heteroatom-containing hydrocarbyl moi eties.
- Hydrocarbyl refers to a diradical hydrocarbyl group.
- substituted is meant that in a hydrocarbyl moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.
- substituents include, without limitation: functional groups, such as, halo, hydroxyl, sulfhydryl, Cl to about C24 alkoxy, C2 to about C24 alkenyloxy, C2 to about C24 alkynyloxy, C5 to about C20 aryloxy, acyl (including C2 to about C24 alkylcarbonyl (— CO-alkyl) and C6 to about C20 arylcarbonyl (— CO-aryl)), acyloxy (— O-acyl) and so on.
- functional groups such as, halo, hydroxyl, sulfhydryl, Cl to about C24 alkoxy, C2 to about C24 alkenyloxy, C2 to about C24 alkynyloxy, C5 to about C20 aryloxy, acy
- the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties.
- the above-mentioned hydrocarbyl moieties may be substituted further with one or more functional groups or additional hydrocarbyl moieties.
- the aforementioned functional groups may, if a particular group permits, be substituted further with one or more additional functional groups or with one or more hydrocarbyl moieties.
- the above-mentioned hydrocarbyl moieties may be substituted further with one or more functional groups or additional hydrocarbyl moieties.
- substituted or grammatic forms thereof, such as, “substituent,” appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group.
- substituted alkyl and aryl is to be interpreted as, “substituted alkyl and substituted aryl.”
- An, “alternative,” species of a base compound includes a derivative thereof, a structural analog thereof, a change therefrom and so on, which change includes addition of, for example, a substituent, a functional group, a replaced atom and so on, which change may enhance efficiency of production, may enhance pharmacologic activity, may reduce immunogenicity and so on.
- Synonyms include, “derivative,” and grammatic forms thereof, “variant,” and grammatic forms thereof, “modified,” and grammatic forms thereof, “functionalized,” and grammatic forms thereof, “substituted form,” and grammatic forms thereof, “analogs,” and grammatic forms thereof, and so on.
- the terms, "functional group,” “active moiety,” “reactive site,” “chemically reactive group,” “chemically reactive moiety,” synonyms thereof and grammatic forms thereof refer to portions or units of a molecule. (Verb forms can be used, such as, functionalized, modified, derivatized and so on.) The terms are used herein to indicate portions of molecules that perform some function or activity and are reactive with other molecules.
- “Active,” when used in conjunction with a functional group includes functional groups that react readily with, for example, electrophilic or nucleophilic groups on other molecules.
- active esters examples include N-hydroxysuccinimidyl esters or 1 -benzotriazol yl esters.
- An active ester can react with an amine in aqueous medium in a matter of minutes, whereas certain esters, such as, methyl or ethyl esters, can require a strong catalyst to react with a nucleophilic group.
- A "protected functional group,” “protecting group,” “protective group” synonyms thereof, including a blocking group as taught herein, grammatic forms thereof and so on refers to presence of a moiety (that is, the protecting group) that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions.
- linkage refers to an atom or a collection of atoms used to link, such as, by one or more, for example, covalent bonds, interconnecting moieties, such as, a psychoactive compound and a reactive functional group.
- a linker may be hydrolytically stable or may include a physiologically hydrolyzable or enzymatically degradable linkage.
- A, "physiologically hydrolysable,” or, “hydrolytically degradable,” bond is one that is labile and can react with water (is hydrolyzed) under physiologic conditions. Tendency of a bond to hydrolyze in water can depend on the general type of linkage connecting two central atoms and on the substituents attached to those central atoms.
- Known hydrolytically unstable or degradable linkages include, but are not limited to, carboxylate ester, phosphate ester, anhydrides, acetals, ketals, acyloxyalkyl ether, imines, orthoesters and so on.
- hydrolytically stable linkage or bond refers to a chemical bond, such as, a covalent bond, that is substantially stable in water, that is, does not undergo hydrolysis under physiologic conditions to any appreciable extent over an extended period of time.
- hydrolytically stable linkages include, but are not limited to, carbon-carbon bonds (for example, in aliphatic chains), ethers, amides, urethanes and the like.
- An, "enzymatically unstable,” or, degradable linkage is a linkage that can be degraded by one or more enzymes.
- Chemical groups can be added to a base structure or to substitute for an atom or a functional group of a base structure to obtain a derivative or functionalized form thereof.
- Those added or replacing chemical groups can be known as, “substituent,” “functional group,” “component,” and so on.
- the group added can be a, “radical.”
- the added group in embodiments, can be considered a, “pendant group.”
- Base compound “base structure,” “reference compound,” grammatic forms thereof and so on are equivalent terms and used synonymously herein and refer to an original compound or structure from which a modified form is made.
- a base compound can be one that is unmodified or does not contain a modification or functional group.
- a base compound can be modified and engineered to include one or more additional modifications.
- a derivative thereof is that base compound made to contain a new medication or functional group.
- a base compound can be a molecular entity from which an atom, group and so on is removed to form a derivative. So a halogenated base compound can be treated to remove the halogen group to yield a dehalogenated derivative thereof.
- vitamin is a nutrient, some can be synthesized in or by a subject.
- a vitamin includes choline, vitamin A (retinoic acids, retinals and so on), thiamine (vitamin Bi), riboflavin (vitamin B2), niacin (vitamin B3), a biotin (vitamin B7), a folate (vitamin B9), ascorbic acid and so on.
- vitamin B retinoic acids, retinals and so on
- vitamin Bi thiamine
- vitamin B2 riboflavin
- vitamin B3 riboflavin
- vitamin B3 niacin
- vitamin B7 niacin
- vitamin B7 niacin
- vitamin B7 a biotin
- vitamin B9 folate
- ascorbic acid and so on A synonym is, “vitamer.”
- A “sugar,” includes a monosaccharide, such as, glucose, fucose, glucuronic acid, glucosamine, mannose, galactose and so on, polymers thereof, such as, oligosaccharides, disaccharide, polysaccharides and so on, such as, lactose, a starch, a cellulose, glycogen, hyaluronic acid, sucrose and so on.
- a monosaccharide such as, glucose, fucose, glucuronic acid, glucosamine, mannose, galactose and so on
- polymers thereof such as, oligosaccharides, disaccharide, polysaccharides and so on, such as, lactose, a starch, a cellulose, glycogen, hyaluronic acid, sucrose and so on.
- amino acid relates to proteogenic, non-proteogenic, non-naturally occurring, naturally occurring, synthetic or other forms of amino acids.
- amino acids are organic compounds where a carbon atom, known as the a-carbon, is attached to an amine group and to a carboxylate group.
- Various side chains, which define a particular amino acid, are attached to the a-carbon.
- Naturally occurring amino acids are generally L stereoisomers, although D-amino acids exist or can be made and can be found in vivo.
- amino and carboxylate groups of amino acids can react in a condensation reaction, releasing water, to form an amide or peptide bond.
- Amino acid as used herein includes not only single amino acids, such as, lysine (Lys), serine (Ser), threonine (Thr) and so on, but also polymers thereof and so on. Included in the definition are dipeptides, tripeptides, oligopeptides, polypeptides and so on, as well as polymers, linear or branched, composed of a combination of proteogenic, non-proteogenic, non-naturally occurring, naturally occurring, synthetic or other forms of amino acids.
- lipid is any compound that does not (or is not substantially or easily dissolvable) dissolve in water, aqueous medium or hydrophilic medium. Examples, include, fatty acids, steroids, fats, waxes, some vitamins and so on.
- nucleic acid includes not only polymeric forms including dinucleotides, oligonucleotides, polynucleotides and so on, but also monomers used to construct a nucleic acid, for example, adenine triphosphate (ATP), uridine triphosphate (UTP) and so on, as well as the nitrogenous bases that a components of nucleotides, such as, uracil, thymidine and so on.
- ATP adenine triphosphate
- UDP uridine triphosphate
- A "pharmaceutically active molecule,” “active pharmaceutical ingredient (API),” or, “entity,” and so on, and grammatic forms thereof are synonyms as used herein and relate to a compound which has a beneficial effect on or in a subject when administered thereto or used by a subject in a therapeutically, pharmacologically or biologically effective amount and so on.
- a pharmaceutically active entity can have a curative effect, reduce symptoms of a disorder, affliction, disease and so on, or a palliative property.
- a pharmaceutically active compound may have a prophylactic property by reducing or preventing occurrence of one or more symptoms of a disease, disorder, affliction and so on, or a disease, disorder, affliction and so on.
- a pharmaceutically active moiety may be used for recreational purposes.
- Pharmaceutically active compounds include analogs and variants thereof.
- Bioly active is meant to indicate an introduced (into a subject) molecular entity initiates, stimulates, instigates, precipitates, elicits and so on a biologic response in a receiving subject.
- the response can have a positive or beneficial effect on the subject; can have a neutral effect on the subject; can have a negative or deleterious effect on the subject; and so on.
- a drug, medicine or compound that is pharmacologically active or pharmaceutically active is an example of a biologically active compound.
- a compound used for recreational purpose is one that is biologically active.
- PAI pharmaceutically active ingredient
- Subject is an organism or entity (as relating to a life form) that benefits from ingesting or being exposed to a compound of interest. Synonyms include, “recipient,” “individual,” “host,” “organism,” “patient,” “person,” and so on. Subject can be human.
- administering indicates a compound is one administered to a subject.
- An administrable compound is one safe for administration to a subject.
- the term, "approximately,” refers to a quantity, level, value or amount that varies by as much as 30%, as much as 20%, as much as 10% of a reference or stated quantity, level, value or amount.
- nucleophile is a chemical entity that can form a bond with an, “electrophile,” by donating an electron pair to the electrophile.
- Suitable nucleophilic compounds are those with a free pair of electrons or at least one n (pi) bond.
- Nucleophiles generally are Lewis bases or Bronsted bases. Nucleophilicity can be related to basicity. Examples include halogen anions, halogenated compounds, ammonia, hydroxides, thiocyanates, cyanides, organometallic compounds, enols, azides, amines, nitrites and so on.
- Nucleophilic reagents comprise one or more nucleophilic groups, such as, hydroxyl, ether, carboxyl (for example, -COO—), amine, azide, sulfhydryl and the like.
- Nucleophilic reagents include monohydric alcohols, diols, polyols, amines, diamines, polyamines, sulfhydryls, di sulfhydryls, poly sulfhydryls and so on, and combinations thereof. Examples include amino alcohols and sulfhydryl alcohols.
- Electrophiles are chemical entities complement to a nucleophile and forms a bond therewith by accepting an electron pair. Electrophiles, hence, generally are Lewis acids or Bronsted acids. Most are positively charged or can have an empty molecular orbital of the proper energy for bond formation with a nucleophile. Electrophiles and nucleophiles generally react together in addition reactions or substitution reactions. Common electrophiles include cations, carbonyls and so on.
- nucleophilic substitution reaction is a reaction between a nucleophile and an electrophile in which a covalent bond is formed between the nucleophile and the electrophile and often a bond is broken between the electrophile and a leaving group. Thus, a leaving group that had been bound to the electrophile is replaced by the nucleophile.
- reaction occurs between a nucleophile and, for example, a conjugated unsaturated group or conjugated unsaturated bond.
- a nucleophile can react with an a,p unsaturated aldehyde or ketone, resulting in formation of a covalent bond between the nucleophile and the P carbon and a bond between a hydrogen atom and the a carbon.
- a bond between the a and P carbons also is converted from a double to a single bond.
- glycocone refers to the non-glycosidic portion of a sugared compound, a glycoside compound; the entity lacking a sugar substituent or component; the base compound to which a sugar is attached or bound.
- binding pair are two complementary molecules or molecular entities that bind one another. Examples include a lectin and a cognate carbohydrate; biotin and avidin/streptavidin; antibody and cognate antigen; antibody and F c receptor; receptor and ligand; anion and cation; anion and complexing agent and so on.
- One member of a binding pair can be attached to a psychoactive agent to tether or to target the agent to a desired target that is attached to the complementary, other member of the binding pair.
- Reactive refers to a functional group that reacts readily with an electrophile or a nucleophile on another molecule, in contrast to those groups that require strong catalysts or highly impractical reaction conditions to react (that is a, “nonreactive,” “stable,” or, “inert,” group), US Pat No 7,790,835.
- protecting group refers to presence of a moiety that prevents or blocks reaction of a particular chemically reactive functional group in a molecule.
- the protecting group will vary depending on the type of chemically reactive group being protected as well as the reaction conditions employed and presence of additional reactive or protecting groups in the molecule, if any. Generally, protecting or blocking groups are removable. Protecting groups known in the art can be found in Greene et al., “Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, N.Y. (1999).
- prodrug refers to a compound that on administration to a subject, undergoes a chemical conversion or reaction by metabolic, biologic, biochemic or physiologic processes to become an active, pharmacologic agent. Prodrugs normally undergo a transformation to regenerate a pharmaceutically, pharmacologically or biologically active entity, such as a cleavage-type reaction that releases the PAI or drug on the one hand, and the once bound functional group or modification on the other.
- A. A, “psychoactive,” compound; “psychopharmaceutic;” “psychoactive,” agent; “hallucinogen;” “psychedelic;” “psychostimulatory,” drug; “psychotropic,” drug; and so on, and grammatic forms thereof, are synonyms as used herein, and relate to a chemical substance that alters nervous system function and results in alteration of, for example, perception, mood, consciousness, cognition, behavior and so on.
- the substances may: be used medically; be used recreationally; improve performance; alter consciousness; be used as an entheogen for ritual, spiritual or shamanic purposes; be used for research; and so on.
- Such compounds may be used to study consciousness; to enhance meditation; to produce a better understanding of one’s thoughts, one’s self, one’s traumas, one’s intentions and so on.
- Some psychoactive compounds with therapeutic value can be prescribed for a medical purpose. Examples include anesthetics, analgesics, anticonvulsants and antiparkinsonian drugs, as well as medications used to treat neuropsychiatric disorders, such as, antidepressants, anxiolytics, antipsychotics, stimulants and so on.
- Some psychoactive substances may be used in detoxification and rehabilitation programs for persons dependent on or addicted to a drug or other psychoactive compounds, persons who have behaviors or habits that are not beneficial or conducive to that individual; and so on.
- a psychoactive compound as used herein does not include a cannabinoid.
- a psychoactive compound can be an alkaloid.
- alkaloid is a compound or a precursor thereof, which can be of plant origin, having a nitrogen atom, such as, an amine, and a pharmacologic or physiologic effect in warm-blooded animals, including human, Cassels, Nat Prod Comm 14:85-90, 2019. Alkaloids can be used as medications and recreational drugs.
- alkaloids include, but are not limited to, ephedrine; pseudoephedrine, phenyl propanolamine; opiates, such as, oxycodone, morphine, hydrocodone, oxymorphone and the like; and so on.
- Alkaloids can be classified by structural similarity.
- alkaloids with a pyridine group include piperine, coniine, arecoline, cytisine, nicotine, anabasine, sparteine, pelletierine and the like.
- Pyrrolidines include hygrine, cuscohygrine, nicotine and the like.
- Tropanes include atropine, cocaine, ecgonine, scopolamine, catuabine and the like.
- Quinolines include quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, veratrine and the like.
- Isoquinolines include opium alkaloids (papaverine, narcotine (noscapine), narceine and the like), sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine and the like.
- Phenanthrene alkaloids include opium alkaloids, morphine, codeine, thebaine and the like.
- Phenethylamines include mescaline, ephedrine, dopamine, amphetamines, 3,4-methylenedioxymethamphetamine (MDMA), 2C compounds, cathinone and the like.
- Indoles include tryptamines, serotonin, dimethyltryptamine (DMT), 5 -methoxy dimethyl tryptamine (5MeO-DMT), N,N,N-trimethyl-4- phosporyloxytryptamine, 4-hydroxy-N-methytryptaine (4-HO-NMT), bufotenine, psilocyin, psilocybin, ergolines, ergot alkaloids, lysergic acid, tetrahydroharmine, reserpine, N-nitrosodimethylamine (NDMA) also known as, dimethylnitrosoamine (DMN), yohimbine, vinca alkaloids, vinblastine, vincristine, mitragynine, ibogaine, voacangine, coronaridine, strychnine, brucine and the like.
- DMT dimethyltryptamine
- 5MeO-DMT 5 -methoxy dimethyl tryptamine
- Purines include xanthines, caffeine, theobromine, theophylline and the like.
- Terpenoids include aconite alkaloids, aconitine, steroid alkaloids (containing a steroid skeleton with a nitrogen containing group), solanum (for example, potato and tomato) alkaloids, chaconine, veratrum alkaloids, cyclopamine, cycloposine, jervine, muldamine, newt alkaloids, such as, samandarin; conessine, and the like.
- Quaternary ammonium compounds include muscarine, choline, aeruginascins, neurine and the like.
- Miscellaneous alkaloids include capsaicin, cynarin, harmine, phytolaccatoxin and the like.
- Mescaline (3,4,5-trimethoxyphenethylamine) is produced in some types of cactus found in the desert Southwest and in South America, such as, peyote and Peruvian torch. Mescaline has a free amine group.
- Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine (DMT)) is a prodrug converted to the pharmacologically active compound, psilocin, by dephosphorylation. That reaction takes place under strongly acidic conditions; or under physiologic conditions by enzymes called alkaline phosphatases.
- Psilocybin is a tryptamine with an indole heterocycle linked to an ethylamine substituent.
- Psilocybin is chemically related to tryptophan and is structurally similar to serotonin.
- Psilocybin is soluble in water, methanol and aqueous ethanol, but insoluble in organic solvents, such as, chloroform and ether.
- 2C compound (2C or 2C-x) is a general name for the family of phenethylamines containing methoxy groups at the 2 and 5 positions of the benzene ring. Many 2C compounds carry lipophilic substituents at the 4 position, which can result in increased potency, increased metabolic stability and greater in vivo persistence.
- the term, “2C,” is derived from and represents the 2 carbon atoms between the benzene ring and the amine group.
- Ketamine is an arylcyclohexylamine often used as an anesthetic.
- N,N-dimethyl tryptamine occurs in many plants and animals.
- DMT can be used as a recreational drug and is used as an entheogen.
- Dimethyltryptamine is an indole alkaloid derived from the shikimate pathway.
- DMT has two reactive amine groups.
- LSD Lysergic acid diethylamide
- Indolamines are a family of monoamine neurotransmitter.
- An example is the tryptophan derivative, serotonin, a neurotransmitter involved in mood and sleep.
- Another example is melatonin.
- GI gastrointestinal
- CNS central nervous system
- serotonin is secreted luminally and basolaterally, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons resulting in gastrointestinal motility.
- the remainder of total serotonin is synthesized in serotonergic neurons of the CNS where serotonin regulates mood, appetite and sleep. Serotonin also has influence on some cognitive functions, including memory and learning.
- 5-hydroxyindoleacetic acid 5-HTAA
- Other neurotransmitters include catecholamines and ethylamines.
- J. Tryptamines, or serotonin analogues contain an indole ring, joined to an amine group via an ethyl sidechain.
- Phenethylamines contain a phenyl ring joined to an amino group via a two-carbon sidechain.
- Serotonin binds 5 -hydroxytryptamine (5-HT) receptors or serotonin receptors which are G protein-coupled receptors (molecules with a portion exposed on the cell surface and which traverse the cell membrane) or are ligand-gated ion channels found, for example, in the central and peripheral nervous systems. The receptors mediate both excitatory and inhibitory neurotransmission. Serotonin is the natural ligand.
- 5-HT 5 -hydroxytryptamine
- serotonin receptors which are G protein-coupled receptors (molecules with a portion exposed on the cell surface and which traverse the cell membrane) or are ligand-gated ion channels found, for example, in the central and peripheral nervous systems. The receptors mediate both excitatory and inhibitory neurotransmission. Serotonin is the natural ligand.
- the serotonin receptors modulate release of many neurotransmitters, including glutamate, y-amino butyric acid (GABA), dopamine, epinephrine/norepinephrine, acetylcholine and so on, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, substance P and so on.
- GABA y-amino butyric acid
- Serotonin receptors influence various biologic and neurologic processes, such as, aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep and thermoregulation.
- Serotonin receptors fall into 7 families that generally, on binding serotonin, either increase or decrease intracellular cAMP (one family comprises ion channels). A decrease in cAMP generally results in an inhibitory response to serotonin and an increase in cAMP generally results in an excitatory response to serotonin. Those 7 families contain 14 different receptors.
- family 5 includes three species of receptor.
- the family 5 receptors do not mediate cell response by impacting cAMP level, family 5 receptors instead rely on G protein signaling.
- Heterotri meric G proteins comprise a family of intracellular membrane-associated proteins that form a heterotrimeric complex which associates with G protein-coupled receptors (GPCR) located at the cell surface and traversing the cell membrane.
- GPCR G protein-coupled receptors
- a GPCR receptor portion or moiety displayed outside a cell can bind a specific, cognate ligand.
- GPCR G protein-coupled receptors
- G proteins are made of a, P and y subunits.
- the a subunit is attached to either a guanosine triphosphate (GTP) or a guanosine diphosphate (GDP) and serves as an on-off switch for activating the G protein complex and for activating the downstream signaling cascade.
- GTP guanosine triphosphate
- GDP guanosine diphosphate
- G q protein is one of 18 types of a. subunit, also commonly called Gq/n (Gq/Gn), which associates with G protein-coupled receptors which when serotonin is bound, thereby results in activation of -type phospholipase C (PLC-P).
- PLC-P in turn hydrolyzes phosphatidylinositol 4, 5 -bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3) at the inner face of the cell membrane.
- IP3 moves deeper into the cytoplasm to act as a second messenger ultimately controlling release of a number of hormones, while DAG remains in association with the cell membrane and activates protein kinase C (PKC), a family of enzymes that activate protein substrates by phosphorylating same, which are involved with producing many functions in cells, tissues and organs, such as, smooth muscle, kidney tubule cells, neurons, platelets, heart, serous cells, adipocytes and so on.
- PLC protein kinase C
- 5-HT2A is an excitatory receptor subtype among the GPCR’s for serotonin, although 5-HT2A also may have an inhibitory effect in certain tissues and cells, such as, the visual cortex and the orbitofrontal cortex.
- the receptor is a target of serotonergic psychedelic drugs, such as, LSD and psilocybin.
- the 5-HT2B receptor mediates many central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets. Central nervous system (CNS) effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of amphetamines.
- the 5-HT2B receptor is expressed highly in liver and kidney, with lower levels found in the cerebral cortex, whole brain, pancreas and spleen.
- Dopamine receptors are G protein-coupled receptors prominent in the central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein (for example, dopamine receptor-interacting proteins) interactions. Dopamine receptors are implicated in many neurologic processes, including motivation, pleasure, cognition, memory, learning, fine motor control and so on, as well as modulation of neuroendocrine signaling.
- dopamine receptors are common neurologic drug targets, antipsychotics often are dopamine receptor antagonists while psychostimulants typically are indirect agonists of dopamine receptors.
- Dopamine is the primary neurotransmitter involved in the reward pathway in the brain. Thus, drugs that increase dopamine signaling may produce a euphoria. Many recreational drugs, such as, cocaine and amphetamines, inhibit the dopamine transporter (DAT) responsible for removing dopamine from neural synapses. When DAT activity is blocked, synapses flood with dopamine and increase dopaminergic signaling, and hence, for example, euphoria.
- DAT dopamine transporter
- the joining can be by a covalent linkage, a non-covalent linkage, such as, by an ionic interaction, a hydrophobic interaction, hydrogen bonding and so on.
- the joining also can be obtained using an intervening linking molecule (linker, linker molecule, synonyms thereof and so on) wherein one portion of a linking molecule attaches to a psychoactive compound and another portion of a linking molecule distal from the psychoactive compound attaches to a substituent, functional group and so on, see, for example, US Pat No 9,968,683.
- a synonym of functionalize is, "couple,” and grammatic forms thereof, which means reacted with or attached to, possibly through a series of covalent bonds.
- a psychoactive compound can be coupled to a functional group or to a linker.
- a "derivative,” of an organic molecule is a compound having a portion of the organic molecule and having the same function or activity as the organic molecule.
- a derivative may have one more functional groups that are not present in the parent organic molecule might not have one or more functional groups present in the parent organic molecule.
- a synonym is modified or functionalized.
- methods of conjugating two molecules can be obtained by reacting an aliphatic dialdehyde or aromatic dialdehyde with an amine moiety to form a stable product under mild conditions.
- the reaction does not produce side products that must be removed from the reaction mixture, and does not require a catalyst or a reducing agent.
- the reaction mechanics may involve reducing, and therefore stabilizing the imine adduct formed between the amine and the aldehyde, see, for example, US Pat No 10,188,719.
- conjugates can be formed, for example, by mixing a saccharide comprising an aldehyde group with a psychoactive compound comprising an amine group under suitable reaction conditions.
- Two types of conjugate can be made: (a) a conjugate where an individual saccharide is attached to a psychoactive compound through a reducing terminus; and (b) a conjugate where an individual saccharide is attached to multiple psychoactive compounds because several functional groups of a monosaccharide subunit are reactive.
- a single psychoactive compound can link to more than one saccharide because of more than one amine groups.
- a saccharide is oxidized to form an aldehyde, and the aldehyde then can be used for reaction, such as, reductive amination.
- Oxidation of hydroxyl groups to yield aldehydes can be achieved chemically or enzymatically. Such reactions can occur under aqueous conditions, see, for example, WO94/06467.
- Periodate salts such as, sodium or potassium periodate (NaIO4), can oxidize vicinal hydroxides.
- Other oxidation conditions can be used, for example, with osmium tetroxide.
- a hydroxyl that is oxidized can be primary, that is, not a secondary or anomeric hydroxyl, which is attached to C-6.
- galactose can be converted to galactohexodialose, which can be attained using a galactose oxidase enzyme, such as, from Fusarium fungi or Dactylium dendroides.
- the enzyme can be used in recombinant form or purified from a natural source. Therefore, the oxidation reactions involve the terminal carbon atoms in the monosaccharides, that is, the highest-numbered carbons by standard nomenclature.
- reductive amination of the aldehyde group can be used to achieve conjugation.
- reductive amination can involve a primary amine (NH2R). That can be achieved by using an ammonium salt (for example, ammonium chloride) with an appropriate reducing agent (for example, cyanoborohydrides, such as, sodium cyanoborohydride NaBH3CN; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin and so on).
- an ammonium salt for example, ammonium chloride
- an appropriate reducing agent for example, cyanoborohydrides, such as, sodium cyanoborohydride NaBH3CN; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin and so on.
- cyanoborohydrides such as, sodium cyanoborohydride NaBH3CN; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin and so on.
- cyanoborohydrides such as,
- a sugar acid can be activated by introducing an amine at the carboxylate group, for example, by carbodiimide-mediated coupling using an active ester intermediate, see, for example, US Pat. No. 7,196,180.
- Different terminal functional groups for crosslinking including, acetals, aldehydes, amines and hydrazides can be added at the carboxylate group.
- Many functionalized amines are commercially available for introducing a variety of different functional groups for crosslinking under physiologic conditions, including mal eimides that react with sulfhydryls or arylazides for photocrosslinking.
- Direct carbodiimide-mediated coupling of amines to a carboxyl group in an aqueous environment can be attained, for example, with active carboxylic esters N-hydroxysuccinimide (NHS) esters, nitrophenol esters, triazole esters, sulfonic esters and so on, as long as the reagent is soluble in water or a polar solvent, such as, dimethyl sulfoxide or dimethylformamide.
- NHS N-hydroxysuccinimide
- An active ester of a sugar acid can be obtained with 1 -hydroxybenzotriazole (HOBT) or NHS using a water soluble carbodiimide, such as, l-ethyl-3-(3-dimthylaminopropyl)carbodiimide (EDC) for coupling.
- HOBT 1 -hydroxybenzotriazole
- NHS water soluble carbodiimide
- EDC l-ethyl-3-(3-dimthylaminopropyl)carbodiimide
- the reactant conjugated to the sugar acid can provide a range of terminal functional groups including an aldehyde, an amine, an arylazide, a maleimide, a sulfhydryl and so on.
- diaminoethane, histidine or adipic dihydrazide can be coupled to a sugar acid using HOBT and EDC (up to 5-fold excess depending on the desired degree of modification) and adjusting the pH to about.6.5 by repeated addition of 0.1M HC1 during the reaction.
- Sugar acid derivatives also can be prepared using NHS and primary amines containing unconjugated amino groups with a higher pKa (>9) such as 1,4-diaminobutane.
- the sugar acid derivatives can be purified by repeated ethanol precipitation and dialysis.
- Degree of modification can be ascertained by, for example, NMR. Amount of carbodiimide can correlate with degree of modification.
- Reagents such as, succinic or suberic dihydrazide or diaminoethane, diaminohexane and so on provide different lengths of spacer separating the introduced functional group from the sugar acid, which may impact subsequent crosslinking.
- an added modification or functional group is removable after attachment to a psychoactive compound.
- a functional group or modification is removed from a psychoactive compound, which retains or regains biologic effect.
- removal can enable a psychoactive compound to exhibit a biologic effect. Removal can be obtained by a chemical reaction; an enzymic reaction; or combination thereof.
- a prodrug is an example where removal of a modification can enable a psychoactive compound to exert a biologic effect, and so on.
- Non-covalent and covalent methods can be used to change a base compound, for example, to add to a base compound, a functional group, one member of a binding pair and so on, for example, to improve properties of a base compound, such as, associating a base compound with a carrier, such as, a carbohydrate, such as, a cyclized maltodextrin; and so on.
- a base compound such as, associating a base compound with a carrier, such as, a carbohydrate, such as, a cyclized maltodextrin; and so on.
- the present invention relates to derivatives of psychoactive compounds where a base compound is modified to include an added moiety can be any atomic or molecular entity, such as, a carbohydrate, such as, a polysialic acid, such as, a sialic acid, and so on.
- One approach to adding a carbohydrate to a psychoactive compound is to employ succinimide chemistry for adding a moiety at an amine group of a psychoactive compound.
- an N-hydroxysuccinimide (NHS) group can be added to a carboxyl group of a sugar by carbodiimide activation.
- NHS N-hydroxysuccinimide
- sulfo-NHS is a commercially available reagent for making such as derivative.
- An NHS derivatized sugar then can react with an amine group of a psychoactive compound where an amide bond is formed, covalently linking the sugar to the psychoactive compound with release of the NHS entity.
- the NHS chemistry is useful for conjugation to amine-group containing substrates, such as, a psychoactive compound.
- a monosaccharide, an oligosaccharide or a polysaccharide may be covalently or non-covalently associated with a psychoactive compound.
- Covalent linkages can be, for example, by ester, amide or other linkage, to, for example, carboxy, hydroxy, phosphoryl or amino sites of a psychoactive compound.
- Non-reducing sugars can be derivatized by selective oxidation using periodate, J. Immunol. 127, 1011 (1981), to form an aldehyde group for coupling in an amination conjugation reaction with a receptive psychoactive compound.
- a carboxylate group of a sugar, a nucleophile can be added to an amine group of a psychoactive compound in presence of a carbodiimide, FEBS Lett. 202, 86 (1986).
- An alternative reaction involves diazotization of an aromatic amine group introduced into a sugar, for example, using p-phenylenediamine reacted onto a carboxylic acid group, followed by reaction with a hydroxyl group, Biochim. Biophys. Acta, 772, 288 (1984) and Biochim Biphys Acta 1003, 58, (1989).
- Free hydroxyl groups of a polysaccharide compound can be linked to free hydroxyl groups or thiol groups of a psychoactive compound, for example, by esterification using a dibasic acid or an acid derivative.
- a psychoactive compound to be coupled to a sugar contains (or can be derivatized, for example, via an aryl group, to contain) an isothiocyanate group
- conjugation can occur at a free hydroxyl group of the sugar, for example, by reaction in methyl sulfoxide, catalyzed by dibutyl tin dilaurate, Carb Res (1973) 30, 375-378.
- the product is a thiocarbamoyl derivative that may be reacted to form an O-linked derivative.
- PEG Polyethylene glycol
- a functional group or modification can include an atom, a cofactor, one member of a binding pair, a sugar, a nucleic acid a lipid, a vitamin, an amino acid and so on, and combinations thereof, without limitation so long as a beneficial endpoint is attached and biologic activity of the psychoactive base compound is retained, regained and so on, for example, in vivo.
- a modification can be a monosaccharide; a polysaccharide; an amino acid; an oligopeptide; a polypeptide; a vitamin or vitamer, such as, a biotin, a folate and so on; a lipid; and so on. Also included are glycolipid, glycoprotein, lipoprotein and so on.
- a functional group can facilitate separation; enhance bioavailability; enhance biologic effect; and so on.
- a functional group can enhance half-life; can target an organ; can target a tissue; can target a cell; can enhance entry into an organ; can enhance entry into a tissue; can enhance entry into a cell; and so on.
- A. Modification of a psychoactive compound may enhance properties of same, production of same and so on.
- a modified psychoactive compound can be used as a prodrug, may reduce toxicity thereof, may be made more hydrophobic or more hydrophilic, can have greater functionality; may be larger; can have enhanced solubility; can have altered function; and so on.
- a modified psychoactive compound may be restored enzymatically or chemically to the original, base compound by removing the added group.
- a modified psychoactive compound may enhance manufacturing efficacy.
- Mineral acid salts of a base compound are a common tool to impart immediate release characteristics to that compound, such as in an acidic environment.
- a dissolution profile can influence absorption.
- a psychoactive compound delivered by nasal inhalation would benefit from rapid dissolution in nasal fluid.
- pH in the nasal cavity is about 4.5 which provides an environment for rapid dissolution and absorption of a highly soluble, mineral acid salt of a psychoactive compound, see US Pat. No. 9,421,266.
- modifying a psychoactive compound can endow the psychoactive compound with one or more new properties that can be exploited for a beneficial use.
- a modified psychoactive compound of interest can facilitate separation, isolation and/or purification.
- a modified psychoactive compound of interest may be heavier; may be bulkier; may be more hydrophobic; may be more hydrophilic; may be charged; may be cationic or more cationic; may be anionic or more anionic; may carry a recognizable or a bindable functional group; may carry one member of a binding pair; and so on.
- Separation methods which are known in the art, and which can be used in practice of the instant invention, include fdtration, sublimation, sedimentation, distillation, evaporation, precipitation, chromatography, magnetic separation and so on.
- Derivatized psychoactive compounds can have enhanced pharmacologic function and/or efficacy; enhanced half-life; enhanced bioavailability; enhanced tissue or organ targeting; enable access to tissues and organs not normally exposed to the normal circulation such as, brain because of the blood-brain barrier (BBB) and testes because of the barrier generated by the Sertoli cells and other privileged sites; and so on.
- BBB blood-brain barrier
- a functionalized psychoactive compound can have properties that are directed to a specific mode of administration.
- an organic acid salt of an amine-containing psychoactive is soluble and the psychoactive compound on oral digestion, which compound is digested or recreated in the acid environment of the stomach.
- the organic acid salt is stable at the higher pH of mucosa, see, US Pat. No. 9,421,266, the entire content of which herein is incorporated by reference in entirety. That organic acid salt derivative of a psychoactive compound can be effective in the acidic milieu of the nasal cavity.
- a robust form of attachment of a psychoactive compound to a surface or other support, or to a functional group is via a covalent bond.
- bonds are heteroatom-based (for example, amide, ester, disulfide and so on bonds).
- Covalent bonds can be formed under mild conditions.
- Non-covalent attachment via, for example, specific binding pairs also can be employed, but such methods require, for example, conjugation of the specific binding pair to the psychoactive compound and to the functional group and may not be as robust as a covalent bond; and so on.
- specific binding pairs for example, biotin-avidin, antibody-antigen, carbohydrate-lectin, hydrophobic and so on interactions
- Carbon-carbon bonds also can be used, for example, if a psychoactive compound comprises an unsaturated site.
- the method for covalent bond formation is a design choice, and the decision may be governed by solubility in organic solvents, pH, temperature sensitivity and so on.
- functionalization may need to be directed which can require protecting or blocking particular sensitive or reactive groups on a psychoactive compound.
- compounds of the invention may be modified by using protecting groups yielding a prodrug. That can be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", McOmie, ed., Plenum Press, 1973; and Greene & Wuts, "Protective Groups in Organic Synthesis", 3rd ed., John Wiley & Sons, 1999.
- the protecting groups may be removed at a convenient subsequent stage using methods known in the art or in a physiologic environment, such as, physiologic pH, an enzyme and so on.
- Protecting groups for a hydroxyl group include methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and so on.
- Substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, benzyloxymethyl, 4-pentenyloxymethyl and so on.
- substituted ethyl ethers examples include 1 -ethoxy ethyl, l-(2- chloroethoxyjethyl, 1 -methyl- 1 -methoxyethyl, 1-methyl-l-benzyloxyethyl, 1-methyl- l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, benzyl and so on.
- substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and so on.
- silyl ethers include trimethylsilyl, tri ethyl silyl, tri isopropyl silyl, dimethylisopropylsilyl and so on.
- a hydroxyl group also may be protected as an ester.
- esters include formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate and so on.
- Carbonates that can be used to block a hysroxyl group include methyl, ethyl, isobutyl, vinyl, allyl, p- nitrophenyl, benzyl and so on.
- 1,2- and 1 ,3 -diols can be protected using cyclic acetals and ketals.
- cyclic acetals and ketals include methylene, ethylidene, acetonide, cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene and so on.
- cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1 -ethoxyethylidine and so on.
- Amino (or alkylamino) groups can be protected with carbamates, amides and so on.
- carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, urea-type derivatives and so on.
- methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl and so on.
- substituted ethyl carbamates examples include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l -methyl ethyl, l,l-dimethyl-2- haloethyl, l,l-dimethyl-2,2-dibromoethyl, l,l-dimethyl-2, 2, 2 -tri chloroethyl t-butyl, vinyl, allyl, benzyl, p-methoxybenzyl, p -nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfmylbenzyl, 9-anthrylmethyl and diphenylmethyl and so on.
- urea-type derivatives examples include phenothiazinyl-(10)-carbonyl, N'-p- tol
- amides include N-formyl, N-acetyl, N- chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenyl acetyl, N-3- phenylpropionyl, N-picolinoyl, N-3 -pyridylcarboxamide, N-benzoyl, N-p- phenylbenzoyl and so on.
- Amino groups also can be protected with N-alkyl and N-aryl amines, quaternary ammonium salts and so on.
- deprotection conditions vary with the protecting group.
- Groups such as, an alkanoyl, alkoxycarbonyl or aroyl, may be removed, for example, by hydrolysis with a suitable base, such as, an alkali metal hydroxide.
- a t-butoxy carbonyl group may be removed by, for example, treatment with an acid, such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid.
- Arylmethoxycarbonyl groups such as, benzyloxycarbonyl
- a phthaloyl group protecting a primary amino group may be removed by, for example, treatment with an alkylamine, such as, di methyl ami nopropyl amine, or with hydrazine.
- Dicarbonyl groups such as, a- and P-diketones can be protected with enamines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl, morpholinyl, 4-methyl-l,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and trimethyl silyl.
- a carboxyl group can be protected with an ester.
- substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl and N-phthalimidomethyl.
- 2-substituted ethyl esters include 2,2,2- trichloroethyl, 2-haloethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, benzyl and so on.
- substituted benzyl esters include triphenylmethyl, diphenylmethyl, o- nitrobenzyl, p -nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and so on.
- Amides and hydrazides for protecting amino groups include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-l,2,3,4-tetrahydroquinolyl, and p-P -benzenesulfonamides; and examples of hydrazides include N-phenyl and N,N'-diisopropyl, for example, US Pat No 7,807,837.
- a thiolated protein can be conjugated with a maleimido-derivatized saccharide (Meth. Enzymol. 1994, 242:17).
- N-acryloyl amidophenyl glycosides may be coupled using a Michael addition reaction (Romanowska et al., Meth. Enzymol. 1994, 242:90).
- NHS reagents can be used with organic solvents and can employ a hydrophobic carbodiimide, such as, dicyclohexylcarbodiimide (DCC) or, for example, N,N'-diisopropylcarbodiimide (DIC).
- a hydrophobic carbodiimide such as, dicyclohexylcarbodiimide (DCC) or, for example, N,N'-diisopropylcarbodiimide (DIC).
- DCC dicyclohexylcarbodiimide
- DIC N,N'-diisopropylcarbodiimide
- Reactions involving aqueous conditions, or substantially aqueous conditions can use a water soluble carbodiimide such as l-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC; also EDAC) or N-cyclohexyl-N'-(P-[N-methylmorpholin
- a hydroxyl group of a sugar can be converted into a reactive functional group to form an, "activated,” sugar or reagent.
- cyanuric chloride or cyanuric fluoride reacts with a hydroxyl group to yield, for example, an alkyl chloride or acyl chloride, activated forms.
- the chloride then can be replaced by a nitrogen of a nucleophile forming a covalent bond.
- Nucleophilic functional groups can serve as attachment sites for a functional group, for example, by a nucleophilic substitution reaction.
- Suitable nucleophilic functional groups include amine or amino groups, amido groups, negatively charged amine groups, free carboxylic acid groups, suitably activated carbonyl groups, oxidized carbohydrate moieties, carboxylates, mercapto groups, alcohols, alkoxides, thiolates and so on.
- Another activating form can be a succinate, such as, a succinimidyl succinate or a carbonate.
- Those electrophilic sites on the conjugating reagent can react, for example, with an amine group or an alcohol.
- a carboxylic acid can react with a hydroxyl group of a nucleophilic psychoactive compound to form an ester-linked functionalized psychoactive compound. Ester bonds are susceptible to cleavage by esterases, common enzymes found in vivo. Hence, ester-linked functionalized psychoactive compounds can be prodrugs.
- Electrophilic substitution also can be enhanced by producing acid halides.
- a compound comprising a negative anion such as, a chloride, bromide, iodide and so on can be a leaving group when reacted with an amine, imide, alcohol, alkoxide and so on to produce the corresponding ester or amide.
- Other leaving groups include polyatomic anions which can be attached to a carboxyl group to facilitate formation of new molecular species.
- a psychoactive compound can be modified by a chemical reaction to carry one or more modifications, such as, a functional group, a carbohydrate, a carrier and so on. Materials and methods for such reactions are known and are available commercially.
- Amide linkages can be formed by reacting an amino group with, for example, an acyl chloride functional group.
- N-alkylimide compounds may be prepared as taught in Barrow (J. Chem. Soc. (London), p. 638, 1939) by condensation of carboxylic acid and primary amine, condensation of carboxylic acid ester and primary amine or condensation of carboxylic acid anhydride and primary amine.
- N-alkylimide compounds can be prepared from an imide, for example, by the methods presented in US Pat. Nos. 2,628,963 and 2,753,356 where carboxyimide and primary amine are reacted at high temperature and under high pressure.
- a P-sulfonimide compound can be prepared by nucleophilic addition of a compound having at least one vinylsulfonyl group with a psychoactive compound having at least one imide group in presence of a catalyst.
- a nucleophilic addition is a Michael-type addition reaction.
- a nucleophile is used as Michael donor and an activated unsaturated compound, for example, an a,p- unsaturated carbonyl compound, is used as Michael acceptor.
- the imide of a psychoactive compound is used as Michael donor and vinylsulfone can be used as Michael acceptor, see, for example, US Pat No 8,362,276.
- nucleophilic compound can be an organic hydrocarbon compound that may be acyclic or cyclic and comprises at least one atom carrying a free electron pair, such as, a nitrogen, an oxygen, a sulfur or a phosphorus atom, or comprises a carbon atom that may donate an electron pair.
- a nucleophilic compound comprises at least one atom carrying a free electron pair, which can be carried by a functional group, US Pat. No. 6,960,665.
- a nucleophilic compound comprises a functional group which carries one or more negative charges
- that compound is a salt.
- the counter-ion can be a metallic cation, such as, an alkali metal, such as, sodium or lithium, or an alkaline-earth metal, such as, calcium, or residue of an organometallic compound, such as, a magnesium or zinc compound.
- Psychoactive compounds can comprise a nucleophilic site such as, nitrogen-containing compounds, such as, primary or secondary amines; hydrazine or hydrazone derivatives; amides; sulphonamides; urea derivatives, heterocyclic derivatives and so on, US Pat. No. 8,362,276.
- nitrogen-containing compounds such as, primary or secondary amines; hydrazine or hydrazone derivatives; amides; sulphonamides; urea derivatives, heterocyclic derivatives and so on, US Pat. No. 8,362,276.
- Tertiary amines in psychoactive compounds also can serve as a site of modification.
- Other functional group reagents for reacting with, for example, an amine group of a nucleophilic psychoactive compound include a carbonate, a carbonyldiimidazole, an azlactone, an isocyanate, an isothiocyanate and so on.
- Other electrophilic functional group reagents that can react with a carboxylic acid group or a reactive carbonyl group of a nucleophilic psychoactive compound include an amine; a hydrazine; a hydrazide, such as, an acyl hydrazide; a carbazate; a semicarbamate; a thiocarbazate; and so on, see, for example, US Pat. Nos. 5,093,531; 5,349,001 and 6,113,906, the disclosure of each of which hereby is incorporated by reference in entirety.
- a hydroxyl group can be activated by reaction with, for example, a formate group, such as, p-nitrophenyl chloroformate, to form a reactive p-nitrophenyl carbonate activated conjugating reagent that reacts with a nucleophile.
- a formate group such as, p-nitrophenyl chloroformate
- a psychoactive nucleophile occurs at a nitrogen, oxygen or sulfur thereof.
- reaction with an NHS reagent can be performed, for example, in about 0 to about 100% dimethylsulfoxide (DMSO) solutions (which can be with a minimum amount of water, for example, about 10%) at a temperature of between, for example, about 0 to about 150° C.
- DMSO dimethylsulfoxide
- Water soluble NHS reagents can be used when presence of organic solvent in subsequent uses of the product is not favored.
- a water soluble NHS reagent can be used, for example, where use of the product is for cell surface conjugation as any unreacted reagent not removed from the product may not permeate the cell membrane, see, for example, US Pat. Nos. 5,846,951 and 8,952,141.
- Some reactions of an NHS derivatized functional group with a psychoactive compound can be done, for example, in phosphate, carbonate, (4-(2 -hydroxy ethyl)- 1 -piperazine ethane sulfonic acid (HEPES)), borate, bicarbonate/ carbonate and so on buffers at concentrations, for example, between about 5 to about 200 mM.
- HEPES 4-(2 -hydroxy ethyl)- 1 -piperazine ethane sulfonic acid
- Tris tris(hydroxymethyl)amino methane
- a reaction may be performed at a pH of between about 7 to about 9 at a temperature of about 4° C. to about 20° C. for about 30 minutes to about 2 hours.
- the NHS compound may be used in a about 2 to about 50-fold molar excess to psychoactive compound, depending on concentration of amine. Concentration of the NHS compound may vary from about 0.1 to about 10 mM.
- the amine can be from around 10 to about 100 pM, see, for example, US Pat. No. 5,846,951.
- a modified psychoactive compound may be linked in stoichiometric amounts with a functional group, that is, one molecule of psychoactive compound may be linked to one molecule of a functional group compound.
- molar ratio be greater than 1, namely, with a relative greater amount to psychoactive compound or less than 1, namely, with a greater amount of functional group, which may drive a reaction to completion.
- a psychoactive compound can be modified to carry a sugar. That joining can be obtained with a variety of known chemistries. As taught herein one way of derivatizing a sugar is by oxidation with sodium periodate which forms an aldehyde group at the non-reducing end of a sugar. The aldehyde group acts as a reducing agent. A Schiff base reaction then can occur with an amino group of a psychoactive compound.
- a psychoactive compound may be functionalized by non-covalent association with a sugar.
- a sugar and a psychoactive compound may be linked via hydrophobic interactions, electrostatic interactions, ionic interactions and so on.
- doxorubicin ionically interacts with carboxylate groups of polysaccharide B.
- reagents that serve as a potential functional group can be made reactive or activated to form an activated reagent, for example, forming an ionized species by reaction, practicing methods known in the art (or purchasing such a reagent).
- an activated functional group reagent can be purified by conventional methods and then reacted with receptive psychoactive compounds, for example, containing a nucleophile group.
- a nucleophile of interest can be obtained with a P-dicarbonyl compound, such as, a P-ketoester, under mild reaction conditions of temperature and temperature, see, for example, US Pat. No. 5, 113,011.
- a psychoactive compound of interest can be modified by acetoacetylation.
- Acetoacetylated materials can be prepared in a variety of ways.
- an appropriate nucleophile can be treated with diketene.
- a nucleophilic psychoactive compound of interest can be subjected to a thermal reaction with 2,2,6-trimethyl-4H-l,3-dioxin-4-one (TKD, a diketene-acetone adduct).
- TKD 2,2,6-trimethyl-4H-l,3-dioxin-4-one
- such a nucleophile can be subjected to transesterification with another acetoacetate moiety.
- a functionalization reaction can be carried out under a wide variety of conditions as known in the art.
- reaction can be carried out in presence or absence of solvent.
- suitable solvents include aromatic hydrocarbons (for example, toluene, xylene and the like); esters (for example, butyl acetate, ethyl amyl acetate, ethyl-3 -ethoxy propionate and the like); ketones (for example, methyl isobutyl ketone, methyl amyl ketone, methyl isoamyl ketone, ethyl butyl ketone and the like); as well as a solvent that azeotropes with t-butanol (for example, cyclohexane).
- aromatic hydrocarbons for example, toluene, xylene and the like
- esters for example, butyl acetate, ethyl amyl acetate, ethyl-3 -ethoxy propionate and
- Conjugation can occur under a range of temperatures of about 80° up to about 200° C.
- Reaction times can be in the range of about 0.5 hours up to about 24 hours. Those of skill in the art recognize that reaction time can vary as a function of variables, such as, for example, reaction temperature, desired degree of conversion, particular reactants employed and so on.
- a psychoactive nucleophile can be reacted with an activated, electrophilic conjugating reagent in an aqueous reaction medium, which can be buffered, depending on pH requirements of a nucleophile.
- Organic nucleophiles can be reacted in an organic, non-aqueous medium. Determining optimum reaction conditions for nucleophile stability, reaction efficiency and so on is within level of ordinary skill in the art.
- Nucleophiles can be reacted with an excess of electrophilic conjugation reagent, which may be in an activated form. Following reaction, a derivatized psychoactive compound is recovered and purified, such as, by filtration, column chromatography and so on, or combinations thereof.
- a psychoactive compound can occur enzymatically.
- a psychoactive compound may be converted to what should be a water soluble form by functionalization with a sugar.
- glycosyltransferases are known and are commercially available, as are suitable sugar donors, such as, nucleotide sugars.
- suitable sugar donors such as, nucleotide sugars.
- one or more glycosyltransferases such as, a uridine diphosphate (UDP)-glucuronosyltransferase (UGT), catalyze glucuronosylation or glucuronidation of a psychoactive compound.
- UDP uridine diphosphate
- UGT uridine diphosphate
- Glucuronidation may consist of transfer of a glucuronic acid component of uridine diphosphate glucuronic acid to a psychoactive compound substrate.
- Conversion of a functionalized psychoactive compound can occur at a hydroxyl group of an originating, base psychoactive compound.
- Hydroxylation of a psychoactive compound may be used to prepare that compound for further derivatization, such as, glycosylation.
- Chemical hydroxylation reactions are known, as are hydroxylases which enzymatically hydroxylate a substrate.
- Many psychoactive compounds of interest contain one or more reactive amine groups, which can serve as nucleophilic sites in a functionalization reaction.
- Glycation reactions can involve a vitamin. Glycation reactions can involve, for example, glucose, galactose, fucose, but other sugars can be used.
- an Amadori-type rearrangement reaction can be used; a Schiff base-type reaction can be used; a Maillard-type reaction can be used and so on, as a means to attach a sugar to a psychoactive compound.
- an Amadori-type rearrangement reaction can occur, for example, with an amine of a psychoactive compound and an aldose sugar.
- a Maillard-type reaction can occur between a carbonyl group of a sugar reacting with a nucleophilic amine group of a psychoactive compound.
- a Schiff base can be an amine that can be an intermediate when an amine of a psychoactive compound reacts with an aldehyde or a ketone of a sugar.
- Pyridoxal phosphate (vitamin B&) can form a Schiff base with an amine group.
- Vitamin A such as Vitamin A aldehyde or retinal, can form a Schiff base with an amine group of a psychoactive compound.
- Folic acid is a member of vitamin B group known as having various physiologic activities, which is transported into cells via endocytosis or potocytosis, mediated by a folic acid receptor present at the cell surface.
- Folic acid functional group can be bonded to a psychoactive compound for positive transport of the psychoactive compound into cells by the folic acid receptor, see, for example, US Pat. No. 7,585,973.
- Folic acid can be conjugated with a psychoactive compound, for example, with a condensing agent such as, DCC. Products can be obtained as a-carboxylate and y-carboxylate mixtures (a-folic acid derivatives may not be recognized by the receptors.)
- Biotin also known as vitamin H is an essential growth factor found in animals, plants, fungi and bacteria. Biotin is found, for example, bound to proteins or polypeptides in liver, pancreas, kidney, milk and in yeast. Biotin is a cofactor for a group of enzymes that catalyze carboxylation reactions, transcarboxylation reactions and decarboxylation reactions. The reactions catalyzed by biotin-dependent enzymes are involved in several essential metabolic pathways, including gluconeogenesis, fatty acid synthesis and amino acid catabolism.
- conjugate refers to a composite molecule comprising a psychoactive compound and a functional group, which may be a biotin compound, a biotin-binding compound, a complex of biotin (or a biotinylated moiety) with streptavidin (avidin), in which the biotin compound and biotin-binding compound are linked; and so on.
- biotin or, “biotin compound,” as used herein are interchangeable and refer to biotin (cis-hexahydro-2-oxo-lH-thieno[3,4]imidazole-4- pentanoic acid) and any biotin derivatives and analogs.
- Such compounds include, for example, biotin-s-N-lysine, biocytin (an amide of biotin and Lys) hydrazide, amino or sulfhydryl derivatives of 2-iminobiotin, biotinyl-s-aminocaproic acid-N- hydroxysuccinimide ester, sulfosuccinimideiminobiotin, biotinbromoacetylhydrazide, p-diazobenzoyl biocytin, 3-(N-maleimidopropionyl)biocytin and any covalent or non-covalent adduct of biotin with other moieties, see, for example, US Pat. No. 7,2
- Functionalized psychoactive compounds of interest can be prepared by reacting a biotin with an amino group of a psychoactive compound in which the terminal carboxylic acid is protected with a suitable protecting group, such as, a t-butyl ester, in presence of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide (DAEC), hydroxybenzotriazole (HOBT) and N-methylmorpholine.
- DAEC l-(3-dimethylaminopropyl)-3-ethyl carbodiimide
- HOBT hydroxybenzotriazole
- N-methylmorpholine N-methylmorpholine
- Maleimide chemistry can be used to conjugate a functional group-containing moiety to a psychoactive compound, see, for example, US Pat. No. 7,790,835.
- the maleimide reagent can be functionalized at the nitrogen to carry a variety of functional groups of varying size.
- a psychoactive compound can react with a maleimide regent through, for example, a Diels- Alder reaction yielding an adduct as a maleimide precursor, the Diels- Alder adduct being covalently attached.
- a Diels-Alder adduct can refer to a cyclic structure that can undergo a reverse or retro Diels-Alder reaction that fractures the adduct into a maleimide group and a diene, which is released from the adduct.
- the Diels- Alder adduct is typically a structure formed by a cycloaddition reaction between a conjugated diene and a dienophile (i.e., a Diels-Alder reaction).
- a psychoactive compound can include an active ester and thus undergo a nucleophilic substitution at a carbonyl group. Also, the nucleophilic nitrogen can serve as a Diels-Alder adduct reagent.
- An amino group of an amine-bearing psychoactive compound can act as a nucleophilic component and an anhydride of an anhydride-bearing Diels- Alder adduct reagent can serve as an electrophilic component.
- a maleimide electrophilic reagent can react with a nucleophilic sulfhydryl or thiol group of a psychoactive compound, for example, in a Michael-type reaction.
- Michael acceptors maleimides react with sulfhydryl groups to form stable thioether bonds.
- maleimides react preferably with sulfhydryl groups rather than amine groups (Smyth et al., Biochem. J., 91, 589, 1964; Gorin et al. Arch. Biochem. Biophys. 115, 593, 1966; Partis et al., J. Protein Chem, 2, 263-277, 1983).
- pH for example, values of 8 or above, maleimides react more readily with amine groups (Brewer & Riehm, Anal. Biochem. 18, 248, 1967).
- A, "protein tag,” or “protein functional group,” refers to an amino acid sequence that provides new characteristics when joined to a psychoactive compound, for example, to assist in purification, identification, activity, affinity and so on.
- a common protein tag used in purification is a poly-His tag where a series of about six to about nine histidine (His) residues are added to a base compound which enables a conjugate to bind to purification matrices chelated to metal ions, such as, nickel or cobalt, which is bound by the His tag.
- tags include Strep tag (about 8 amino acids which bind specifically avidin or streptavidin), chitin binding protein, maltose binding protein, glutathione-S-transferase, FLAG-tag (a synthetic octapeptide bound by monoclonal antibodies (mAb’s); and so on.
- Tags such as, "epitope tags,” confer a psychoactive compound with affinity to a cognate antibody.
- Common antibody epitope tags include, V5-tag, Myc-tag, HA-tag and so on, see, for example, US Pat. No. 9,951,108.
- Glycosides may serve as prodrugs with a therapeutic effect.
- Glycoside prodrugs may improve bioavailability; may improve pharmacokinetics; may enable site-specific or tissue-specific PAI delivery; may yield sustained or delayed release forms; and so on.
- Glycosylation may enhance stability or survival in the acidic stomach environment.
- Glycosides have greater bulk and weight.
- Glycosides have different properties.
- a sugar moiety of a glycoside can be one member of a binding pair, for example, the other member of the binding pair may be an antibody or a lectin.
- Glycosidases may enable specific delivery of a glycoside. By removal of a sugar functional group to yield an active psychoactive compound where a glycosidase resides. Glycosidases are present in the gut so liberation of a sugar from a glycosylated psychoactive compound to yield a biologically active psychoactive compound can occur in the gut. Glycosidases are present in different tissues so glycosides enable delivery by modes that bypass the digestive tract and colon. For example, intravenous administration may enable targeted delivery to other cells and tissues where a glycosidase is resident or is expressed. A psychoactive agent functionalized with other modifications can be manufactured to carry modified psychoactive compounds to targets sites in the body for directed delivery.
- Glucose residues of glycosides commonly are acid-hydrolyzed in the stomach or are cleaved by a glycosidase, for example, in the intestinal tract, including by a-glycosidases and P-glycosidases, which are expressed by intestinal microflora across different regions of the intestine. Accordingly, ingested glycosides are hydrolyzed to release the aglycone, the psychoactive compound, in the intestines.
- the aglycone On parenteral administration of a glycoside prodrug to a subject, the aglycone is liberated by a glycosidase at, near or in a target tissue.
- Glycosides can enhance purification.
- a conjugate or derivative can have different physical properties, which can be exploited, for example, by chromatography, precipitation and so on.
- a conjugate is heavier, which may be exploited for separation.
- a sugar moiety can be a target for purification.
- an entity that binds a sugar such as, a lectin, can be used for affinity separation.
- Conjugation or functionalization of a psychoactive compound using a sugar as the functional group can occur by use of a variety of chemical reactions. Chemical adding of a carbohydrate to a psychoactive compound can be known as glycation.
- a method of producing a psychoactive agent glycoside comprises incubating an aglycone with one or more sugar donors in presence of a glycosyltransferase under conditions that allow for glycosylation.
- Glycosyltransferases are common in plants (Srivatava et al., JBC 297(3)101045, 2021; Lim & Bowles, EMBO J 23:2915-2922, 2004; Hansen et al., Front Plant Sci 3:59, 2012; and Ross et al., Genome Biol 2(2):reviews, 3004.1-3006.6, 2001), animals and microbes (Breton et al., Glycobiol 16:29R-37R, 2006; and Yakovliev & Walvoort, ACS Chem Biol 15:3-16, 2020), and enzymes are available commercially.
- Some enzymes are specific as to substrate and sugar donor, other are less specific, less discriminate or are degenerate by acting on more than one substrate or can utilize more than type of sugar donor, for example, where the vehicle for carrying the sugar can vary or the enzyme can accept and join different sugars.
- a sugar donor such as, UDP-glucose
- a reaction mixture to a well containing a psychoactive compound.
- the plate is incubated and then the reaction mixtures are assessed for glycosylation, for example, by HPLC or other screening assay.
- Reaction conditions may need to be altered, such as, reagent amount, sugar donor, reaction conditions and so on, to obtain glycosylation. Once suitable enzyme or enzymes are identified, reaction conditions can be optimized and scaled.
- a sugar donor can be a nucleotide sugar, such as, UDP-glucose, UDP-glucuronic acid, UDP-mannose, UDP-fructose, UDP -xylose, UDP -rhamnose, UDP-fluoro-deoxyglucose, combinations thereof; and so on.
- nucleotide sugar such as, UDP-glucose, UDP-glucuronic acid, UDP-mannose, UDP-fructose, UDP -xylose, UDP -rhamnose, UDP-fluoro-deoxyglucose, combinations thereof; and so on.
- Mannose can be joined to a hydroxyl group of a psychoactive compound.
- Mannosyl transferase with an appropriate sugar donor can be used to join a mannose residue to a psychoactive compound.
- Mannose is a reducing sugar that can be reacted with an amine as taught herein.
- Fucose can be joined to a hydroxyl group of a psychoactive compound. Fucosyl transferase with an appropriate sugar donor, such as, GDP-fucose, can be used to join a fucose residue to a psychoactive compound.
- Protein A binds to a site on the heavy chain F c portion of immunoglobulins, primarily IgG.
- Protein G binds to both the F a b and F c portions of immunoglobulins.
- Protein L binds light chain of immunoglobulins (Ig).
- immunoglobulin-binding proteins or Ig-binding portions thereof, can be used as one member of a binding pair, for example, in affinity chromatography to isolate a psychoactive compound.
- Fluorine substituted cannabinoids were created through synthetic chemical reaction, see, for example, WO2014108899. That reference provides a roadmap for fluorinating a psychoactive compound.
- linker moiety refers to a molecule that joins two or more other molecules together.
- a linker can contain two different reactive or functional groups to provide directional reactivity with the two or more other molecules.
- linker moiety can comprise at least one ester or amide linkage, and other linker moi eties include ethers, thioethers, thioamides, thioesters, amines and so on, US Pat. No. 9,968,683.
- a linker moiety may include atoms, such as, carbon, hydrogen, oxygen and/or nitrogen, US Pat.
- a linker can overcome poor reactivity of a psychoactive compound by introducing a reactive functional group, can provide distance, for example, minimizing steric hindrance or interference, or minimizing reactivity of an introduced functional group with the psychoactive compound and so on, between a functional group and the psychoactive compound and so on.
- conjugation of a saccharide or a polysaccharide and a psychoactive compound can occur by coupling a sugar to a linker to form a sugar-linker intermediate (or an activated sugar) in which a free terminus of the linker bears a functional group, such as, an ester group; and then reacting the intermediate, for example, the ester group, with, for example, a primary amine group in the psychoactive compound to form a sugar-linker-psychoactive compound conjugate (a functionalized psychoactive compound) in which the linker is coupled to the psychoactive compound via an amide linkage.
- a sugar-linker intermediate or an activated sugar
- a functional group such as, an ester group
- a sugar can be coupled to the linker using a primary amine group in an amino sugar, or an amine group introduced into a sugar.
- a linker that can be used has an ester group at both termini.
- Such a linker can be homobifunctional where the two termini are chemically the same.
- the ester groups can be separated by an intermediate portion of the linker that can be of varying length and complexity.
- the intermediate portion can comprise a straight chain alkyl with 1 to more than 10 carbon atoms.
- a terminal group can be N- oxysuccinimide.
- An intermediate portion can comprise a four carbon chain, such as, adipic acid N-hydroxysuccinimide diester.
- the first coupling with one of the ester groups with the primary amine group of the sugar occurs by nucleophilic acyl substitution.
- an additional linker can be used to derivatize the sugar prior to joining to the linker.
- a sugar can be coupled to the additional linker, for example, at a carbonyl group at the reducing terminus of the sugar or polysaccharide.
- the additional linker can have a primary amine group at both termini, thereby allowing one of the primary amine groups to react with the carbonyl group in the sugar or polysaccharide by reductive amination.
- a hydrazide or a hydroxylamino group can be used in the additional linker.
- the same primary amine group can be present at both termini of the additional linker. The reaction results in a sugar/polysaccharide-additional linker intermediate via a C— N linkage.
- the additional linker can be coupled to a carboxyl group.
- An additional linker can have a primary amine group at both termini, thereby allowing coupling of the additional linker to the carboxyl group of the sugar or polysaccharide by carbodiimide activation.
- a primary amine group can be one that is reactive with a carbodiimide-activated carboxyl group in the sugar or polysaccharide.
- a hydrazide group can be used.
- the same primary amine group can be present at both termini of the additional linker. The result is a sugar/polysaccharide-additional linker intermediate in which the sugar/polysaccharide is coupled to the additional linker via an amide linkage.
- the free terminus of the additional linker can be a primary amine group and reacted with a linker as described herein or as known in the art.
- the additional linker can be coupled to the linker via an amide linkage.
- the additional linker is a bifunctional linker that provides a first primary amine group for reacting with the carbonyl (or carboxyl) group in the sugar/polysaccharide and a second primary amine group for reacting with one of the ester groups in the linker.
- a suitable terminal group of the additional linker is an --NHNH2 group with an intermediate portion as described above.
- a suitable additional linker can be adipic acid dihydrazide.
- ester group at the free terminus of the linker in the sugar/polysaccharide-linker intermediate is reacted with a primary amine group in the psychoactive compound. That can occur by nucleophilic acyl substitution to form a sugar/polysaccharide-linker-carrier molecule conjugate in which the linker is coupled to the carrier molecule via an amide linkage.
- conjugate After conjugation, free and conjugated sugar/polysaccharide can be separated, for example, by hydrophobic interaction chromatography, tangential flow filtration, size exclusion chromatography, countercurrent chromatography and other known separation methods. [00268] Carrying a sugar, the conjugate generally is soluble in water and/or in an aqueous or physiologic buffer.
- coupling can occur by reductive amination of a carbonyl group at the reducing terminus of a polysaccharide.
- the conjugation can involve a suitably functionalized additional linker as provided herein.
- Reductive amination is known and can be achieved by combining the sugar/polysaccharide with the primary amine group in the presence of a reducing agent (for example, cyanoborohydrides, such as, sodium cyanoborohydride; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin; and so on) see, for example, US Pat. No. 9,358,284.
- a reducing agent for example, cyanoborohydrides, such as, sodium cyanoborohydride; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin; and so on
- a suitable sugar for conjugation has a reducing terminus, which can be activated.
- Methods are known for random activation of a polysaccharide chain (for example, with cyanogen bromide (CNBr) or l-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP)) prior to conjugation with a linker or a psychoactive compound (Watson et al., Infect Imm 60(11)4679-4686, 1992; Konadu et al., Infect Imm 7:2709-2715, 1996.)
- Other methods are more selective, involving a specific residue on the chain (for example, a 2-keto-3-deoxyoctanoic acid (KDO) residue, found, for example, in certain bacterial saccharides) (Chu et al., Infect Imm 59(12)4450-4458, 1991; Taylor et al., Infect Imm 61(9)3678-3687,
- a sugar can comprise a reducing end.
- That reducing end can be a KDO subunit, which comprises a carbonyl group.
- the carbonyl group can be used for coupling the sugar to the linker or the carbonyl group takes part in the reductive amination process.
- Other sugars that comprise a carbonyl group at the reducing termini can be used.
- the KDO subunit also comprises a carboxyl group that can be reacted as taught herein or as known in the art.
- a functionalized group reagent can be purified by conventional methods and reacted with a psychoactive compound, for example, containing a nucleophilic site capable of bonding with an electrophilic functional group reagent os using an enzyme and sugar donor, while maintaining at least some activity associated with the unmodified psychoactive compound.
- a modified psychoactive compound may be isolated and purified by, for example, affinity chromatography; applied to various commercial schemes and reagents; and so on.
- a modified compound may be restored and reconstituted by, for example, an enzymic reaction, such as, using a glycosidase or an esterase, or a chemical reaction.
- a psychoactive compound with a pharmacologic activity can be described as, "biologically active.” The term, however, is not limited to physiologic or pharmacologic activities as a psychoactive compound can be used, for example, for recreational purposes.
- a modified psychoactive compound may or may not be biologically active.
- a key feature of conjugates or modified psychoactive compounds is that at least some portion of activity associated with the unmodified psychoactive compound is maintained or can be restored when the modification is removed.
- Chromatography no matter the mode, such as, paper, solid phase, column, batch, affinity liquid-liquid, countercurrent and so on, can be used for separation of molecules.
- Affinity chromatography can be used for purification.
- Affinity chromatography relies on a binding pair reaction, for example, a lectin and a cognate carbohydrate; an antibody and a cognate antigen, epitope or determinant; a factor and a cofactor; an enzyme and a substrate; and so on.
- a binding pair reaction for example, a lectin and a cognate carbohydrate; an antibody and a cognate antigen, epitope or determinant; a factor and a cofactor; an enzyme and a substrate; and so on.
- a binding pair reaction for example, a lectin and a cognate carbohydrate; an antibody and a cognate antigen, epitope or determinant; a factor and a cofactor; an enzyme and a substrate; and so on.
- one member of a binding pair is immobilized or coupled to a solid phase or support. That derivatized phase or support is exposed to a mixture that contains a functionalized psychoactive
- Non-binding elements and non-specific binding elements present with the derivatized psychoactive compound are separated and removed in the mobile phase.
- the bound modified psychoactive may be eluted or displaced from the solid phase or support by, for example, a competing member of the binding pair, altering the environment, such as, changing the pH; and so on to displace or to disrupt the binding pair bond.
- biotin has found use to label, to detect and to purify target molecules.
- the uses are based on affinity between biotin and the proteins, avidin and streptavidin.
- the dissociation constant of biotin and avidin or streptavidin is about 10' 15 M, one of the strongest known interactions between a protein and a ligand. While all parts of the biotin molecule contribute to that tight binding, hydrogen bonding donation by the ureido nitrogens is considered a major contributor.
- Countercurrent chromatography is a cost effective, gentle, discriminating method for separating molecular species.
- the process is continuous.
- the process does not require costly solid phase or regeneration of solid phase.
- the separation is gentle without the need for harsh reagents.
- the method can be used, for example, to separate carbon nanotubes, mAb, nucleic acids, see, for example, US Pat. Nos. 9,713,778 and 8,597,509; viruses, see for example, US Pat. No. 10,851,349; and cannabinoids, see, for example, WO 2020/180759.
- Entities that can be affixed or immobilized on or to a solid phase include, a lectin, a chelated metal ion, avidin/streptavidin, one member of a binding pair and so on.
- a modified psychoactive compound is bound to a derivatized solid phase by an affinity interaction, the functionalized psychoactive compound is separated from other reagents, compounds and medium.
- the functionalized then can be recovered by dissociating the bound psychoactive compound from the support, for example, by altering the binding environment, such as, changing a salt concentration, changing pH, exposure to a detergent, surfactant, amphiphile and so on. Those methods of desorption are known. However, the high binding affinity of biotin and streptavidin commands different methods.
- US Pat. No. 7,279,285 teaches a method for dissociating biotin from avidin.
- the exact mode of action of the aqueous solution on biotin dissociation from avidin/streptavidin is not known.
- it is believed that the mechanism behind the reversible dissociation is due to a conformational change in the biotin-binding compound that results in release of the bound biotin. That theory is supported by the observation that dissociation between the biotin-binding compound and biotin is completely reversed when salt is added.
- a substantially aqueous solution such as, purified or distilled water.
- Purified water is obtained or obtainable by passing water, such as, distilled water, through an appropriate ion-exchange matrix or system, for example an appropriate Milli-Q matrix or system, which is commercially available (Millipore Sigma, MA) and standard in the art. Distilled water is passed through a Milli-Q system using a Millipore Purification Pak, QPAK1. The resulting water is generally at approximately 18.2 MQ.
- Such methods of purifying water and equivalent methods are known and standard in the art.
- Such purified water also is sometimes referred to as Milli-Q water.
- Incubation times may vary depending on temperature used and may readily be determined by those skilled in the art for any given temperature condition. Incubation times can range up to about 10 minutes, up to about 5 minutes, up to about 2 minutes, up to about 1 minute.
- Incubation can occur at a temperature in the range of from about 20 to about 95° C., from about 50 to about 90° C., from about 60 to about 90° C. from about 70 to about 90° C. Incubation can be at a temperature of about 80° C. Incubation can be conducted with a gradual or stepped increase in temperature from ambient to the desired temperature at which incubation is to take place. For example, temperature may be stepped by +1° C. every 2 seconds.
- Reagents can be stored and reactions conducted in aqueous solutions. Solutions generally have a low content of dissolved solids (for example, Mg 2+ , Ca 2+ , Na + , Li + , monovalent and divalent ions in general, chlorides, sulfates and so on). The solutions can be purified using conventional purification techniques, such as, distillation or ion-exchange, and will be substantially free from chemical impurities.
- the aqueous solution can be substantially free of ammonia or an amine.
- the aqueous solution can be substantially free of any monovalent and divalent salts, for example, sodium chloride, lithium chloride and magnesium chloride.
- pH can be in the range from about 5 to about 7.
- Chelating agents such as, ethylene diamine tetraacetic acid (EDTA), in the incubating solution can decrease efficiency of complex dissociation.
- EDTA ethylene diamine tetraacetic acid
- a biotin conjugate can be disrupted under relatively mild conditions such that the structure of both the biotin compound and the biotin-binding compound remain intact. Appropriate reaction conditions are selected in which both components of the conjugate are stable, see, for example, US Pat. No. 7,279,285.
- chromatography can be practiced to separate, to separate, to purify and so on, a modified psychoactive compound of interest.
- Chromatography can be practiced in a variety of format, such as, paper, countercurrent centrifugation, column, batch and so on. Chromatography capitalizes on physical differences of a target compound, such as, size, shape, charge, specific binding and so on for separation.
- Filtration enables separation of molecules differing in, for example, mass, shape and so on.
- One format employs cross-linked polymer gels, such as, dextran, polyacrylamide, for example, which can be in the shape of beads.
- the degree of cross linking can provide a sieving action.
- a cross-linked gel can be provided in the form of a slab. Molecules can be sieved and separated with a mobile phase under the influence of gravity, an applied electric current or field, and so on.
- Differential precipitation is a means for separation that depends on altering the solvation potential of a solvent, lowering solubility of a solute by addition of a reagent, such as, ammonium sulfate.
- a reagent such as, ammonium sulfate.
- Trichloroacetic acid (TCA) also can be used when TCA disrupts hydrogen-bonded water molecules.
- Recrystallization is s known method for purifying a compound. Impurities and a modified psychoactive compound of interest are dissolved in a solvent in which with impurities or compound of interest dissolve leaving the other behind. Alternatively, both species may dissolve in solvent at an elevated temperature and on cooling to allow the compound of interest to crystallize. Crystallization may be benefited by seeding. The crystals can be isolated by filtration with disposal of the solvent. [00301] V. Precursor/Prodrug
- prodrug refers to a precursor of a biologically active psychoactive compound (drug) where the psychoactive compound is functionalized. Prodrugs undergo chemical or metabolic conversion or reaction to become the biologically active pharmaceutic agent.
- a prodrug can be converted ex vivo to the biologically active pharmaceutic agent by a transformative process. In vivo, a prodrug generally is converted to the biologically active pharmaceutic agent by action of a metabolic process; an enzymatic process; a degradative process; a particular environment; and so on that removes the prodrug moiety (the functional group) to form the biologically active, base psychoactive compound.
- composition refers to combination of an API and other inert ingredients in any physical form including, but not limited to, a mixture, a complex or the like, which renders the composition suitable for ingestion, administration or instillation.
- active pharmacologic ingredient or, “API,” as used herein is intended to refer to any compound capable of inducing a biologic, physiologic or pharmacologic response (for example, a sopoforic effect, a hypnotic effect and so on) in a warm-blooded animal, including, human. Synonyms include, “pharmaceutically active agent,” drug, “pharmacologically active agent,” “lead compound,” and so on.
- an API can be delivered to a patient for prescribed medical use, but is diversion-resistant and/or abuse-resistant to, at least, deter illicit use of the API.
- US Pat. No. 9,649,282 herein incorporated by reference in entirety, which teaches a pharmaceutic composition containing an API and an additive, which prevents effective separation of the API by conventional separation techniques and/or prevents the administration of the API for a non-therapeutic or non-medical effect.
- compositions may be formulated in whole or in part as pharmaceutic compositions, whether prophylactic or therapeutic Pharmaceutic compositions include two or more components.
- a pharmaceutic composition may include two or more compositions including two or more different therapeutic and/or prophylactic modified psychoactive compounds.
- Pharmaceutic compositions may include one or more pharmaceutically acceptable excipients or accessory ingredients, such as, those known or described herein. General guidelines for formulation and manufacture of pharmaceutic compositions and agents are available and are known. Conventional excipients and accessory ingredients may be used in a pharmaceutic composition, except insofar as any conventional excipient or accessory ingredient may be incompatible with one or more components and/or functions of a modified psychoactive compound composition of interest.
- one or more accessory ingredients may make up greater than about 50% of total mass or volume of a pharmaceutic composition.
- one or more accessory ingredients may comprise up to about 50%, about 60%, about 70%, about 80%, about 90% or more of a pharmaceutic composition.
- a, “pharmaceutically acceptable,” ingredient is at least about 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% pure.
- a, “pharmaceutically acceptable accessory ingredient,” is approved for use in human and perhaps also for veterinary use.
- a pharmaceutically accessory ingredient is approved by the United States Food and Drug Administration (FDA).
- FDA United States Food and Drug Administration
- a pharmaceutically acceptable ingredient or entity may be generally regarded as safe (GRAS).
- An, “accessory ingredient,” is a compound that can be included in a pharmaceutic composition as an additive for a particular purpose, such as, a buffer, a flavorant, a glidant and so on.
- An accessory ingredient can be a diluent, an excipient or a carrier.
- An accessory ingredient generally does not have a biologic activity or a biologic activity of a psychoactive compound.
- a pharmaceutic composition of interest includes one or more modified psychoactive compounds of interest and pharmaceutically acceptable excipients, diluents and/or carriers.
- a pharmaceutic composition of the instant disclosure is formulated to be compatible with an intended route of administration.
- routes of administration include subcutaneous, oral, inhalable, intramuscular, subcutaneous, nasal, buccal, vaginal, transmucosal, rectal and so on.
- systemic administration refers to administration of a therapeutically effective or pharmacologically effective (synonymous terms) agent for distribution in much of the body of an individual in effective amounts and develops a biologic or pharmacologic effect.
- an agent may develop a desired effect by delivery in blood and/or reaches a desired site of action via the vascular or circulatory system.
- Typical systemic routes of administration include administration into the vascular or circulatory system, or oral, pulmonary or intramuscular administration wherein an agent is adsorbed, enters the vascular or circulatory system and is carried to one or more desired site(s) of action in a body via blood or lymph and the circulatory system.
- a pharmaceutic composition is generally applied in a, "pharmaceutically effective amount,” “pharmacologically,” “biologically,” or, “ pharmaceutically effective amount,” are considered synonyms herein and are used equivalently herein, refers to non-toxicity of a material which does not interact with function or action of a psychoactive compound component of a pharmaceutic composition and comprises various additives with generally no adverse impact on or in a recipient.
- an entity that is pharmaceutically acceptable is one approved for use in food or drug preparations by the FDA and European Medicines Agency (EMA), respectively.
- a pharmaceutically effective amount is one that yields a desired biologic endpoint or effect of a psychoactive compound of interest.
- a composition can comprises one or more detergents (for example, Tween 20, Tween 80, Pluronic F68, bile acid salts and so on), protease inhibitors, surfactants (for example, sodium lauryl sulfate and so on), permeation enhancers, solubilizing agents (for example, glycerol, polyethylene glycerol and so on), stabilizers (for example, hydroxypropyl cellulose, hyroxypropylm ethyl cellulose and so on), viscosity increasing agents (for example, carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum and so on), sweeteners (for example, aspartame, citric acid and so on), flow aids (for example, colloidal silicon dioxide and so on), plasticizers (for example, diethyl phthalate, triethyl citrate and so on), emulsifiers (for example, carbomer, hydroxypropy
- surfactants for example
- a pharmaceutic composition of interest may contain salts, buffers, preserving agents, carriers, optionally, other therapeutic agents, and so on.
- a pharmaceutic composition of the instant invention can comprise one or more pharmaceutically acceptable carriers, diluents, excipients and so on.
- excipient can indicate substances, such as, binders, lubricants, thickeners, surface active agents, preservatives, emulsifiers, buffers, flavoring agents, colorants and so on.
- diluent relates to a diluting, a thinning agent and so on.
- Diluent includes any one or more of fluid, liquid or solid, a mixing medium and so on. Examples of suitable diluents include ethanol, glycerol, water and so on.
- diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar and so on, and/or combinations thereof in solid or liquid form, such as, dissolved or suspended in a fluid, such as, a saline, a buffer, a water and so on.
- a fluid such as, a saline, a buffer, a water and so on.
- carrier relates to one or more compatible solid or liquid fdlers or diluents, which are suitable for administration to a human.
- Carrier relates to a natural or synthetic organic or inorganic component that is combined with an active component to facilitate application or administration of the active component.
- Carriers can be sterile liquids, such as, a water, an oil, including those which are derived from mineral oil, animals or plants, such as, peanut oil, soy bean oil, sesame oil, sunflower oil and so on; and other natural or synthetic transporting materials. Salt solutions and aqueous dextrose and glycerin solutions also may be used as aqueous carriers.
- suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like, in solid or liquid form, for example, suspended or dissolved in an aqueous, organic or oleaginous fluid.
- suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like, in solid or liquid form, for example, suspended or dissolved in an aqueous, organic or oleaginous fluid.
- Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are known in the pharmaceutic art, and are described in, for example, Remington's Pharmaceutical Sciences.
- Antibacterial agents include benzyl alcohol, a paraben, chlorobutanol, phenol, ascorbic acid and the like.
- antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol and so on.
- antifungal preservatives examples include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid and so on.
- alcohol preservatives include ethanol, polyethylene glycol, a phenolic compound, bisphenol, hydroxybenzoate, phenylethyl alcohol and so on.
- acidic preservatives include vitamin A, vitamin E, [3-carotene, citric acid, acetic acid, dehydroascorbic acid, sorbic acid, phytic acid and so on.
- preservatives include tocopherol, tocopherol acetate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite and so on.
- Antioxidants such as, ascorbic acid, sodium bisulfite, sodium metabisulfite, butylated hydroxyanisole and so on, can be included.
- antioxidants include a-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium sulfite and so on.
- Granulating and dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, a clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, a wood product, natural sponge, a cation exchange resin, calcium carbonate, a silicate, sodium carbonate, polyvinyl pyrrolidone (PVP) (which may be crosslinked), sodium carboxymethyl starch, carboxymethyl cellulose, methyl cellulose, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds and so on, and combinations thereof.
- PVP polyvinyl pyrrolidone
- binders examples include starch, gelatin, a natural sugar, such as, glucose and so on; anhydrous lactose,
- Disintegrants include cornstarch, potato starch, alginic acid, silicon dioxide, guar gum and so on.
- Surface active agents and/or emulsifiers include a natural emulsifier (for example, acacia, agar, alginic acid, sodium alginate, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, lecithin and so on), a colloidal clay (for example, bentonite [aluminum silicate], magnesium aluminum silicate and so on), a long chain amino acid derivative, a sorbitan fatty acid ester, a sucrose fatty acid ester, a polyethylene glycol fatty acid ester, a polyoxyethylene ether, PVP, diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,
- Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, a hydrogenated vegetable oil, polyethylene glycol (PEG) and so on, and combinations thereof.
- chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, tartaric acid and so on.
- EDTA ethylenediaminetetraacetic acid
- citric acid monohydrate disodium edetate
- dipotassium edetate edetic acid
- fumaric acid malic acid
- phosphoric acid tartaric acid and so on.
- Buffers include acetates, citrates, phosphates; an aminoethane buffer, a Good buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, gluconic acid, calcium glycerophosphate, calcium lactate, calcium lactobionate, propanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, an aminosulfonate buffer, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution
- a pharmaceutic composition of the disclosure has a pH value between about 7 and 8 (for example, 6.8 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0, between 7.5 and 8 or between 7 and 7.8).
- Isotonicfiers and agents for adjustment of tonicity such as, sodium chloride; dextrose; a sugar; a polyalcohol, such as, mannitol, sorbitol and so on; and the like, can be included in the composition.
- the pH can be adjusted with an acid or a base, such as, HC1, NaOH and so on.
- Controlled or delayed release can be brought about by including in a composition, an agent that delays absorption, for example, a coating of aluminum monostearate, a gelatin and so on.
- amodified psychoactive compound is prepared with carriers that protect a compound against rapid elimination from a body, such as, inclusion in implants, depots and so on.
- Biodegradable, biocompatible polymers can be used, such as, ethylene vinyl acetate, a polyanhydride, polyglycolic acid, collagen, a polyorthoester, polylactic acid and so on.
- Liquid dosage forms for oral and parenteral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and so on.
- liquid dosage forms may comprise inert diluents commonly used in the art, such as, water, other solvents and so on; solubilizing agents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as, cottonseed, groundnut, corn, germ, olive, castor oil, sesame oil and so on), glycerol, tetrahydrofurfuryl alcohol, a polyethylene glycol, a fatty acid ester of sorbitan and so on; and mixtures thereof.
- Oral compositions can include additional agents,
- compositions can be mixed with solubilizing agents, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and so on; and combinations thereof.
- Oral compositions generally include an inert diluent, flavorant, odorant, an edible carrier and so on.
- a composition can be enclosed in gelatin capsules or compressed into tablets or troches.
- parenteral administration refers to administration of a therapeutically effective amount of a modified psychoactive compound such that the active ingredient does not pass the intestine.
- Parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration and so on.
- Solutions or suspensions used for parenteral can include a sterile diluent, such as, water for injection, a saline, an oil, a polyethylene glycol, ethanol, glycerine, a polyol, such as, propylene glycol and so on; other solvent and so on.
- a parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic as an article of manufacture.
- a composition generally is sterile and is fluid to the extent that syringability or delivery success exists. Proper fluidity can be maintained, for example, by use of a coating, such as, a lecithin and so on; by maintenance of required particle size in the case of a dispersion, use of a thickener and so on; by use of surfactants and so on.
- a coating such as, a lecithin and so on
- surfactants and so on.
- Sterile injectable solutions can be prepared by incorporating a modified psychoactive compound in a required amount of an appropriate solvent with one or a combination of accessory ingredients enumerated herein, as required, followed by filter sterilization.
- dispersions are prepared by incorporating a modified psychoactive compound in a sterile vehicle that contains a basic dispersion medium and required other ingredients, as known in the art.
- a solution of a modified psychoactive compound can he treated by, for example, lyophilization, vacuum drying, freeze drying and so on, to yield a dry powder of finely divided modified psychoactive compound plus any additional accessory ingredients from the previously sterile-filtered solution.
- a preparation of interest can be stored and reconstituted with a suitable liquid for use.
- An injectable formulation can be sterilized, for example, by filtration through a filter and/or by incorporating sterilizing agents in the form of sterile, solid compositions that are dissolved or dispersed in sterile water or other sterile injectable medium, such as, a water, a buffer, a salt solution and so on prior to use.
- Tablets, pills, troches and the like can contain a binder, such as, microcrystalline cellulose, gum tragacanth, gelatin and so on; an excipient, such as, starch, lactose and so on; a disintegrating agent, such as, alginic acid, com starch and so on; a lubricant, such as, magnesium stearate and so on; a glidant, such as, colloidal silicon dioxide and so on; a sweetening agent, such as, sucrose, saccharin and so on; a flavoring agent, such as, peppermint, methyl salicylate, a flavoring; and so on.
- a binder such as, microcrystalline cellulose, gum tragacanth, gelatin and so on
- an excipient such as, starch, lactose and so on
- a disintegrating agent such as, alginic acid, com starch and so on
- a lubricant such as, magnesium stearate and so on
- Oral compositions also can be prepared using a fluid carrier to yield a syrup or liquid formulation for injection, or for use as a mouthwash, wherein a solution comprising a modified psychoactive compound in a fluid carrier is applied orally, swished and expectorated or swallowed.
- a pharmaceutic composition may be suitable for buccal administration.
- Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may include, for example, 0.1% to 20% (wt/wt) active ingredient and so on, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the accessory ingredients described herein.
- formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient.
- Such formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any accessory ingredients described herein.
- a buccal preparation can include a flavorant, an odorant and so on.
- a compound for administration by inhalation, can be delivered in the form of, for example, a wet or dry aerosol spray, for example, from a pressurized container or dispenser that can contain a suitable propellant, for example, a gas, such as, carbon dioxide and so on; a nebulizer; a mister; and so on, see, for example, US Pat. No. 6,595,202, the content of which is incorporated by reference herein in entirety.
- a suitable propellant for example, a gas, such as, carbon dioxide and so on; a nebulizer; a mister; and so on, see, for example, US Pat. No. 6,595,202, the content of which is incorporated by reference herein in entirety.
- inhalation is meant to encompass delivery of a substance to blood via a respiratory system, such as, lungs and so on; wherein delivery takes place across a respiratory tract, such as, pulmonary epithelium and so on.
- Inhalation can be via mouth, nose or intratracheal.
- Absorption can occur in any part of a respiratory system, including, mouth, throat and so on.
- Pharmaceutic compositions formulated for pulmonary delivery may provide a modified psychoactive compound ingredient in the form of droplets of a solution and/or a suspension.
- Such formulations may be an aqueous and/or a dilute alcoholic solution and/or a suspension, optionally sterile, comprising a modified psychoactive compound composition, and may be administered using any nebulization and/or atomization device.
- Such formulations may comprise one or more accessory ingredients including a flavoring agent, such as, saccharin sodium and so on; a volatile oil, a buffering agent, a surface active agent; a preservative, such as, methylhydroxybenzoate and so on; and the like.
- Droplets provided by that route of administration may have an average diameter in the range from about 1 nm to about 200 nm.
- a liquid inhaler may deliver about 50 pl/puff (at 20 mg/ml). Generally, about 65% of an inhaled composition arrives at lungs, which, at the above concentration, can be about 650 pg.
- a dry inhaler may deliver up to 25-30 mg/puff. Generally, about 50% of an inhaled composition gets to lungs, which can be about 15 mg.
- Formulations described herein as useful for pulmonary delivery also may be used for intranasal delivery.
- a formulation for intranasal administration may be a coarse powder comprising active ingredients and having an average particle size of from about 0.2 pm to about 500 pm. Such a formulation may be administered in a manner in which snuff is taken, that is, by rapid inhalation through a nasal passage from a container of powder held close to a nostril.
- Formulations suitable for nasal administration may, for example, comprise from about as little as about 0.1% (wt/wt) to as much as about 100% (wt/wt) of active ingredient and so on, and may comprise one or more of additional ingredients described herein.
- a fine mist is generated by a handheld device and a user inhales by nose as a spray is generated.
- a pharmaceutic composition may be prepared for ophthalmic administration.
- Such a formulation may, for example, be in a form of eye drops including, for example, an about 0.1/1.0% (wt/wt) solution and/or suspension of active ingredient and so on in an aqueous or oily liquid excipient.
- Such drops may comprise buffering agents, salts, one or more other accessory ingredients and so on, as described herein or as known in the art.
- ophthalmically-administrable formulations that are useful include those that comprise active ingredient in microcrystalline form and/or in an ointment.
- a modified psychoactive compound of interest can be delivered as a suppository, a foam, a fluid, such as, an enema and so on; and the like.
- a liquid can be prepared as described herein for other liquid formulations.
- a liquid can be applied rectally using a reservoir, and a liquid carrying a modified psychoactive compound of interest can be retained or discharged after a certain period.
- a foam may be used for delivery.
- a foam can contain water and/or an oleaginous base, a polymer, a surfactant, a gelling agent, a foam stabilizing agent and so on, along with, when used with a canister for foam production, a liquid or compressed gas propellant, see, for example, US Pat. Nos. 6,818,204 and 9,539,208.
- a modified psychoactive compound is mixed with liquid ingredients, mixed with propellant and encased in a pressurized container.
- a foam may be produced by a manually operated device, such as one finger actuated, without need for a propellant.
- a modified psychoactive compound also can be prepared as a suppository (for example, with conventional suppository bases, such as, cocoa butter, glycerides and so on).
- Compositions for rectal or vaginal administration can be suppositories prepared by mixing compositions with suitable non-irritating excipients, such as, polyethylene glycol, a suppository wax and so on which are solid at ambient temperature but liquid at body temperature and therefore melt in rectum or vagina and release active ingredient therein. Suppositories can be administered manually or with a dedicated device, see, for example, US Pat. No. 10,653,623.
- a formulation comprises a pharmaceutically acceptable oleaginous base or substance.
- An oleaginous base can be naturally occurring, semi-synthetic or synthetic.
- an oleaginous base includes glycerides (for example, monoglycerides, diglycerides, triglycerides and so on); and so on.
- an oleaginous base can include a mixture of monoglycerides, diglycerides, triglycerides and so on, in a variety of ratios.
- an oleaginous base includes triglycerides (for example, more than about 50% of glyceride content can be triglycerides and so on).
- oleaginous bases include, for example, theobroma oil/cocoa butter, triglycerides from vegetable oils, hydrogenated coco-glycerides, trilaurin triglycerides (for example, glyceryl tridodecanoate, glycerin trilaurate and so on), lecithin and hydrogenated lecithin, synthetic or semi-synthetic triglycerides and so on; and mixtures thereof.
- a formulation includes triglycerides from a hydrogenated vegetable oil.
- an oleaginous base is a semi-synthetic glyceride base comprising saturated Cs-Cis triglyceride fatty acids, lecithin and so on.
- Fatty acids for example, those with aliphatic or hydrocarbon chains of about 8 to about 18 carbons in length can be used a modifying groups or in pharmaceutic formulations. Fatty acids can enhance bioavailability, can enhance stability and delivery of a modified psychoactive compound and so on.
- Phospholipids also can find use as a modifying group or can be used in an administrable formulation. Examples include phosphatidyethanolamine, phosphatidylserine and so on.
- a lecithin, inositol, ethanolamine, cholesterol and other lipids can be used as a modifying group or in a formulation.
- Suppository formulations generally are semi-solid or solid.
- a formulation has a melting temperature in a range of about 35° C. to about 41° C., of about 37° C. to about 39° C.; and so on.
- a suppository can have a weight of about
- a suppository can have an oblong shape.
- an oblong shape further comprises a cylindrical shape.
- a suppository has a shape that allows contact between an outer surface of a suppository and a rectal mucosal membrane when a suppository is situated in a rectum.
- Suppositories can have a (dry) density of about 0.001 to about 0.1 gm/cc, as such suppositories dissolved readily while being sturdy, yet soft and flexible. That provides a suppository that is comfortable to a user and yet does not readily break or fracture on insertion.
- a formulation can be used as a vaginal suppository.
- a rectal delivery vehicle or a vaginal delivery vehicle can be a foam, can be a lyophilized foam, see, for example, US Pat. No. 5,863,553.
- an aqueous dispersion is made comprising at least one or several, water-soluble polymers, and a modified psychoactive compound of interest.
- aqueous dispersion is meant to include dispersions (including solutions) in which a solvent is water or a water miscible liquid.
- Cellulose, cellulose ethers, derivatives thereof, polymers of the type disclosed in US Pat. No. 4,615,697 can be used.
- suitable polymers include polycarboxylated vinyl polymers, polyacrylic acid polymers, polysaccharide gums (such as, natural plant exudates including karaya gum, ghatti gum and the like), seed gums (including, for example, guar gum, locust bean gum, psigllium seed gum and the like); and so on can be used.
- polystyrene resin examples include polyurethanes, gelatins, celluloses and cellulose ethers, including hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxypropyl ethylcellulose and so on; carbopol, polyvinyl alcohol and derivatives thereof, dextran, chitosan and derivatives thereof, starch and derivatives thereof, polyacrylamides, poly acrylates, agar, collagen, fibronectin, alginic acid, pectin, hyaluronic acid and so on, or mixtures thereof.
- Cellulose ethers and hydroxypropylmethylcellulose can provide liquid foams that are stable with structural integrity, and dry foams with desirable softness.
- Polymer is added to a dispersion at a concentration of about 1% to about 20% (by weight of total dispersion). At lower concentrations, there may be insufficient polymer to prepare a sturdy foam, whereas at higher concentrations, a dispersion may be too viscous to foam under normal conditions.
- viscosity of a dispersion can be maintained at about 4500 to 7000 cPs, as measured on a Brookfield viscometer at 32° C. using a number 4 spindle at 20 rpm. It may be necessary to cool a dispersion to about 32 to 35° C. by mixing to maintain desired viscosity.
- a continuous, enclosed mixer such as an, "Oakes," foamer used to manufacture, for example, creamy, smooth food products, such as, ice cream and marshmallows, see, for example, US Pat. Nos. 2,572,049, 2,600,569, 2,679,866, and 3,081,069.
- An Oakes foamer is comprised of an electrical system, an air system and a product section.
- a device comprises a pump; a mixing chamber; a head assembly having a rotor; a gas inlet; an outlet for a foamed dispersion; means to measure pump speed, rotor speed, flow rate and pressure of an incoming gas; and means to measure back pressure of a foamed dispersion.
- a product section consists of a positive displacement pump; speed reducer; inlet piping; a back pressure gauge to monitor back pressure; and a mixing chamber.
- a gauge is isolated from product by a diaphragm seal assembly.
- a liquid dispersion is fed to a pump, transmitted through a line to a mixing chamber wherein a liquid is combined with air, under pressure, and mixed by a head assembly with a rotor.
- a dispersion is foamed, and air and dispersion are blended into a substantially uniform, homogeneous mixture. From a mixing chamber, a foamed dispersion then is sent to an outlet pipe.
- Foams of varying liquid density can be produced by varying flow rate of incoming gas.
- Density of a liquid foamed dispersion can range from about 0.1 to about 1.0 gm/cc.
- a foamed dispersion can be lyophilized to yield a foamed suppository of interest carrying a modified psychoactive compound of interest.
- a foamed liquid dispersion is placed into a receptacle having a known volume ("unit dosage"). Since liquid density of a foam and volume of a receptacle are known, foam weight of each unit dosage can be determined. Liquid can be extruded through a tubing into a mold. Various aluminum, plastic and release liner covered molds can be employed.
- Foam is extruded into compartmentalized trays whereby volume of one compartmental unit equals volume of a resulting suppository.
- the mold may be constructed in size and shape of a suppository. The foam is allowed to dry.
- a modified psychoactive compound of interest can be configured into small particles, which can be coated with a hydrophilic and degradable layer or shell. Such a configuration confers stability to a modified psychoactive compound when carried and stored in oleaginous carriers and diluents, such as, those used in suppositories. On melting, a modified psychoactive compound of interest is exposed to an in vivo aqueous environment where that hydrophilic layer or shell dissolves exposing a modified psychoactive compound of interest to tissues and cells of mucosa.
- a mucosal formulation comprises a water soluble, water miscible base.
- water-soluble miscible bases include glycerinated gelatins, polyethylene glycol (PEG) polymers (for example, PEG 300, PEG 1450, PEG 3350, PEG 6000, PEG 8000 and the like); and so on.
- a mucosal formulation further comprises an accessory ingredient including adsorbents, surface acting agents (for example, mucosal adhesives, such as, xanthan gum, lisinopril, hydroxypropyl methylcellulose, carboxy methylcellulose, chitosan and so on), viscosity-influencing agents, suspending/dispersing agents, plasticizers (for example, diethylhexyl phthalate and so on), melting point-adjusting agents (for example, white wax and so on), antimicrobial agents, antioxidants and so on.
- surface acting agents for example, mucosal adhesives, such as, xanthan gum, lisinopril, hydroxypropyl methylcellulose, carboxy methylcellulose, chitosan and so on
- viscosity-influencing agents for example, suspending/dispersing agents, plasticizers (for example, diethylhexyl phthalate and so on), melting point-adjusting agents (for example, white wax and so on), antimicrobial
- Mucosa refers to mucosal tissue of a host including respiratory passages (including bronchial passages, lung epithelium, nasal epithelium and so on), genital passages (including vaginal mucosa, penile mucosa, anal mucosa and so on), urinary passages (for example, urethra, bladder and so on), mouth, eyes, vocal cords and so on.
- respiratory passages including bronchial passages, lung epithelium, nasal epithelium and so on
- genital passages including vaginal mucosa, penile mucosa, anal mucosa and so on
- urinary passages for example, urethra, bladder and so on
- Mucosal administration can be accomplished, for example, through use of nasal sprays, eye drops, nebulizers, inhalers, atomizers, foams, suppositories and so on. Administration can be to nose, trachea, lung and so on.
- a mucolytic agent can be administered together with a modified psychoactive compound composition of interest or at about the same time a modified psychoactive compound composition is administered to thin a mucus.
- a mucolytic can be administered before a modified psychoactive compound composition is administered.
- Examples of a mucolytic includes acetyl cysteine, ammonium chloride, ammonium carbonate, DNase I and so on.
- a desired reaction refers to an amount that achieves a desired reaction or a desired effect in vivo alone or with further doses.
- a desired reaction relates to inhibition or diminution of a symptom or course of a disease. That can comprise slowing down progress of disease and/or interrupting or reversing progress of disease.
- a desired reaction in treatment of disease also may be delay of onset or prevention of onset of said disease or said condition.
- An effective amount of a modified psychoactive compound described herein can depend on condition to be treated, severity of disease, individual parameters of a patient, including age, physiologic condition, size and weight; duration of treatment, type of an accompanying therapy (if present), specific route of administration and so on. Efficacy can manifest at different levels, such as, reduction of one symptom, removal of one symptom, reduction of plural symptoms, reduction of plural symptoms, improvement of a disease state, cure from a disease and so on.
- a modified psychoactive compound can be used in topical form, such as, gels, creams, ointments, lotions, unguents, other cosmetics and the like.
- a modified psychoactive compound can be carried in a formulation comprising emollients, bleaching agents, antiperspirants, moisturizers, scents, colorants, pigments, dyes, antioxidants, oils, fatty acids, lipids, inorganic salts, organic molecules, opacifiers, vitamins, pharmaceutics, keratolytic agents, UV blocking agents, tanning accelerators, depigmenting agents, deodorants, perfumes, insect repellants and the like.
- compositions include liquid and/or semi liquid preparations, such as, liniments, lotions, oil in water emulsions, water in oil emulsions, such as, pastes and like; and so on.
- Topically-administrable formulations may, for example, comprise from about 1% to about 10% (wt/wt) modified psychoactive compound, although concentration of active ingredient may be as high as solubility limit of a modified psychoactive compound in a solvent.
- Another method of administration comprises addition of a compound of interest into or with a food or drink, such as, a food supplement, an additive and so on.
- a modified psychoactive compound can be encapsulated into forms that survive passage through a gastric environment. Such forms are commonly known, for example, as enteric formulations.
- Dosage unit form refers to physically discrete units suited as unitary dosages for a subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce a desired therapeutic endpoint.
- a, "unit dose,” is a discrete amount of a pharmaceutic composition comprising a predetermined amount of each modified psychoactive compound.
- Amount of active ingredient generally is equal to dosage of an active ingredient which would be administered to a subject; a convenient fraction of such a dosage, such as, for example, one-half, one-third and so on of such a dosage; and so on is administered to a subject.
- Dosages for example, preferred routes of administration and amounts are obtainable based on empiric data obtained from preclinical and clinical studies, practicing methods known in the art. Dosage and delivery form can be dictated by and can be dependent on characteristics of a modified psychoactive compound, particular biologic or therapeutic effect to be achieved, characteristics and condition of a recipient and so on. For repeated administration over several days or longer, depending on condition, treatment can be sustained until a desired endpoint is attained.
- Amount of a modified psychoactive compound, one or more pharmaceutically acceptable accessory ingredients, and/or any additional ingredients in a pharmaceutic composition in accordance with the instant disclosure may vary, depending on, for example, identity, size, and/or condition of a subject treated and further depending on route by which a composition is administered.
- a pharmaceutic composition may comprise between about 0.1 mg and about 1000 mg of a modified psychoactive compound.
- compositions of interest are administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 10 mg/kg from about 0.0001 mg/kg to about 5 mg/kg, from about 0.0001 mg/kg to about 2.5 mg/kg, from about 0.0001 mg/kg to about 1 mg/kg, from about 0.0001 mg/kg to about 0.25 mg/kg or greater of a modified psychoactive compound.
- a dose may be administered one or more times per day, in same or a different amount, to obtain a desired level of a therapeutic or prophylactic effect.
- a unit dose or a single dose of a composition of interest can comprise from about 1 pg to about 500 pg, from about 1 pg to about 400 pg, from about 1 pg to about 300 pg, from about 1 pg to about 200 pg, from about 1 pg to about 100 pg, from about 3 pg to about 500 pg, from about 3 pg to about 400 pg, from about 3 pg to about 300 pg, from about 3 pg to about 200 pg, from about 3 pg to about 100 pg, from about 5 pg to about 500 pg, from about 5 pg to about 400 pg, from about 5 pg to about 300 pg, from about 5 pg to about 200 pg, from about 5 pg to about 100 pg, from about 7 pg to about 500 pg, from about 7 pg to about 400 pg, from about 7 pg to about
- An effective amount of a modified psychoactive compound may include amounts between: 0.01 mg to 0.1 mg; 0.01 mg to 0.5 mg; 0.01 mg to 1 mg; 0.01 mg to 5 mg; 0.01 mg to 10 mg; 0.01 mg to 25 mg; 0.01 mg to 50 mg; 0.01 mg to 75 mg; 0.01 mg to 100 mg; 0.01 mg to 125 mg; 0.01 mg to 150 mg; 0.01 mg to 175 mg; 0.01 mg to 200 mg; 0.01 mg to 225 mg; 0.01 mg to 250 mg; 0.01 mg to 275 mg; 0.01 mg to 300 mg; 0.01 mg to 225 mg; 0.01 mg to 350 mg; 0.01 mg to 375 mg; 0.01 mg to 400 mg; 0.01 mg to 425 mg; 0.01 mg to 450 mg; 0.01 mg to
- formulations also may be constructed to locate passively or actively to different cell types in vivo, including, but not limited to particular sites in a body, such as, hepatocytes, brain cells and so on. Such targeting can occur as taught hereinabove, by employing particular modifications or functional groups and so on, which targeting can be active or passive.
- adeno-associated virus 9 may traverse the BBB (Merkel et al., J Neurochem. 140(2)216-230, 2017) and can infect brain cells (Dayton et al., Expert Opn. Biol. Therap. 12(6)757-766, 2012; Foust et al., Nat. Biotech. 27(1)56-95, 2009).
- AAV9 virus-like particles VLP can be made (Le et al., Sci. Rep. 9:18631, 2019; Womer et al., Nat. Comm. 12: 1642, 2021) and the particles can be made to carry a modified psychoactive compound.
- AAV9 capsid proteins can self-reconstitute particles and are available commercially, Creative Biolabs, Shirley, NY.
- AAV9 packaging components are mixed a modified psychoactive compound and allowed to form particles, which will entrap the modified psychoactive compound within.
- the VLP’s are introduced into the circulatory system and home to the brain, where the VLP’s can fuse with brain cells and release the modified psychoactive compound.
- An example of targeting a formulation to brain cells relies on a modified psychoactive compound contained within a delivery vehicle, such as, a liposome, a lipid nanoparticle and so on, and on the surface of the delivery vehicle is exposed or displayed a molecular entity that attracts the delivery vehicle, and hence, the modified psychoactive compound, to a particular site in the body, such as, endothelial cells of capillaries of the blood-brain barrier (BBB).
- a modified psychoactive compound contained within a delivery vehicle such as, a liposome, a lipid nanoparticle and so on
- a molecular entity that attracts the delivery vehicle, and hence, the modified psychoactive compound, to a particular site in the body, such as, endothelial cells of capillaries of the blood-brain barrier (BBB).
- BBB blood-brain barrier
- Formulations also can be selectively targeted through expression of different ligands or one of a binding pair on a surface of a modified psychoactive compound delivery vehicle, as exemplified by, for example, an antibody targeted approach, wherein a targeting antibody is attached to a delivery vehicle, wherein that antibody specifically binds an organ-specific molecule, a tissue-specific molecule, a cell-specific molecule and so on, see, for example, Curr Drug Discov Technol 2011, 8:197-206; Front Biosci 2011, 16:1388-1412; Mol Membr Biol 2010, 27:286-298; Crit Rev Ther Drug Carrier Syst 2008, 25: 1-61; Biomacromol 2011, 12:2708-2714; Expert Opin Drug Deliv 2008, 5:309-319; Mol Ther 2010, 18: 1357-1364; Methods Mol Biol 2012, 820: 105-116; Meth Mol Biol 2012, 757:497-507; J Cont Rel 20:63-68, 2010; PNAS 2007, ] 04:4095-4100, 2007
- Drug delivery vehicles such as, liposomes, lipid nanoparticles, dendrimers, micelles, hydrogels, nanotubes, quantum dots, virus-like particles, cyclodextrins and so on are known and commercially available.
- Liposomes can be made from phospholipids, such as phosphatidylcholine.
- a modified psychoactive compound suspended/dissolved in an aqueous, polar medium is mixed with a lipid suspended/dissolved in a volatile organic or non-polar solvent. The mixture can be sonicated or organic solvent evaporated to form liposomes.
- Lipid nanoparticles are another delivery form.
- a hydrophilic core carrying a modified psychoactive compound is encased with a boundary/layer comprised, for example, with an ionizable cationic lipid, a phospholipid and cholesterol, and optionally, a PEGylated lipid.
- An LNP can be prepared by mixing organic and aqueous solutions carrying the reagents using high shear homogenization and ultrasound, microemulsion-forming methods and so on.
- LAT1 large amino acid transporter-1 , also known as CD98
- CD98 brain capillary endothelial cells
- the amino acid sequence of LAT1 is known (UniProt Q96QB2 or Q01650) and can be purchased (Solvo Biotech, SF, CA; and Novus Biol, Centennial, CO).
- mAh can be made as known in the art or purchased (AbCam, Shirley, NY).
- Drug delivery vehicles carrying a modified psychoactive compound within can be constructed to express on the surface thereof an antibody or antigen binding portion thereof which specifically binds LAT1. Those vehicles could be administered directly to a vessel that supplies the brain (because LAT1 is not specific to the brain) to maximize exposure of the targeting vehicle to the capillary endothelium. Although LAT1 is not brain specific, the targeting vehicles may be administered by any mode as delivery of a modified psychoactive compound to sites other than brain may not be detrimental.
- a modified psychoactive compound may be used in combination with one or more other therapeutic or prophylactic agents.
- “in combination with,” is not intended to imply agents must be administered at the same time and/or formulated for delivery together, although methods of such delivery are within the scope of the instant disclosure.
- two or more modified psychoactive compound may be administered in combination.
- Compositions can be administered concurrently with, prior to, or subsequent to one or more other desired therapeutics or medical procedures.
- Such an other agent that is not a psychoactive compound may be, for example, an anti-inflammatory compound, a steroid (for example, a corticosteroid and so on), a statin, an analgesic and so on.
- a steroid for example, a corticosteroid and so on
- a statin for example, an analgesic and so on.
- a pharmaceutic composition can be included in a container, pack or dispenser together with instructions for administration, forming a kit, an article of manufacture.
- a kit can comprise a unit dosage form, a multiple unit dosage form, a bulk container for dispensing unit doses and so on.
- a kit can include a device for delivering a dose, such as, a syringe, a suppository applicator or insertion device; and so on.
- a kit can include a liquid diluent.
- a pharmaceutic composition including a modified psychoactive compound composition may be prepared by any method known in the art of pharmacology.
- Such preparatory methods include bringing an active ingredient into association with one or more other accessory ingredients, and then, if desirable or necessary, dividing, shaping, packaging and so on a product into a desired single-dose or multi -dose unit as an article of manufacture.
- Pharmaceutic compositions may be prepared in a variety of forms suitable for a variety of routes and methods of administration.
- pharmaceutic compositions may be prepared in liquid dosage forms (for example, emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, elixirs and so on), injectable forms, solid dosage forms (for example, capsules, tablets, pills, powders granules and so on), dosage forms for topical and/or transdermal administration (for example, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, patches and so on), suspensions, powders; and other forms.
- liquid dosage forms for example, emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, elixirs and so on
- injectable forms for example, capsules, tablets, pills, powders granules and so on
- dosage forms for topical and/or transdermal administration for
- modified psychoactive compound compositions and/or pharmaceutic compositions of the disclosure are refrigerated or frozen for storage and/or shipment (for example, stored at a temperature of about 4° C., or lower, about 0° C.
- a modified psychoactive formulation can be stored at normal room temperatures (RT) of about 20-22° C.
- Compositions and/or pharmaceutic compositions disclosed herein are stable for about at least 1 week, about at least 2 weeks, about at least 3 weeks, about at least 4 weeks, about at least 5 weeks, about at least 6 weeks, about at least 1 month or longer, for example, at RT or at a temperature of about 4° C. or lower.
- a modified psychoactive composition formulation of interest is desiccated to a dry powder, for example, by freeze drying, lyophilization and so on, practicing methods and material known in the art.
- compositions are suitable for administration to any other animal, such as, a mammal. Modification of compositions suitable for administration to various animals is understood by a veterinarian or veterinary pharmacologist using ordinary and routine measures.
- a modified psychoactive compound can be enhanced by functionalization of a psychoactive compound.
- a psychoactive compound may be hydrophobic. While that property may enhance cell uptake of that psychoactive compound, hydrophobic compound may not survive long in vivo after administration, for example, being captured by circulating protein, such as, albumin.
- modifying a psychoactive compound with a hydrophilic modification group can enhance aqueous solubility and stability of that modified psychoactive compound in circulation.
- bioavailability means percentage of an administered compound that enter the circulatory system following administration.
- a synonymous term is, “absorption,” although absorption can be viewed as going further than bioavailability to include travel from the site of administration to the site of action.
- functionalization can endow aqueous solubility on a psychoactive compound of interest.
- Hydrophilicity can enhance use as a deliverable formulation to a subject.
- glycosylation can enhance solubility as carbohydrates are water soluble.
- a functionalized or modified psychoactive compound may have enhanced access to an organ, tissue or cell.
- a modification or functional group may target a psychoactive agent to a particular organ tissue of cell.
- a formulation of interest may be used to locate and to traverse a tissue barrier, such as, the blood-brain barrier.
- a modified psychoactive compound of interest can have affinity to a cell membrane through the psychoactive compound, through the modification or both.
- a hydrophobic modified psychoactive compound or a hydrophobic psychoactive compound with a modification removed can have affinity with a cell membrane, facilitating entry into a cell.
- a psychoactive compound in proximity to a cell or delivered to a cell by a modification attached thereto, and which engages a cell surface receptor can have an enhanced biologic effect.
- a modification can reduce or temper toxicity of a psychoactive compound of interest, thereby making such compound available for administration to a subject.
- toxicity can be reduced or tempered by encapsulating a psychoactive compound of interest, for example, in a liposome or an I.NP.
- Hydrophilicity or greater hydrophilicity may reduce likelihood a modified psychoactive compound being recognized or taken up by tissues and being catabolized. Hydrophilicity can be conferred, for example, by pendant carboxyl groups, hydroxyl groups, amines, sulfates and so on.
- Terminal galactose residues might be avoided because such can be recognized by galactose receptors on hepatocytes and Kuppfer cells and may therefore be cleared more readily from circulation.
- a proportion of an administered modified psychoactive compound is rapidly taken into the bloodstream and the remainder is eliminated, usually at steady rate.
- Half-life of a compound following initial rapid uptake can be an indicator of suitability of a modified psychoactive compound for prolonged circulation times and/or stability of a modified psychoactive compound and/or reduced immunogenicity. Generally, longer half-life can be beneficial.
- proportion of compound eliminated in the first rapid step can be an indicator of utility, useful compounds would have none or only a small proportion of compound removed from circulation in the first step.
- a functionalized psychoactive compound can be one in which less than about 50%, less than about 25%, less than about 20%, or less is removed from circulation following intravenous administration, for example, within a period of about 15 minutes, from about 10 minutes, from about 5 minutes from injection.
- a functionalized psychoactive compound can have a half-life following the rapid removal stage of at least about 10 hours, at least about 20 hours, at least about 30 hours, or more.
- a compound comprising a larger molar ratio of functional group to psychoactive compound can have a longer half-life.
- Compounds displaying larger functional groups, such as, a branched sugar may have prolonged half-life.
- SC-PEG is prepared as described in US Pat. No. 5,122,614, using the m-PEG described above.
- m-PEG-N-acyl-thiazolidine is prepared as described in US Pat. No. 5,349,001.
- a branched PEG is prepared by adding 100 mg (1.1 mmol) of l,3-diamino-2-propanol to a solution of 10.0 g (2 mmol) of SC-PEG in 50 mL of methylene chloride. The mixture is stirred for 18 hours at room temperature then filtered. Excess solvent is removed by distillation in vacuo. The residue is recrystallized from 2-propanol to yield 7.1 g of product (70% yield).
- Glycosylation reactions consist of 50 mM KPO4 pH 7.2, 3 mM MgCh, 0.005% psilocin, 2.5% purified UDP-glycosyltransferase and 2.5 mM UDP-glucose. Buffers are degassed and tubes are purged with nitrogen. Reactions are protected from light and are incubated at 28° C. with 180 rpm agitation for 18 hours. Reactions then are extracted 3 times with an equal volume of ethyl acetate, evaporated to dryness and dissolved in a half volume of HPLC grade methanol. A sample, 50 pl, is injected on a reverse phase C 18 column and eluted with a gradient of acetonitrile starting at 10% and increasing to 99%.
- One pg of morphine (1 pl of a 1 mg/ml solution dissolved in methanol, 0.016 mM final concentration) is added to 200 pl of a mixture containing 50 mM potassium phosphate buffer (pH 7.2), 3 mM magnesium chloride (MgCb), 2.5 mM uridine diphosphate glucose (UDPG) as the sugar donor and 10 ml of a 50% UDP-glycosyltransferase glycerol stock solution (1.5 mg/ml stock solution, 1.44 pM final protein concentration). The reaction mixtures are incubated at 28° C with shaking at 180 rpm for 18 hrs.
- reaction mixture is extracted three times with 200 pl of ethyl acetate each time.
- the organic layers containing morphine glycosides and any unreacted substrate are combined, and the ethyl acetate is removed under vacuum.
- the samples are redissolved in 100 pl of 50% MeOH by volume.
- Reaction products re analyzed by RP-HPLC on a Dionex 3000 LC system using a Phenomenex Kinetex 5 pm XB-C18 IOOA column (150 x 4.6 mm).
- Glycosylation reaction is scaled up proportionally to 100 ml to obtain an adequate amount of glycosylated morphine for characterization by LC-MS and L H NMR. Enzyme is deactivated and precipitated from the glycosylation reaction mixture by treatment at 95° C for 10 minutes. The clarified reaction mixture is obtained by centrifugation.
- Glycosides are purified to homogeneity by Cl 8 solid phase extraction using a 100 mg Hypersep C 18 column (Thermo) hydrated in methanol, rinsed with 50% methanol in water and rinsed with water. Glycosylation reactions are passed through the column, washed with water, washed with 10%, 20%, and 30% methanol, and the glycoside products are eluted with 45 and 60% methanol in water. Eluates are dried, extracted with ethyl acetate and dried to completion to yield >95% pure morphine-glycosides.
- mescaline is conjugated to maleimide-activated polyethylene glycol (PEG) (Creative PEGWorks, Chapel Hill, NC) at a 1 : 1 molar ratio of mescaline to PEG at a pH of 9 to facilitate reaction with the mescaline free amine group by mixing on a rocker platform for 2 hours at room temperature, followed by dialysis against phosphate-buffered saline (PBS) at 4° C.
- PEG polyethylene glycol
- PBS phosphate-buffered saline
- PEG conjugates are isolated by gel chromatography.
- Example 7 The method of Example 7 is practiced but with ketamine as the ketone acceptor.
- Indole (Sigma-Adrich) is mixed with oxalyl chloride (Sigma- Aldrich). To that mixture then is added dimethylamine (Sigma-Aldrich). The carbonyl groups are reduced with lithium aluminum hydride (Sigma- Aldrich) to form dimethyl tryptamine (DMT).
- DMT dimethyl tryptamine
- the residue is chromatographed to reveal three species of conjugate, with addition of the phenylmethyl sulfonyl group to the tertiary amine, the indole amine or both.
Abstract
Psychoactive compounds are derivatized to carry one or more functional groups to assist in manufacturing and to obtain beneficial pharmacologic and biologic properties.
Description
FUNCTIONALIZED PSYCHOACTIVE COMPOUNDS
FIELD OF THE INVENTION
[0001] The invention relates to psychoactive drugs, derivatized to enhance properties thereof, for example, to facilitate manufacturing or to obtain beneficial pharmacologic properties.
BACKGROUND OF THE INVENTION
[0002] Psychoactive compounds, also known as, for example, psychopharmaceutic, psychoactive agent, hallucinogen, psychedelic, psychostimulatory drug, psychotropic drug and so on relate to a chemical substance that alters nervous system function and results in alteration of, for example, perception, mood, consciousness, cognition, behavior and so on. Some substances have a propensity to cause increase in dendrite formation and some can cause neural plasticity (or neuroplasticity). Psychoactive compounds may initiate or trigger neural plasticity. The substances may be used medically, may be used recreationally, may improve performance, may alter consciousness, may be used as an entheogen for ritual, spiritual or shamanic purposes, may be used for research, and so on. Some psychoactive compounds with therapeutic value can be prescribed for a medical purpose. Examples include anti-inflammatories, anesthetics, analgesics, anticonvulsants and antiparkinson drugs, as well as medications used to treat neuropsychiatric disorders, such as, antidepressants, anxiolytics, antipsychotics, stimulants and so on. Some psychoactive substances may be used in detoxification and rehabilitation programs for persons dependent on or addicted to other psychoactive compounds.
[0003] Psychoactive compounds may and could induce many, if not all psychologic, psychiatric, cognitive, sensory, behavioral and neural effects and observations,
[0004] Functionalization, derivatization, conjugation, coupling, modifying and similar synonyms relate to changing a base compound, such as, a psychoactive compound, generally by adding a moiety thereto. The entity added is a functional group, any reagent that can be added to a base compound for a desired purpose. The joining can be by any known method and is a design choice. Modification also can
occur by other means and does not necessarily require an addition, for example, can occur by ionization.
[0005] For example, modifying compounds can reduce cytotoxicity thereof. For example, compounds can be modified to carry a sugar residue, for example, being converted to a glycoside. Glycosylation can occur, for example, with a glycosyltransferase using an appropriate sugar donor.
SUMMARY OF THE INVENTION
[0006] The instant invention relates to modifying psychoactive compounds to attain beneficial properties. Any psychoactive compound aside from cannabinoids can be used in practice of the instant invention. The modification is a design choice, based on, for example, psychoactive compound chemistry and structure; desired property; starting reactant; method of modifying; and so on. Modification method is a design choice, such as, a known chemical reaction, which can occur, for example, in liquid phase, solid phase, gas phase or any combination thereof, which can, for example, facilitate or enhance reaction kinetics, progression and so on; use of an enzymic reaction (enzyme(s) can be in a liquid phase, immobilized on a solid phase, substrate or support); and so on. Desired properties include, for example, adding bulk or another property to enable or to assist physical separation; adding a functional group to enable or to assist separation, for example, a chemical property, such as, charge, for example, through formation of an ionic bond or a chemical bond, as one member of a binding pair and so on; instilling a new chemical property on a psychoactive compound, such as, hydrophilicity, hydrophobicity steric bulk, or lack thereof, and so on; instilling a desired pharmacologic property, such as, extended half-life, shortened half-life, facilitate organ or tissue uptake, facilitate cell uptake, enable and facilitate use as a prodrug and so on; and the like.
[0007] In embodiments, a first modification of a psychoactive compound provides a reaction site for a second modification and so on, a psychoactive compound can comprise a plurality of modifications or modification groups, which can be added sequentially one on to another, concurrently, for example, at plural sites of a psychoactive compound, or combination thereof. Hence, a modified psychoactive compound of interest can comprise more than one modification at one or more sites of the base psychoactive compound.
[0008] In embodiments, a modification can be a linking entity, linker and so on, which can be bifunctional, polyfunctional and so on, with one end of a linking moiety attached to a psychoactive compound and other end(s) serve as site(s) for modification.
[0009] A psychoactive compound of interest can be, for example, an alkaloid, an opioid, a phenethylamine, a tryptamine, a psychoactive compound comprising an indole group, a 2C compound and so on. Examples include mescaline, psilocybin, psilocin and so on.
[0010] A psychoactive compound of interest is one which binds to and activates a serotonin receptor, a dopamine receptor and so on.
[0011] The moiety added to a psychoactive compound of interest includes an amino acid, a lipid, a nucleic acid, a carbohydrate and combinations thereof. An amino acid includes single amino acids and polymers thereof. A carbohydrate includes a single sugar and polymers thereof. A nucleic acid includes a nucleotide and polymers thereof.
[0012] The added moiety can be one member of a binding pair.
[0013] In embodiments, the added moiety can be a vitamin or a vitamer, such as, a biotin or a folate.
[0014] In embodiments, one or more, or all of the added moiety or moi eties are removable from the modified psychoactive compound of interest to recover or to reform the original, based psychoactive compound.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Features and advantages of the instant invention may be understood more readily, by those of ordinary skill in the art, from reading the following detailed description. It is to be appreciated that certain features of the invention, which are described above and below, in the context, at times, of separate embodiments, also encompass features, aspects, embodiments and so on in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, encompass those features, aspects, descriptions and the like separately or may be provided in any combination or sub-combination.
[0016] Terms used herein generally are known in the art, for example, as described in Leuenberger et al., eds., Helv Chim Acta, Basel, CH (1995). Terms used herein include grammatic forms and variants thereof.
[0017] Practice of the instant invention employs, unless otherwise indicated, conventional methods of chemistry, biochemistry, cell biology, pharmaceutics, pharmacology and so on.
[0018] References in the singular also may include the plural (for example, “a,” and, “an” may refer to one, or one or more), unless the context specifically states otherwise.
[0019] Use of numeric values in ranges specified herein, unless expressly indicated otherwise, are stated as approximations as though minimum and maximum values of stated ranges both may be preceded by the word, "about.” Tn that manner, slight variations above and below the stated limits of a range can be tolerated to achieve substantially the same results as for values within ranges in practice of the instant invention. Disclosure of ranges is intended as continuous with and within that disclosed range including every value (of the same degree of accuracy of the two range limit values) between the minimum and maximum values and including the cited minimum and maximum values. Hence, the range, 1-3, includes, 1, 2 and 3; and the range, 1.4- 1.7, includes 1.4, 1.5, 1.6 and 1.7.
[0020] The term, "about," to describe a value, amount or variable means greater or less than that value, amount or variable (includes all values within a range to the same degree of accuracy as of that value) by 1/10 of that stated value, but is not intended to limit any value or range of values. For instance, a concentration value of about 30% means a concentration between 27% and 33%, or 27%, 28%, 29%, 30%, 31%, 32% and 33%. Each value or range of values preceded by, "about," is intended to encompass an embodiment of a stated absolute value and a range of values.
[0021] As used herein, the phrase, "having the formula," or, "having the structure," is not intended to be limiting.
[0022] "Alkyl," refers to a linear, branched or cyclic saturated hydrocarbon group containing 1 to about 24 carbon atoms or more, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and so on, as well as, cycloalkyl groups, such as, cyclopentyl, cyclohexyl and the like. "Lower alkyl", can refer to an alkyl group of 1 to
about 6 carbon atoms. A, "substituted alkyl," refers to alkyl substituted with one or more substituent or functional groups, including where two hydrogen atoms from the same carbon atom in an alkyl substituent are replaced, such as, in a carbonyl group (hence, a substituted alkyl group may include a -C=O moiety). "Heteroatomcontaining alkyl," and, "heteroalkyl," refer to an alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, “alkyl," and, "lower alkyl," include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl or lower alkyl, respectively.
[0023] "Alkenyl," as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms, or more, containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl and so on. "Lower alkenyl," can refer to an alkenyl group of 2 to about 6 carbon atoms. The term, "substituted alkenyl," refers to alkenyl substituted with one or more substituent or functional groups, and, "heteroatom-containing alkenyl," and, "heteroalkenyl," refer to alkenyl where at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms, "alkenyl," and, "lower alkenyl," include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
[0024] "Alkynyl," refers to a linear or branched hydrocarbon group of 2 to about 24 carbon atoms, or more, containing at least one triple bond, such as, ethynyl, n-propynyl and so on. "Lower alkynyl," can refer to an alkynyl group of 2 to about 6 carbon atoms. "Substituted alkynyl," refers to alkynyl substituted with one or more substituent groups, and, "heteroatom-containing alkynyl," and, "heteroalkynyl," refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms, "alkynyl," and, "lower alkynyl," include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
[0025] "Alkoxy," refers to an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy," group. A, "lower alkoxy," group relates to an alkoxy group containing 1 to about 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy and so on. Substituents identified
as, "C1-C6 alkoxy," or, "lower alkoxy," herein may, for example, contain 1 to about 3 carbon atoms. "Alkylthio," refers to a group with a sulfur atom attached to an alkyl.
[0026] "Aryl," refers to an aromatic substituent generally, although not necessarily, containing 5 to about 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings, that may be fused together, directly linked or indirectly linked (such that the different aromatic rings are bound to a common group, such as, a methylene or ethylene moiety). Aryl groups may, for example, contain 5 to about 20 carbon atoms. For example, aryl groups may contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl -substituted aryl and so on). Examples include phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and the like. "Substituted aryl," refers to an aryl moiety substituted with one or more substituent groups, and, "heteroatom-containing aryl," and, "heteroaryl," refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the term, "aryl," includes unsubstituted, substituted, and/or heteroatomcontaining aromatic substituents.
[0027] "Aralkyl," refers to an alkyl group with an aryl substituent, and, "alkaryl," refers to an aryl group with an alkyl substituent. In general, aralkyl and alkaryl groups herein contain 6 to about 30 carbon atoms.
[0028] "Alkylene," refers to a diradical alkyl group. Such groups include saturated hydrocarbon chains containing from 1 to about 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, may be heteroatom-containing. "Lower alkylene," refers to alkylene linkages containing from 1 to about 6 carbon atoms. Examples include, for example, methylene (— CH2— ), ethylene (— CH2CH2— ), propylene (— CH2CH2CH2— ), 2-methylpropylene (— CH2— CH(CH3)— CH2— ) and so on.
[0029] Similarly, the terms, "alkenylene," "alkynylene," "arylene," "aralkyl ene," and "alkarylene," as used herein refer to diradical alkenyl, alkynyl, aryl, aralkyl and alkaryl groups, respectively.
[0030] "Amino," refers to — NZ1Z2 wherein Z1 and Z2 are hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, substituted and/or heteroatom-containing variants thereof and so on.
[0031] "Halo," and, "halogen," are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
[0032] The term, "heteroatom-containing," as in a, "heteroatom-containing alkyl group," (also termed a, "heteroalkyl," group) or a, "heteroatom-containing aryl group," (also termed a, "heteroaryl," group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, for example, nitrogen, oxygen, sulfur, phosphorus, silicon and so on, for example. Similarly, "heteroalkyl," refers to an alkyl substituent that is heteroatom-containing, "heterocyclic," refers to a cyclic substituent that is heteroatom-containing, "heteroaryl," and, "heteroaromatic," respectively, refer to, "aryl," and, "aromatic," substituents that are heteroatom-containing and the like. Examples of heteroalkyl groups include alkoxyaryl, alkyl sulfanyl -substituted alkyl, N-alkylated amino alkyl and so on. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl and so on. Examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl and so on.
[0033] "Hydrocarb yl," refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as, alkyl groups, alkenyl groups, aryl groups and the like. "Substituted hydrocarbyl," refers to hydrocarbyl substituted with one or more substituent groups, and, "heteroatom-containing hydrocarbyl," refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, "hydrocarbyl," is to be interpreted as including substituted, unsubstituted and/or heteroatom-containing hydrocarbyl moi eties. “Hydrocarb ylene," refers to a diradical hydrocarbyl group.
[0034] By, "substituted," is meant that in a hydrocarbyl moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents. Examples of such substituents include, without limitation: functional groups, such as, halo, hydroxyl, sulfhydryl, Cl to about C24 alkoxy, C2 to about C24 alkenyloxy, C2 to about C24 alkynyloxy, C5 to about C20 aryloxy, acyl (including C2 to about C24 alkylcarbonyl (— CO-alkyl) and C6 to about C20 arylcarbonyl (— CO-aryl)), acyloxy (— O-acyl) and so on. In addition, the
aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties. Analogously, the above-mentioned hydrocarbyl moieties may be substituted further with one or more functional groups or additional hydrocarbyl moieties.
[0035] The aforementioned functional groups may, if a particular group permits, be substituted further with one or more additional functional groups or with one or more hydrocarbyl moieties. Analogously, the above-mentioned hydrocarbyl moieties may be substituted further with one or more functional groups or additional hydrocarbyl moieties.
[0036] When the term, "substituted," or grammatic forms thereof, such as, “substituent,” appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase, "substituted alkyl and aryl," is to be interpreted as, "substituted alkyl and substituted aryl."
[0037] Electrophilic linkages may include, for example, ester linkages (-(CO)- O-), carbonate linkages (-O-(CO)-O)-, urethane linkages (-O-(CO)-NH), substituted urethane linkages (-O-(CO)-NR-, where R is a nonhydrogen substituent, such as, alkyl, aryl, alkaryl and the like), amido linkages (-(CO)-NH-), substituted amido linkages (- (CO)-NR-, where R is as defined previously), thioester linkages (-(CO)-S-), sulfonic ester linkages (-S(O)2-O-), ketone linkages (-C=O-) and the like.
[0038] An, “alternative,” species of a base compound includes a derivative thereof, a structural analog thereof, a change therefrom and so on, which change includes addition of, for example, a substituent, a functional group, a replaced atom and so on, which change may enhance efficiency of production, may enhance pharmacologic activity, may reduce immunogenicity and so on. Synonyms include, “derivative,” and grammatic forms thereof, “variant,” and grammatic forms thereof, “modified,” and grammatic forms thereof, “functionalized,” and grammatic forms thereof, “substituted form,” and grammatic forms thereof, “analogs,” and grammatic forms thereof, and so on.
[0039] The terms, "functional group," "active moiety," "reactive site," "chemically reactive group," “chemically reactive moiety," synonyms thereof and grammatic forms thereof refer to portions or units of a molecule. (Verb forms can be
used, such as, functionalized, modified, derivatized and so on.) The terms are used herein to indicate portions of molecules that perform some function or activity and are reactive with other molecules. "Active," when used in conjunction with a functional group, includes functional groups that react readily with, for example, electrophilic or nucleophilic groups on other molecules. For example, an, "active ester," includes esters that react readily with nucleophilic groups, such as, amines. Examples of active esters include N-hydroxysuccinimidyl esters or 1 -benzotriazol yl esters. An active ester can react with an amine in aqueous medium in a matter of minutes, whereas certain esters, such as, methyl or ethyl esters, can require a strong catalyst to react with a nucleophilic group.
[0040] A, "protected functional group," "protecting group," "protective group" synonyms thereof, including a blocking group as taught herein, grammatic forms thereof and so on refers to presence of a moiety (that is, the protecting group) that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions.
[0041] The term, "linkage," or, "linker," refers to an atom or a collection of atoms used to link, such as, by one or more, for example, covalent bonds, interconnecting moieties, such as, a psychoactive compound and a reactive functional group. A linker may be hydrolytically stable or may include a physiologically hydrolyzable or enzymatically degradable linkage.
[0042] A, "physiologically hydrolysable," or, "hydrolytically degradable," bond is one that is labile and can react with water (is hydrolyzed) under physiologic conditions. Tendency of a bond to hydrolyze in water can depend on the general type of linkage connecting two central atoms and on the substituents attached to those central atoms. Known hydrolytically unstable or degradable linkages include, but are not limited to, carboxylate ester, phosphate ester, anhydrides, acetals, ketals, acyloxyalkyl ether, imines, orthoesters and so on.
[0043] A, "hydrolytically stable," linkage or bond refers to a chemical bond, such as, a covalent bond, that is substantially stable in water, that is, does not undergo hydrolysis under physiologic conditions to any appreciable extent over an extended period of time. Examples of hydrolytically stable linkages include, but are not limited
to, carbon-carbon bonds (for example, in aliphatic chains), ethers, amides, urethanes and the like.
[0044] An, "enzymatically unstable," or, degradable linkage is a linkage that can be degraded by one or more enzymes.
[0045] Chemical groups can be added to a base structure or to substitute for an atom or a functional group of a base structure to obtain a derivative or functionalized form thereof. Those added or replacing chemical groups can be known as, “substituent,” “functional group,” “component,” and so on. The group added can be a, “radical.” The added group, in embodiments, can be considered a, “pendant group.”
[0046] “Base compound,” “base structure,” “reference compound,” grammatic forms thereof and so on are equivalent terms and used synonymously herein and refer to an original compound or structure from which a modified form is made. Hence, a base compound can be one that is unmodified or does not contain a modification or functional group. A base compound can be modified and engineered to include one or more additional modifications. Thus, a derivative thereof is that base compound made to contain a new medication or functional group. A base compound can be a molecular entity from which an atom, group and so on is removed to form a derivative. So a halogenated base compound can be treated to remove the halogen group to yield a dehalogenated derivative thereof.
[0047] A, “vitamin,” is a nutrient, some can be synthesized in or by a subject. A vitamin includes choline, vitamin A (retinoic acids, retinals and so on), thiamine (vitamin Bi), riboflavin (vitamin B2), niacin (vitamin B3), a biotin (vitamin B7), a folate (vitamin B9), ascorbic acid and so on. A synonym is, “vitamer.”
[0048] A, “sugar,” includes a monosaccharide, such as, glucose, fucose, glucuronic acid, glucosamine, mannose, galactose and so on, polymers thereof, such as, oligosaccharides, disaccharide, polysaccharides and so on, such as, lactose, a starch, a cellulose, glycogen, hyaluronic acid, sucrose and so on.
[0049] “Amino acid,” as used herein relates to proteogenic, non-proteogenic, non-naturally occurring, naturally occurring, synthetic or other forms of amino acids. As known in the art, amino acids are organic compounds where a carbon atom, known as the a-carbon, is attached to an amine group and to a carboxylate group. Various side chains, which define a particular amino acid, are attached to the a-carbon. There
are hundreds of naturally occurring amino acid, but only 20 are encoded by nucleic acid and contribute to making a polypeptide or protein (proteogenic). Naturally occurring amino acids are generally L stereoisomers, although D-amino acids exist or can be made and can be found in vivo. The amino and carboxylate groups of amino acids can react in a condensation reaction, releasing water, to form an amide or peptide bond. Amino acid as used herein includes not only single amino acids, such as, lysine (Lys), serine (Ser), threonine (Thr) and so on, but also polymers thereof and so on. Included in the definition are dipeptides, tripeptides, oligopeptides, polypeptides and so on, as well as polymers, linear or branched, composed of a combination of proteogenic, non-proteogenic, non-naturally occurring, naturally occurring, synthetic or other forms of amino acids.
[0050] A, “lipid,” is any compound that does not (or is not substantially or easily dissolvable) dissolve in water, aqueous medium or hydrophilic medium. Examples, include, fatty acids, steroids, fats, waxes, some vitamins and so on.
[0051] A, “nucleic acid,” as used herein includes not only polymeric forms including dinucleotides, oligonucleotides, polynucleotides and so on, but also monomers used to construct a nucleic acid, for example, adenine triphosphate (ATP), uridine triphosphate (UTP) and so on, as well as the nitrogenous bases that a components of nucleotides, such as, uracil, thymidine and so on.
[0052] A, "pharmaceutically active molecule," “active pharmaceutical ingredient (API),” or, “entity,” and so on, and grammatic forms thereof are synonyms as used herein and relate to a compound which has a beneficial effect on or in a subject when administered thereto or used by a subject in a therapeutically, pharmacologically or biologically effective amount and so on. A pharmaceutically active entity can have a curative effect, reduce symptoms of a disorder, affliction, disease and so on, or a palliative property. A pharmaceutically active compound may have a prophylactic property by reducing or preventing occurrence of one or more symptoms of a disease, disorder, affliction and so on, or a disease, disorder, affliction and so on. A pharmaceutically active moiety may be used for recreational purposes. Pharmaceutically active compounds include analogs and variants thereof.
[0053] “Biologically active,” is meant to indicate an introduced (into a subject) molecular entity initiates, stimulates, instigates, precipitates, elicits and so on a
biologic response in a receiving subject. The response can have a positive or beneficial effect on the subject; can have a neutral effect on the subject; can have a negative or deleterious effect on the subject; and so on. A drug, medicine or compound that is pharmacologically active or pharmaceutically active is an example of a biologically active compound. A compound used for recreational purpose is one that is biologically active.
[0054] “Agent,” “drug,” “substance,” “molecule,” entity,” “moiety,” “compound,” and so on as used in the prior paragraph and hereinbelow relating to a chemical compound, are considered synonyms and are used interchangeably herein. A synonymous phrase is, “pharmaceutically active ingredient (PAI).”
[0055] “Subject,” is an organism or entity (as relating to a life form) that benefits from ingesting or being exposed to a compound of interest. Synonyms include, “recipient,” “individual,” “host,” “organism,” “patient,” “person,” and so on. Subject can be human.
[0056] “Administrable,” and grammatic forms thereof, indicates a compound is one administered to a subject. An administrable compound is one safe for administration to a subject.
[0057] “Does not contain,” “aside from,” ’’absent from,” “lacking,” “missing,” “lack of,” “is free of,” “not present,” “not containing,” “does not include,” “omitted,” “absence of,” “devoid,” grammatic forms thereof, and so on, as well as equivalent terms and phrases, describe a negative, that is, lack of or absence of an entity, item or thing. For example, a psychoactive compound of interest does not include a cannabinoid. Hence, all teachings herein do not relate to and do not include cannabinoids.
[0058] The term, "approximately," refers to a quantity, level, value or amount that varies by as much as 30%, as much as 20%, as much as 10% of a reference or stated quantity, level, value or amount.
[0059] A, “nucleophile,” is a chemical entity that can form a bond with an, “electrophile,” by donating an electron pair to the electrophile. Suitable nucleophilic compounds are those with a free pair of electrons or at least one n (pi) bond. Nucleophiles generally are Lewis bases or Bronsted bases. Nucleophilicity can be related to basicity. Examples include halogen anions, halogenated compounds,
ammonia, hydroxides, thiocyanates, cyanides, organometallic compounds, enols, azides, amines, nitrites and so on.
[0060] Nucleophilic reagents comprise one or more nucleophilic groups, such as, hydroxyl, ether, carboxyl (for example, -COO—), amine, azide, sulfhydryl and the like. Nucleophilic reagents include monohydric alcohols, diols, polyols, amines, diamines, polyamines, sulfhydryls, di sulfhydryls, poly sulfhydryls and so on, and combinations thereof. Examples include amino alcohols and sulfhydryl alcohols.
[0061] An, “electrophile,” is a chemical entity complement to a nucleophile and forms a bond therewith by accepting an electron pair. Electrophiles, hence, generally are Lewis acids or Bronsted acids. Most are positively charged or can have an empty molecular orbital of the proper energy for bond formation with a nucleophile. Electrophiles and nucleophiles generally react together in addition reactions or substitution reactions. Common electrophiles include cations, carbonyls and so on.
[0062] A, "nucleophilic substitution reaction," is a reaction between a nucleophile and an electrophile in which a covalent bond is formed between the nucleophile and the electrophile and often a bond is broken between the electrophile and a leaving group. Thus, a leaving group that had been bound to the electrophile is replaced by the nucleophile.
[0063] In an, "addition reaction," reaction occurs between a nucleophile and, for example, a conjugated unsaturated group or conjugated unsaturated bond. For example, a nucleophile can react with an a,p unsaturated aldehyde or ketone, resulting in formation of a covalent bond between the nucleophile and the P carbon and a bond between a hydrogen atom and the a carbon. A bond between the a and P carbons also is converted from a double to a single bond.
[0064] The term, "aglycone," refers to the non-glycosidic portion of a sugared compound, a glycoside compound; the entity lacking a sugar substituent or component; the base compound to which a sugar is attached or bound.
[0065] A, “binding pair,” are two complementary molecules or molecular entities that bind one another. Examples include a lectin and a cognate carbohydrate; biotin and avidin/streptavidin; antibody and cognate antigen; antibody and Fc receptor; receptor and ligand; anion and cation; anion and complexing agent and so on. One
member of a binding pair can be attached to a psychoactive agent to tether or to target the agent to a desired target that is attached to the complementary, other member of the binding pair.
[0066] "Reactive," or, "activated," refers to a functional group that reacts readily with an electrophile or a nucleophile on another molecule, in contrast to those groups that require strong catalysts or highly impractical reaction conditions to react (that is a, "nonreactive," “stable,” or, "inert," group), US Pat No 7,790,835.
[0067] The terms, "protected," “blocked,” "protecting group," “blocking group,” or, "protective group" and synonyms thereof refer to presence of a moiety that prevents or blocks reaction of a particular chemically reactive functional group in a molecule. The protecting group will vary depending on the type of chemically reactive group being protected as well as the reaction conditions employed and presence of additional reactive or protecting groups in the molecule, if any. Generally, protecting or blocking groups are removable. Protecting groups known in the art can be found in Greene et al., “Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, N.Y. (1999).
[0068] The term, "prodrug," refers to a compound that on administration to a subject, undergoes a chemical conversion or reaction by metabolic, biologic, biochemic or physiologic processes to become an active, pharmacologic agent. Prodrugs normally undergo a transformation to regenerate a pharmaceutically, pharmacologically or biologically active entity, such as a cleavage-type reaction that releases the PAI or drug on the one hand, and the once bound functional group or modification on the other.
I. Psychoactive compounds aside from cannabinoids
[0069] A. A, “psychoactive,” compound; “psychopharmaceutic;” “psychoactive,” agent; “hallucinogen;” “psychedelic;” “psychostimulatory,” drug; “psychotropic,” drug; and so on, and grammatic forms thereof, are synonyms as used herein, and relate to a chemical substance that alters nervous system function and results in alteration of, for example, perception, mood, consciousness, cognition, behavior and so on. The substances may: be used medically; be used recreationally; improve performance; alter consciousness; be used as an entheogen for ritual, spiritual or shamanic purposes; be used for research; and so on. Such compounds may be used
to study consciousness; to enhance meditation; to produce a better understanding of one’s thoughts, one’s self, one’s traumas, one’s intentions and so on. Some psychoactive compounds with therapeutic value can be prescribed for a medical purpose. Examples include anesthetics, analgesics, anticonvulsants and antiparkinsonian drugs, as well as medications used to treat neuropsychiatric disorders, such as, antidepressants, anxiolytics, antipsychotics, stimulants and so on. Some psychoactive substances may be used in detoxification and rehabilitation programs for persons dependent on or addicted to a drug or other psychoactive compounds, persons who have behaviors or habits that are not beneficial or conducive to that individual; and so on.
[0070] A psychoactive compound as used herein does not include a cannabinoid.
[0071] A psychoactive compound can be an alkaloid.
[0072] An, "alkaloid," is a compound or a precursor thereof, which can be of plant origin, having a nitrogen atom, such as, an amine, and a pharmacologic or physiologic effect in warm-blooded animals, including human, Cassels, Nat Prod Comm 14:85-90, 2019. Alkaloids can be used as medications and recreational drugs.
[0073] Examples of alkaloids include, but are not limited to, ephedrine; pseudoephedrine, phenyl propanolamine; opiates, such as, oxycodone, morphine, hydrocodone, oxymorphone and the like; and so on.
[0074] Alkaloids can be classified by structural similarity.
[0075] For example, alkaloids with a pyridine group include piperine, coniine, arecoline, cytisine, nicotine, anabasine, sparteine, pelletierine and the like.
[0076] Pyrrolidines include hygrine, cuscohygrine, nicotine and the like.
[0077] Tropanes include atropine, cocaine, ecgonine, scopolamine, catuabine and the like.
[0078] Quinolines include quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine and the like.
[0079] Isoquinolines include opium alkaloids (papaverine, narcotine (noscapine), narceine and the like), sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine and the like.
[0080] Phenanthrene alkaloids include opium alkaloids, morphine, codeine, thebaine and the like.
[0081] Phenethylamines include mescaline, ephedrine, dopamine, amphetamines, 3,4-methylenedioxymethamphetamine (MDMA), 2C compounds, cathinone and the like.
[0082] Indoles include tryptamines, serotonin, dimethyltryptamine (DMT), 5 -methoxy dimethyl tryptamine (5MeO-DMT), N,N,N-trimethyl-4- phosporyloxytryptamine, 4-hydroxy-N-methytryptaine (4-HO-NMT), bufotenine, psilocyin, psilocybin, ergolines, ergot alkaloids, lysergic acid, tetrahydroharmine, reserpine, N-nitrosodimethylamine (NDMA) also known as, dimethylnitrosoamine (DMN), yohimbine, vinca alkaloids, vinblastine, vincristine, mitragynine, ibogaine, voacangine, coronaridine, strychnine, brucine and the like.
[0083] Purines include xanthines, caffeine, theobromine, theophylline and the like.
[0084] Terpenoids include aconite alkaloids, aconitine, steroid alkaloids (containing a steroid skeleton with a nitrogen containing group), solanum (for example, potato and tomato) alkaloids, chaconine, veratrum alkaloids, cyclopamine, cycloposine, jervine, muldamine, newt alkaloids, such as, samandarin; conessine, and the like.
[0085] Quaternary ammonium compounds include muscarine, choline, aeruginascins, neurine and the like.
[0086] Miscellaneous alkaloids include capsaicin, cynarin, harmine, phytolaccatoxin and the like.
[0087] B. Mescaline (3,4,5-trimethoxyphenethylamine) is produced in some types of cactus found in the desert Southwest and in South America, such as, peyote and Peruvian torch. Mescaline has a free amine group.
[0088] C. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine (DMT)) is a prodrug converted to the pharmacologically active compound, psilocin, by dephosphorylation. That reaction takes place under strongly acidic conditions; or under physiologic conditions by enzymes called alkaline phosphatases. Psilocybin is a tryptamine with an indole heterocycle linked to an ethylamine substituent. Psilocybin is chemically related to tryptophan and is structurally similar to serotonin. Psilocybin
is soluble in water, methanol and aqueous ethanol, but insoluble in organic solvents, such as, chloroform and ether.
[0089] D. 2C compound (2C or 2C-x) is a general name for the family of phenethylamines containing methoxy groups at the 2 and 5 positions of the benzene ring. Many 2C compounds carry lipophilic substituents at the 4 position, which can result in increased potency, increased metabolic stability and greater in vivo persistence. The term, “2C,” is derived from and represents the 2 carbon atoms between the benzene ring and the amine group.
[0090] E. Ketamine is an arylcyclohexylamine often used as an anesthetic.
[0091] F. N,N-dimethyl tryptamine (DMT or N,N-DMT) occurs in many plants and animals. DMT can be used as a recreational drug and is used as an entheogen. Dimethyltryptamine is an indole alkaloid derived from the shikimate pathway. DMT has two reactive amine groups.
[0092] G. Lysergic acid diethylamide (LSD) is an ergoline derivative. LSD commonly is synthesized by reacting diethylamine with an activated form of lysergic acid.
[0093] H. Indolamines are a family of monoamine neurotransmitter. An example is the tryptophan derivative, serotonin, a neurotransmitter involved in mood and sleep. Another example is melatonin.
[0094] Approximately 90% of human serotonin is located in the enterochromaffin cells in the gastrointestinal (GI) tract where serotonin regulates intestine movement. About 8% of total serotonin is found in platelets and 1-2% in the central nervous system (CNS). In the GI tract, serotonin is secreted luminally and basolaterally, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons resulting in gastrointestinal motility. The remainder of total serotonin is synthesized in serotonergic neurons of the CNS where serotonin regulates mood, appetite and sleep. Serotonin also has influence on some cognitive functions, including memory and learning.
[0095] When platelets bind a clot, serotonin is metabolized mainly to 5-hydroxyindoleacetic acid (5-HTAA), chiefly by the liver, where the 5-HTAA is secreted for removal from the body.
[0096] I. Other neurotransmitters include catecholamines and ethylamines.
[0097] J. Tryptamines, or serotonin analogues, contain an indole ring, joined to an amine group via an ethyl sidechain.
[0098] K. Phenethylamines contain a phenyl ring joined to an amino group via a two-carbon sidechain.
II. Receptors
[0099] Many psychoactive compounds act or stimulate a physiologic response on binding a cell surface receptor.
A. Serotonin Receptor
[00100] Serotonin binds 5 -hydroxytryptamine (5-HT) receptors or serotonin receptors which are G protein-coupled receptors (molecules with a portion exposed on the cell surface and which traverse the cell membrane) or are ligand-gated ion channels found, for example, in the central and peripheral nervous systems. The receptors mediate both excitatory and inhibitory neurotransmission. Serotonin is the natural ligand. The serotonin receptors modulate release of many neurotransmitters, including glutamate, y-amino butyric acid (GABA), dopamine, epinephrine/norepinephrine, acetylcholine and so on, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, substance P and so on. Serotonin receptors influence various biologic and neurologic processes, such as, aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep and thermoregulation.
[00101] Serotonin receptors fall into 7 families that generally, on binding serotonin, either increase or decrease intracellular cAMP (one family comprises ion channels). A decrease in cAMP generally results in an inhibitory response to serotonin and an increase in cAMP generally results in an excitatory response to serotonin. Those 7 families contain 14 different receptors.
[00102] For example, family 5 includes three species of receptor. The family 5 receptors do not mediate cell response by impacting cAMP level, family 5 receptors instead rely on G protein signaling.
[00103] Heterotri meric G proteins comprise a family of intracellular membrane-associated proteins that form a heterotrimeric complex which associates
with G protein-coupled receptors (GPCR) located at the cell surface and traversing the cell membrane. A GPCR receptor portion or moiety displayed outside a cell can bind a specific, cognate ligand. When a GPCR engages a cognate ligand, the GPCR is activated and the intracellular portion of the GPCR interacts with an intracellular G protein.
[00104] G proteins are made of a, P and y subunits. The a subunit is attached to either a guanosine triphosphate (GTP) or a guanosine diphosphate (GDP) and serves as an on-off switch for activating the G protein complex and for activating the downstream signaling cascade. Generally, a binds membrane-bound effector proteins of a downstream signaling cascade.
[00105] Gq protein is one of 18 types of a. subunit, also commonly called Gq/n (Gq/Gn), which associates with G protein-coupled receptors which when serotonin is bound, thereby results in activation of -type phospholipase C (PLC-P). PLC-P in turn hydrolyzes phosphatidylinositol 4, 5 -bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3) at the inner face of the cell membrane. IP3 moves deeper into the cytoplasm to act as a second messenger ultimately controlling release of a number of hormones, while DAG remains in association with the cell membrane and activates protein kinase C (PKC), a family of enzymes that activate protein substrates by phosphorylating same, which are involved with producing many functions in cells, tissues and organs, such as, smooth muscle, kidney tubule cells, neurons, platelets, heart, serous cells, adipocytes and so on.
[00106] When serotonin binds a family 5 receptor, an excitatory response can be stimulated via binding and activation of Gq/Gn.
[00107] 1. Two of the family 5 receptors are commonly targeted by psychoactive compounds and drugs.
[00108] 5-HT2A is an excitatory receptor subtype among the GPCR’s for serotonin, although 5-HT2A also may have an inhibitory effect in certain tissues and cells, such as, the visual cortex and the orbitofrontal cortex. The receptor is a target of serotonergic psychedelic drugs, such as, LSD and psilocybin.
[00109] The 5-HT2B receptor mediates many central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets. Central nervous system (CNS) effects
include neuronal sensitization to tactile stimuli and mediation of some of the effects of amphetamines. The 5-HT2B receptor is expressed highly in liver and kidney, with lower levels found in the cerebral cortex, whole brain, pancreas and spleen.
[00110] B. Dopamine Receptors
[00111] Dopamine receptors are G protein-coupled receptors prominent in the central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein (for example, dopamine receptor-interacting proteins) interactions. Dopamine receptors are implicated in many neurologic processes, including motivation, pleasure, cognition, memory, learning, fine motor control and so on, as well as modulation of neuroendocrine signaling.
[00112] Abnormal dopamine receptor signaling and dopaminergic nerve function are implicated in several psychiatric disorders. Thus, dopamine receptors are common neurologic drug targets, antipsychotics often are dopamine receptor antagonists while psychostimulants typically are indirect agonists of dopamine receptors.
[00113] Dopamine is the primary neurotransmitter involved in the reward pathway in the brain. Thus, drugs that increase dopamine signaling may produce a euphoria. Many recreational drugs, such as, cocaine and amphetamines, inhibit the dopamine transporter (DAT) responsible for removing dopamine from neural synapses. When DAT activity is blocked, synapses flood with dopamine and increase dopaminergic signaling, and hence, for example, euphoria.
III. Derivatization/Functionalization/Conjugation
[00114] Derivatization, functionalization, conjugation, modification, coupling, other synonyms thereof, grammatic forms thereof and so on relate to changing a base compound for a desired purpose. All of those terms are used interchangeably and equivalently herein. Hence, adding a functional group to a base compound; altering a base compound to form or to remove a functional group, or to form a derivative thereof, a structural analog thereof and so on, joining an entity to a base compound, for example, a coupling or a conjugation, to form a composite molecule or a conjugate; and so on, are forms of such a change, modification, functionalization, alteration of interest.
[00115] The term "conjugating,” means to bind two molecules together. The joining can be by a covalent linkage, a non-covalent linkage, such as, by an ionic interaction, a hydrophobic interaction, hydrogen bonding and so on. The joining also can be obtained using an intervening linking molecule (linker, linker molecule, synonyms thereof and so on) wherein one portion of a linking molecule attaches to a psychoactive compound and another portion of a linking molecule distal from the psychoactive compound attaches to a substituent, functional group and so on, see, for example, US Pat No 9,968,683.
[00116] A synonym of functionalize is, "couple," and grammatic forms thereof, which means reacted with or attached to, possibly through a series of covalent bonds. A psychoactive compound can be coupled to a functional group or to a linker.
[00117] As provided herein, a "derivative," of an organic molecule is a compound having a portion of the organic molecule and having the same function or activity as the organic molecule. A derivative may have one more functional groups that are not present in the parent organic molecule might not have one or more functional groups present in the parent organic molecule. A synonym is modified or functionalized.
[00118] For example, methods of conjugating two molecules can be obtained by reacting an aliphatic dialdehyde or aromatic dialdehyde with an amine moiety to form a stable product under mild conditions. Generally, the reaction does not produce side products that must be removed from the reaction mixture, and does not require a catalyst or a reducing agent. The reaction mechanics may involve reducing, and therefore stabilizing the imine adduct formed between the amine and the aldehyde, see, for example, US Pat No 10,188,719.
[00119] Hence, conjugates can be formed, for example, by mixing a saccharide comprising an aldehyde group with a psychoactive compound comprising an amine group under suitable reaction conditions. Two types of conjugate can be made: (a) a conjugate where an individual saccharide is attached to a psychoactive compound through a reducing terminus; and (b) a conjugate where an individual saccharide is attached to multiple psychoactive compounds because several functional groups of a monosaccharide subunit are reactive. A single psychoactive compound can link to more than one saccharide because of more than one amine groups.
[00120] Hence, in embodiments, a saccharide is oxidized to form an aldehyde, and the aldehyde then can be used for reaction, such as, reductive amination.
[00121] Oxidation of hydroxyl groups to yield aldehydes can be achieved chemically or enzymatically. Such reactions can occur under aqueous conditions, see, for example, WO94/06467.
[00122] Periodate salts, such as, sodium or potassium periodate (NaIO4), can oxidize vicinal hydroxides. Other oxidation conditions can be used, for example, with osmium tetroxide.
[00123] A hydroxyl that is oxidized can be primary, that is, not a secondary or anomeric hydroxyl, which is attached to C-6. Thus, for example, galactose can be converted to galactohexodialose, which can be attained using a galactose oxidase enzyme, such as, from Fusarium fungi or Dactylium dendroides. The enzyme can be used in recombinant form or purified from a natural source. Therefore, the oxidation reactions involve the terminal carbon atoms in the monosaccharides, that is, the highest-numbered carbons by standard nomenclature.
[00124] Then, reductive amination of the aldehyde group can be used to achieve conjugation. Hence, reductive amination can involve a primary amine (NH2R). That can be achieved by using an ammonium salt (for example, ammonium chloride) with an appropriate reducing agent (for example, cyanoborohydrides, such as, sodium cyanoborohydride NaBH3CN; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin and so on). The result of reductive amination is, in the case of sialic acid, C-8 carries — NHR rather than =0. That group then can be used for attachment in conjugation. Reductive amination can be conducted in a polar, protic solvent, such as, water or alcohol.
[00125] Alternatively, a sugar acid can be activated by introducing an amine at the carboxylate group, for example, by carbodiimide-mediated coupling using an active ester intermediate, see, for example, US Pat. No. 7,196,180. Different terminal functional groups for crosslinking, including, acetals, aldehydes, amines and hydrazides can be added at the carboxylate group. Many functionalized amines are commercially available for introducing a variety of different functional groups for crosslinking under physiologic conditions, including mal eimides that react with sulfhydryls or arylazides for photocrosslinking.
[00126] Direct carbodiimide-mediated coupling of amines to a carboxyl group in an aqueous environment can be attained, for example, with active carboxylic esters N-hydroxysuccinimide (NHS) esters, nitrophenol esters, triazole esters, sulfonic esters and so on, as long as the reagent is soluble in water or a polar solvent, such as, dimethyl sulfoxide or dimethylformamide. An active ester of a sugar acid can be obtained with 1 -hydroxybenzotriazole (HOBT) or NHS using a water soluble carbodiimide, such as, l-ethyl-3-(3-dimthylaminopropyl)carbodiimide (EDC) for coupling. The NHS-derived intermediate allows for coupling to occur at neutral pH (about 7.0 to 8.5) and consequently yields products by reaction with, for example, simple primary amines.
[00127] The reactant conjugated to the sugar acid can provide a range of terminal functional groups including an aldehyde, an amine, an arylazide, a maleimide, a sulfhydryl and so on.
[00128] Hence, diaminoethane, histidine or adipic dihydrazide can be coupled to a sugar acid using HOBT and EDC (up to 5-fold excess depending on the desired degree of modification) and adjusting the pH to about.6.5 by repeated addition of 0.1M HC1 during the reaction. Sugar acid derivatives also can be prepared using NHS and primary amines containing unconjugated amino groups with a higher pKa (>9) such as 1,4-diaminobutane. The sugar acid derivatives can be purified by repeated ethanol precipitation and dialysis. Degree of modification can be ascertained by, for example, NMR. Amount of carbodiimide can correlate with degree of modification. Reagents such as, succinic or suberic dihydrazide or diaminoethane, diaminohexane and so on provide different lengths of spacer separating the introduced functional group from the sugar acid, which may impact subsequent crosslinking.
[00129] In embodiments, an added modification or functional group is removable after attachment to a psychoactive compound. Hence, once a desired benefit is attached, a functional group or modification is removed from a psychoactive compound, which retains or regains biologic effect. In embodiments, removal can enable a psychoactive compound to exhibit a biologic effect. Removal can be obtained by a chemical reaction; an enzymic reaction; or combination thereof. A prodrug is an example where removal of a modification can enable a psychoactive compound to exert a biologic effect, and so on.
[00130] Non-covalent and covalent methods can be used to change a base compound, for example, to add to a base compound, a functional group, one member of a binding pair and so on, for example, to improve properties of a base compound, such as, associating a base compound with a carrier, such as, a carbohydrate, such as, a cyclized maltodextrin; and so on.
[00131] The present invention relates to derivatives of psychoactive compounds where a base compound is modified to include an added moiety can be any atomic or molecular entity, such as, a carbohydrate, such as, a polysialic acid, such as, a sialic acid, and so on.
[00132] One approach to adding a carbohydrate to a psychoactive compound is to employ succinimide chemistry for adding a moiety at an amine group of a psychoactive compound. Hence, for example, an N-hydroxysuccinimide (NHS) group can be added to a carboxyl group of a sugar by carbodiimide activation. For example, sulfo-NHS is a commercially available reagent for making such as derivative. An NHS derivatized sugar then can react with an amine group of a psychoactive compound where an amide bond is formed, covalently linking the sugar to the psychoactive compound with release of the NHS entity. Hence, the NHS chemistry is useful for conjugation to amine-group containing substrates, such as, a psychoactive compound.
[00133] A monosaccharide, an oligosaccharide or a polysaccharide may be covalently or non-covalently associated with a psychoactive compound. Covalent linkages can be, for example, by ester, amide or other linkage, to, for example, carboxy, hydroxy, phosphoryl or amino sites of a psychoactive compound.
[00134] Examples of processes for producing covalent linkages between a sugar and a psychoactive compound, such as, a reducing sugar, which can be linked, for example, to an amine, group by a reactive amination procedure, Arch. Biochem. Biophys. 163:426 (1974), followed by selective reduction of the enamine by a cyanohydri dob orate anion, J. Am. Chem. Soc. 93, 2897 (1971) to form an amine.
[00135] Non-reducing sugars can be derivatized by selective oxidation using periodate, J. Immunol. 127, 1011 (1981), to form an aldehyde group for coupling in an amination conjugation reaction with a receptive psychoactive compound.
[00136] As described above and as known in the art, a carboxylate group of a sugar, a nucleophile, can be added to an amine group of a psychoactive compound in presence of a carbodiimide, FEBS Lett. 202, 86 (1986).
[00137] An alternative reaction involves diazotization of an aromatic amine group introduced into a sugar, for example, using p-phenylenediamine reacted onto a carboxylic acid group, followed by reaction with a hydroxyl group, Biochim. Biophys. Acta, 772, 288 (1984) and Biochim Biphys Acta 1003, 58, (1989).
[00138] Free hydroxyl groups of a polysaccharide compound can be linked to free hydroxyl groups or thiol groups of a psychoactive compound, for example, by esterification using a dibasic acid or an acid derivative.
[00139] Where a psychoactive compound to be coupled to a sugar contains (or can be derivatized, for example, via an aryl group, to contain) an isothiocyanate group, conjugation can occur at a free hydroxyl group of the sugar, for example, by reaction in methyl sulfoxide, catalyzed by dibutyl tin dilaurate, Carb Res (1973) 30, 375-378. The product is a thiocarbamoyl derivative that may be reacted to form an O-linked derivative.
[00140] Polyethylene glycol (PEG) is a polysaccharide used in biologic pharmaceutics. Covalent attachment of PEG to a protein is described in J. Biol. Chem. (1977) 252, 3282-86. The conjugate displayed reduced immunogenicity and increased half-life in circulation in the mouse. Dextran was not used because dextran could be immunogenic in human or dextran has a carrier function (dextran has been used as a carrier of haptens) and may make PEG immunogenic. GB Pat. No. 2185397B suggested use of xanthan or hyaluronic acid as an alternative to PEG, and those two sugars could minimize uptake of such colloidal particles by liver.
[00141] A functional group or modification can include an atom, a cofactor, one member of a binding pair, a sugar, a nucleic acid a lipid, a vitamin, an amino acid and so on, and combinations thereof, without limitation so long as a beneficial endpoint is attached and biologic activity of the psychoactive base compound is retained, regained and so on, for example, in vivo.
[00142] Hence, a modification can be a monosaccharide; a polysaccharide; an amino acid; an oligopeptide; a polypeptide; a vitamin or vitamer,
such as, a biotin, a folate and so on; a lipid; and so on. Also included are glycolipid, glycoprotein, lipoprotein and so on.
[00143] As taught herein, a functional group can facilitate separation; enhance bioavailability; enhance biologic effect; and so on. Hence, a functional group can enhance half-life; can target an organ; can target a tissue; can target a cell; can enhance entry into an organ; can enhance entry into a tissue; can enhance entry into a cell; and so on.
[00144] A. Modification of a psychoactive compound may enhance properties of same, production of same and so on. For example, a modified psychoactive compound can be used as a prodrug, may reduce toxicity thereof, may be made more hydrophobic or more hydrophilic, can have greater functionality; may be larger; can have enhanced solubility; can have altered function; and so on. A modified psychoactive compound may be restored enzymatically or chemically to the original, base compound by removing the added group. A modified psychoactive compound may enhance manufacturing efficacy.
[00145] Mineral acid salts of a base compound are a common tool to impart immediate release characteristics to that compound, such as in an acidic environment. A dissolution profile can influence absorption. For example, a psychoactive compound delivered by nasal inhalation would benefit from rapid dissolution in nasal fluid. Typically, pH in the nasal cavity is about 4.5 which provides an environment for rapid dissolution and absorption of a highly soluble, mineral acid salt of a psychoactive compound, see US Pat. No. 9,421,266.
[00146] Other factors influencing compound absorption include drug morphology, particle size, particle size distribution and so on.
[00147] 1. Introduce desired properties
[00148] a. Purification
[00149] As mentioned herein, modifying a psychoactive compound can endow the psychoactive compound with one or more new properties that can be exploited for a beneficial use. For example, a modified psychoactive compound of interest can facilitate separation, isolation and/or purification. A modified psychoactive compound of interest may be heavier; may be bulkier; may be more hydrophobic; may be more hydrophilic; may be charged; may be cationic or more
cationic; may be anionic or more anionic; may carry a recognizable or a bindable functional group; may carry one member of a binding pair; and so on.
[00150] Separation methods, which are known in the art, and which can be used in practice of the instant invention, include fdtration, sublimation, sedimentation, distillation, evaporation, precipitation, chromatography, magnetic separation and so on.
[00151] b. Pharmacologic benefits
[00152] Derivatized psychoactive compounds can have enhanced pharmacologic function and/or efficacy; enhanced half-life; enhanced bioavailability; enhanced tissue or organ targeting; enable access to tissues and organs not normally exposed to the normal circulation such as, brain because of the blood-brain barrier (BBB) and testes because of the barrier generated by the Sertoli cells and other privileged sites; and so on.
[00153] A functionalized psychoactive compound can have properties that are directed to a specific mode of administration. For example, an organic acid salt of an amine-containing psychoactive is soluble and the psychoactive compound on oral digestion, which compound is digested or recreated in the acid environment of the stomach. The organic acid salt is stable at the higher pH of mucosa, see, US Pat. No. 9,421,266, the entire content of which herein is incorporated by reference in entirety. That organic acid salt derivative of a psychoactive compound can be effective in the acidic milieu of the nasal cavity.
[00154] B. Methods
[00155] A robust form of attachment of a psychoactive compound to a surface or other support, or to a functional group is via a covalent bond. Typically, such bonds are heteroatom-based (for example, amide, ester, disulfide and so on bonds). Covalent bonds can be formed under mild conditions.
[00156] Non-covalent attachment via, for example, specific binding pairs (for example, biotin-avidin, antibody-antigen, carbohydrate-lectin, hydrophobic and so on interactions) also can be employed, but such methods require, for example, conjugation of the specific binding pair to the psychoactive compound and to the functional group and may not be as robust as a covalent bond; and so on.
Carbon-carbon bonds also can be used, for example, if a psychoactive compound comprises an unsaturated site.
[00157] The method for covalent bond formation is a design choice, and the decision may be governed by solubility in organic solvents, pH, temperature sensitivity and so on.
[00158] Methods have been developed for attachment of a sugar to a psychoactive compound to form conjugates (Contrib. Microbiol. Immunol., Cruse & Lewis, eds., 1989, Karger, Basel; Neoglycoconjugates. Preparation and Applications, Lee & Lee, eds., Academic Press, New York, 1994). Methods may not produce site-specific coupling, unless particular reactive sites are blocked using materials and methods known in the art, where the blocking moiety may be reversibly bound.
[00159] In embodiments, functionalization may need to be directed which can require protecting or blocking particular sensitive or reactive groups on a psychoactive compound. In addition, compounds of the invention may be modified by using protecting groups yielding a prodrug. That can be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", McOmie, ed., Plenum Press, 1973; and Greene & Wuts, "Protective Groups in Organic Synthesis", 3rd ed., John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known in the art or in a physiologic environment, such as, physiologic pH, an enzyme and so on.
[00160] Protecting groups for a hydroxyl group include methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and so on. Substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, benzyloxymethyl, 4-pentenyloxymethyl and so on. Examples of substituted ethyl ethers include 1 -ethoxy ethyl, l-(2- chloroethoxyjethyl, 1 -methyl- 1 -methoxyethyl, 1-methyl-l-benzyloxyethyl, 1-methyl- l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, benzyl and so on. Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and so on. Examples of silyl ethers include trimethylsilyl, tri ethyl silyl, tri isopropyl silyl, dimethylisopropylsilyl and so on.
[00161] A hydroxyl group also may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate and so on. Carbonates that can be used to block a hysroxyl group include methyl, ethyl, isobutyl, vinyl, allyl, p- nitrophenyl, benzyl and so on.
[00162] 1,2- and 1 ,3 -diols can be protected using cyclic acetals and ketals. Examples of cyclic acetals and ketals include methylene, ethylidene, acetonide, cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene and so on. Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1 -ethoxyethylidine and so on.
[00163] Amino (or alkylamino) groups can be protected with carbamates, amides and so on. Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, urea-type derivatives and so on. Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl and so on. Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l -methyl ethyl, l,l-dimethyl-2- haloethyl, l,l-dimethyl-2,2-dibromoethyl, l,l-dimethyl-2, 2, 2 -tri chloroethyl t-butyl, vinyl, allyl, benzyl, p-methoxybenzyl, p -nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfmylbenzyl, 9-anthrylmethyl and diphenylmethyl and so on. Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl, N'-p- toluenesulfonylaminocarbonyl and N' -phenylaminothiocarbonyl.
[00164] Examples of amides include N-formyl, N-acetyl, N- chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenyl acetyl, N-3- phenylpropionyl, N-picolinoyl, N-3 -pyridylcarboxamide, N-benzoyl, N-p- phenylbenzoyl and so on.
[00165] Amino groups also can be protected with N-alkyl and N-aryl amines, quaternary ammonium salts and so on.
[00166] Examples of acyl groups that can be used to protect an amino or alkylamino group include an alkanoyl group, such as, acetyl, an alkoxycarbonyl group, such as, methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl, an
arylmethoxycarbonyl group, such as, benzyloxycarbonyl, and an aroyl group, such as benzoyl.
[00167] As known in the art, deprotection conditions vary with the protecting group. Groups, such as, an alkanoyl, alkoxycarbonyl or aroyl, may be removed, for example, by hydrolysis with a suitable base, such as, an alkali metal hydroxide. A t-butoxy carbonyl group may be removed by, for example, treatment with an acid, such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid. Arylmethoxycarbonyl groups, such as, benzyloxycarbonyl, may be removed by, for example, hydrogenation in presence of a catalyst, such as palladium-on-carbon, or by treatment with a Lewis acid, such as, boron tris(trifluoroacetate). A phthaloyl group protecting a primary amino group may be removed by, for example, treatment with an alkylamine, such as, di methyl ami nopropyl amine, or with hydrazine.
[00168] Dicarbonyl groups, such as, a- and P-diketones can be protected with enamines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl, morpholinyl, 4-methyl-l,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and trimethyl silyl.
[00169] As provided above, a carboxyl group can be protected with an ester. Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl and N-phthalimidomethyl. Examples of 2-substituted ethyl esters include 2,2,2- trichloroethyl, 2-haloethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, benzyl and so on. Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, o- nitrobenzyl, p -nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and so on.
[00170] Amides and hydrazides for protecting amino groups include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-l,2,3,4-tetrahydroquinolyl, and p-P -benzenesulfonamides; and examples of hydrazides include N-phenyl and N,N'-diisopropyl, for example, US Pat No 7,807,837.
[00171 ] In embodiments, a thiolated protein can be conjugated with a maleimido-derivatized saccharide (Meth. Enzymol. 1994, 242:17). In embodiments,
N-acryloyl amidophenyl glycosides may be coupled using a Michael addition reaction (Romanowska et al., Meth. Enzymol. 1994, 242:90).
[00172] NHS reagents can be used with organic solvents and can employ a hydrophobic carbodiimide, such as, dicyclohexylcarbodiimide (DCC) or, for example, N,N'-diisopropylcarbodiimide (DIC). Reactions involving aqueous conditions, or substantially aqueous conditions, can use a water soluble carbodiimide such as l-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC; also EDAC) or N-cyclohexyl-N'-(P-[N-methylmorpholino]ethyl)carbodiimide (CMC).
[00173] Coupling a nucleophile to a compound containing, for example, a hydroxyl group is disclosed in US Pat. No. 4,179,337, the disclosure of which is incorporated herein by reference in entirety.
[00174] A hydroxyl group of a sugar can be converted into a reactive functional group to form an, "activated," sugar or reagent.
[00175] For example, cyanuric chloride or cyanuric fluoride reacts with a hydroxyl group to yield, for example, an alkyl chloride or acyl chloride, activated forms. The chloride then can be replaced by a nitrogen of a nucleophile forming a covalent bond.
[00176] Nucleophilic functional groups can serve as attachment sites for a functional group, for example, by a nucleophilic substitution reaction. Suitable nucleophilic functional groups include amine or amino groups, amido groups, negatively charged amine groups, free carboxylic acid groups, suitably activated carbonyl groups, oxidized carbohydrate moieties, carboxylates, mercapto groups, alcohols, alkoxides, thiolates and so on.
[00177] Another activating form can be a succinate, such as, a succinimidyl succinate or a carbonate. Those electrophilic sites on the conjugating reagent can react, for example, with an amine group or an alcohol. A carboxylic acid can react with a hydroxyl group of a nucleophilic psychoactive compound to form an ester-linked functionalized psychoactive compound. Ester bonds are susceptible to cleavage by esterases, common enzymes found in vivo. Hence, ester-linked functionalized psychoactive compounds can be prodrugs.
[00178] Electrophilic substitution also can be enhanced by producing acid halides. A compound comprising a negative anion, such as, a chloride, bromide,
iodide and so on can be a leaving group when reacted with an amine, imide, alcohol, alkoxide and so on to produce the corresponding ester or amide. Other leaving groups include polyatomic anions which can be attached to a carboxyl group to facilitate formation of new molecular species.
[00179] Other electrophilic and nucleophilic groups are apparent to those of ordinary skill in the art, see, for example, US Pat. Nos. 5,122,614 and 4,179,337, the entire content of each of which herein is incorporated by reference in entirety.
[00180] 1. Chemical
[00181] As taught herein, a psychoactive compound can be modified by a chemical reaction to carry one or more modifications, such as, a functional group, a carbohydrate, a carrier and so on. Materials and methods for such reactions are known and are available commercially.
[00182] Amide linkages can be formed by reacting an amino group with, for example, an acyl chloride functional group.
[00183] N-alkylimide compounds may be prepared as taught in Barrow (J. Chem. Soc. (London), p. 638, 1939) by condensation of carboxylic acid and primary amine, condensation of carboxylic acid ester and primary amine or condensation of carboxylic acid anhydride and primary amine.
[00184] N-alkylimide compounds can be prepared from an imide, for example, by the methods presented in US Pat. Nos. 2,628,963 and 2,753,356 where carboxyimide and primary amine are reacted at high temperature and under high pressure.
[00185] A P-sulfonimide compound can be prepared by nucleophilic addition of a compound having at least one vinylsulfonyl group with a psychoactive compound having at least one imide group in presence of a catalyst. Such a nucleophilic addition is a Michael-type addition reaction. A nucleophile is used as Michael donor and an activated unsaturated compound, for example, an a,p- unsaturated carbonyl compound, is used as Michael acceptor. Hence, the imide of a psychoactive compound is used as Michael donor and vinylsulfone can be used as Michael acceptor, see, for example, US Pat No 8,362,276.
[00186] As provided herein, a, "nucleophilic compound," can be an organic hydrocarbon compound that may be acyclic or cyclic and comprises at least one atom carrying a free electron pair, such as, a nitrogen, an oxygen, a sulfur or a phosphorus atom, or comprises a carbon atom that may donate an electron pair. A nucleophilic compound comprises at least one atom carrying a free electron pair, which can be carried by a functional group, US Pat. No. 6,960,665.
[00187] When a nucleophilic compound comprises a functional group which carries one or more negative charges, that compound is a salt. The counter-ion can be a metallic cation, such as, an alkali metal, such as, sodium or lithium, or an alkaline-earth metal, such as, calcium, or residue of an organometallic compound, such as, a magnesium or zinc compound.
[00188] Psychoactive compounds can comprise a nucleophilic site such as, nitrogen-containing compounds, such as, primary or secondary amines; hydrazine or hydrazone derivatives; amides; sulphonamides; urea derivatives, heterocyclic derivatives and so on, US Pat. No. 8,362,276.
[00189] Tertiary amines in psychoactive compounds also can serve as a site of modification. Tertiary amines, such as those with lower molecular weight R groups, can react with a sulfene, R2C=SO2, or with a halogenated sulfonyl, R2CSO2Halo, where a sulfene may be formed as an intermediate, where R can vary, from H, to an alkyl group, which can be linear or cyclic, varying in size from 1 to about 24 carbons, or longer, can comprise plural rings, which can be fused, can be branched and so on; an aryl group, which can comprise plural rings; can comprise a heteroatom; can comprise one or more functional groups; and so on. The sulfur dioxide portion of the sulfene ionically reacts with the amine to form a complex. Excess sulfene can provide sulfene-based oligomerization (King & Harding, Can J Chem 54, 2652, 1976).
[00190] Other functional group reagents for reacting with, for example, an amine group of a nucleophilic psychoactive compound, include a carbonate, a carbonyldiimidazole, an azlactone, an isocyanate, an isothiocyanate and so on. Other electrophilic functional group reagents that can react with a carboxylic acid group or a reactive carbonyl group of a nucleophilic psychoactive compound include an amine; a hydrazine; a hydrazide, such as, an acyl hydrazide; a carbazate; a semicarbamate; a
thiocarbazate; and so on, see, for example, US Pat. Nos. 5,093,531; 5,349,001 and 6,113,906, the disclosure of each of which hereby is incorporated by reference in entirety.
[00191] A hydroxyl group can be activated by reaction with, for example, a formate group, such as, p-nitrophenyl chloroformate, to form a reactive p-nitrophenyl carbonate activated conjugating reagent that reacts with a nucleophile.
[00192] In embodiments, functionalization of a psychoactive nucleophile occurs at a nitrogen, oxygen or sulfur thereof.
[00193] NHS chemistry, reagents and reactions can be used for joining a molecular entity to a psychoactive compound. Reagents to execute NHS reactions are available commercially,
[00194] For example, reaction with an NHS reagent can be performed, for example, in about 0 to about 100% dimethylsulfoxide (DMSO) solutions (which can be with a minimum amount of water, for example, about 10%) at a temperature of between, for example, about 0 to about 150° C. Water soluble NHS reagents can be used when presence of organic solvent in subsequent uses of the product is not favored. A water soluble NHS reagent can be used, for example, where use of the product is for cell surface conjugation as any unreacted reagent not removed from the product may not permeate the cell membrane, see, for example, US Pat. Nos. 5,846,951 and 8,952,141.
[00195] Some reactions of an NHS derivatized functional group with a psychoactive compound can be done, for example, in phosphate, carbonate, (4-(2 -hydroxy ethyl)- 1 -piperazine ethane sulfonic acid (HEPES)), borate, bicarbonate/ carbonate and so on buffers at concentrations, for example, between about 5 to about 200 mM. Other buffers that do not contain a primary amine can be used, HEPES, for example, contains only tertiary amines. An excess of tris(hydroxymethyl)amino methane (Tris)-glycine at neutral to basic pH may be added to quench a reaction. A reaction may be performed at a pH of between about 7 to about 9 at a temperature of about 4° C. to about 20° C. for about 30 minutes to about 2 hours. The NHS compound may be used in a about 2 to about 50-fold molar excess to psychoactive compound, depending on concentration of amine. Concentration of
the NHS compound may vary from about 0.1 to about 10 mM. The amine can be from around 10 to about 100 pM, see, for example, US Pat. No. 5,846,951.
[00196] A modified psychoactive compound may be linked in stoichiometric amounts with a functional group, that is, one molecule of psychoactive compound may be linked to one molecule of a functional group compound. In embodiments, it may be beneficial that molar ratio be greater than 1, namely, with a relative greater amount to psychoactive compound or less than 1, namely, with a greater amount of functional group, which may drive a reaction to completion.
[00197] As mentioned herein, a psychoactive compound can be modified to carry a sugar. That joining can be obtained with a variety of known chemistries. As taught herein one way of derivatizing a sugar is by oxidation with sodium periodate which forms an aldehyde group at the non-reducing end of a sugar. The aldehyde group acts as a reducing agent. A Schiff base reaction then can occur with an amino group of a psychoactive compound.
[00198] As provided herein, a psychoactive compound may be functionalized by non-covalent association with a sugar. Hence, a sugar and a psychoactive compound may be linked via hydrophobic interactions, electrostatic interactions, ionic interactions and so on. For example, doxorubicin ionically interacts with carboxylate groups of polysaccharide B.
[00199] As will be readily appreciated, numerous variations and combinations of reaction between a conjugating reagent and a psychoactive compound of interest to form a functionalized psychoactive compound of the present invention will be apparent to and can be practiced by one of ordinary skill in the art.
[00200] In embodiments, reagents that serve as a potential functional group can be made reactive or activated to form an activated reagent, for example, forming an ionized species by reaction, practicing methods known in the art (or purchasing such a reagent).
[00201] If an activated functional group reagent is made, an activated conjugating reagent can be purified by conventional methods and then reacted with receptive psychoactive compounds, for example, containing a nucleophile group.
[00202] Functionalization of a nucleophile of interest can be obtained with a P-dicarbonyl compound, such as, a P-ketoester, under mild reaction conditions
of temperature and temperature, see, for example, US Pat. No. 5, 113,011. In embodiments, a psychoactive compound of interest can be modified by acetoacetylation.
[00203] Acetoacetylated materials can be prepared in a variety of ways. For example, an appropriate nucleophile can be treated with diketene. Alternatively, a nucleophilic psychoactive compound of interest can be subjected to a thermal reaction with 2,2,6-trimethyl-4H-l,3-dioxin-4-one (TKD, a diketene-acetone adduct). In embodiments, such a nucleophile can be subjected to transesterification with another acetoacetate moiety.
[00204] A functionalization reaction can be carried out under a wide variety of conditions as known in the art. For example, reaction can be carried out in presence or absence of solvent. When employed, suitable solvents include aromatic hydrocarbons (for example, toluene, xylene and the like); esters (for example, butyl acetate, ethyl amyl acetate, ethyl-3 -ethoxy propionate and the like); ketones (for example, methyl isobutyl ketone, methyl amyl ketone, methyl isoamyl ketone, ethyl butyl ketone and the like); as well as a solvent that azeotropes with t-butanol (for example, cyclohexane).
[00205] Conjugation can occur under a range of temperatures of about 80° up to about 200° C.
[00206] Reaction times can be in the range of about 0.5 hours up to about 24 hours. Those of skill in the art recognize that reaction time can vary as a function of variables, such as, for example, reaction temperature, desired degree of conversion, particular reactants employed and so on.
[00207] A psychoactive nucleophile can be reacted with an activated, electrophilic conjugating reagent in an aqueous reaction medium, which can be buffered, depending on pH requirements of a nucleophile. Organic nucleophiles can be reacted in an organic, non-aqueous medium. Determining optimum reaction conditions for nucleophile stability, reaction efficiency and so on is within level of ordinary skill in the art. Nucleophiles can be reacted with an excess of electrophilic conjugation reagent, which may be in an activated form. Following reaction, a derivatized psychoactive compound is recovered and purified, such as, by filtration, column chromatography and so on, or combinations thereof.
[00208] 2. Enzymic
[00209] Functionalization of a psychoactive compound, whether previously functionalized or not, can occur enzymatically. For example, a psychoactive compound may be converted to what should be a water soluble form by functionalization with a sugar.
[00210] A number of glycosyltransferases are known and are commercially available, as are suitable sugar donors, such as, nucleotide sugars. For example, one or more glycosyltransferases, such as, a uridine diphosphate (UDP)-glucuronosyltransferase (UGT), catalyze glucuronosylation or glucuronidation of a psychoactive compound. Glucuronidation may consist of transfer of a glucuronic acid component of uridine diphosphate glucuronic acid to a psychoactive compound substrate.
[00211] Conversion of a functionalized psychoactive compound can occur at a hydroxyl group of an originating, base psychoactive compound.
[00212] C. Functional group/conjugate reagent
[00213] Hydroxylation of a psychoactive compound may be used to prepare that compound for further derivatization, such as, glycosylation. Chemical hydroxylation reactions are known, as are hydroxylases which enzymatically hydroxylate a substrate.
[00214] Many psychoactive compounds of interest contain one or more reactive amine groups, which can serve as nucleophilic sites in a functionalization reaction.
[00215] For example, monoacylated and diacylated derivatives of rapamycin (esterified at the 28 and 43 positions, or depending on the numbering scheme, positions 31 and 42) have been shown to be useful as antifungal agents (US Pat. No. 4,316,885) and used to make water soluble prodrugs of rapamycin (US Pat. No. 4,650,803). US Pat. No. 5,100,883 discloses fluorinated esters of rapamycin. US Pat. No. 5,118,677 discloses amide esters of rapamycin. US Pat. No. 5,118,678 discloses carbamates of rapamycin. US Pat. No. 5,130, 307 discloses aminoesters of rapamycin. US Pat. No. 4,650,803 discloses aminoacyl esters of rapamycin. US Pat. No. 5,177,203 discloses sulfonates and sulfamates of rapamycin. US Pat. No. 5,194,447 discloses sulfonylcarbamates of rapamycin. PCT Publ. No. WO 92/05179
discloses carboxylic acid esters of rapamycin. Those references for functionalizing rapamycin provide a road map of the sort of functional groups that can be added to a psychoactive compound of interest.
[00216] 1. Vitamins
[00217] Glycation reactions can involve a vitamin. Glycation reactions can involve, for example, glucose, galactose, fucose, but other sugars can be used. Hence, an Amadori-type rearrangement reaction can be used; a Schiff base-type reaction can be used; a Maillard-type reaction can be used and so on, as a means to attach a sugar to a psychoactive compound. For example, an Amadori-type rearrangement reaction can occur, for example, with an amine of a psychoactive compound and an aldose sugar. A Maillard-type reaction can occur between a carbonyl group of a sugar reacting with a nucleophilic amine group of a psychoactive compound.
[00218] A Schiff base can be an amine that can be an intermediate when an amine of a psychoactive compound reacts with an aldehyde or a ketone of a sugar. Pyridoxal phosphate (vitamin B&) can form a Schiff base with an amine group. Vitamin A, such as Vitamin A aldehyde or retinal, can form a Schiff base with an amine group of a psychoactive compound.
[00219] a. B9 (folic acid)
[00220] Folic acid is a member of vitamin B group known as having various physiologic activities, which is transported into cells via endocytosis or potocytosis, mediated by a folic acid receptor present at the cell surface. Folic acid functional group can be bonded to a psychoactive compound for positive transport of the psychoactive compound into cells by the folic acid receptor, see, for example, US Pat. No. 7,585,973.
[00221] Folic acid can be conjugated with a psychoactive compound, for example, with a condensing agent such as, DCC. Products can be obtained as a-carboxylate and y-carboxylate mixtures (a-folic acid derivatives may not be recognized by the receptors.)
[00222] b. B7 (biotin)
[00223] Biotin (also known as vitamin H) is an essential growth factor found in animals, plants, fungi and bacteria. Biotin is found, for example, bound to
proteins or polypeptides in liver, pancreas, kidney, milk and in yeast. Biotin is a cofactor for a group of enzymes that catalyze carboxylation reactions, transcarboxylation reactions and decarboxylation reactions. The reactions catalyzed by biotin-dependent enzymes are involved in several essential metabolic pathways, including gluconeogenesis, fatty acid synthesis and amino acid catabolism.
[00224] The terms, "conjugate," “adduct,” “composite,” and, "complex," as used herein are interchangeable and are synonyms, and refer to a composite molecule comprising a psychoactive compound and a functional group, which may be a biotin compound, a biotin-binding compound, a complex of biotin (or a biotinylated moiety) with streptavidin (avidin), in which the biotin compound and biotin-binding compound are linked; and so on.
[00225] The terms, "biotin," or, "biotin compound," as used herein are interchangeable and refer to biotin (cis-hexahydro-2-oxo-lH-thieno[3,4]imidazole-4- pentanoic acid) and any biotin derivatives and analogs. Such compounds include, for example, biotin-s-N-lysine, biocytin (an amide of biotin and Lys) hydrazide, amino or sulfhydryl derivatives of 2-iminobiotin, biotinyl-s-aminocaproic acid-N- hydroxysuccinimide ester, sulfosuccinimideiminobiotin, biotinbromoacetylhydrazide, p-diazobenzoyl biocytin, 3-(N-maleimidopropionyl)biocytin and any covalent or non-covalent adduct of biotin with other moieties, see, for example, US Pat. No. 7,2
[00226] Functionalized psychoactive compounds of interest can be prepared by reacting a biotin with an amino group of a psychoactive compound in which the terminal carboxylic acid is protected with a suitable protecting group, such as, a t-butyl ester, in presence of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide (DAEC), hydroxybenzotriazole (HOBT) and N-methylmorpholine. The carboxylic acid protecting group then is removed under standard conditions, for example, for a t-butyl ester, exposure to trifluoacetic acid in methylene chloride, see, for example, US Pat. No. 5,504,091.
[00227] Maleimide chemistry can be used to conjugate a functional group-containing moiety to a psychoactive compound, see, for example, US Pat. No. 7,790,835. The maleimide reagent can be functionalized at the nitrogen to carry a variety of functional groups of varying size.
[00228] A psychoactive compound can react with a maleimide regent through, for example, a Diels- Alder reaction yielding an adduct as a maleimide precursor, the Diels- Alder adduct being covalently attached. A Diels-Alder adduct can refer to a cyclic structure that can undergo a reverse or retro Diels-Alder reaction that fractures the adduct into a maleimide group and a diene, which is released from the adduct. The Diels- Alder adduct is typically a structure formed by a cycloaddition reaction between a conjugated diene and a dienophile (i.e., a Diels-Alder reaction).
[00229] A psychoactive compound can include an active ester and thus undergo a nucleophilic substitution at a carbonyl group. Also, the nucleophilic nitrogen can serve as a Diels-Alder adduct reagent.
[00230] An amino group of an amine-bearing psychoactive compound can act as a nucleophilic component and an anhydride of an anhydride-bearing Diels- Alder adduct reagent can serve as an electrophilic component.
[00231] In embodiments, a maleimide electrophilic reagent can react with a nucleophilic sulfhydryl or thiol group of a psychoactive compound, for example, in a Michael-type reaction. As Michael acceptors, maleimides react with sulfhydryl groups to form stable thioether bonds. At approximately neutral pH, maleimides react preferably with sulfhydryl groups rather than amine groups (Smyth et al., Biochem. J., 91, 589, 1964; Gorin et al. Arch. Biochem. Biophys. 115, 593, 1966; Partis et al., J. Protein Chem, 2, 263-277, 1983). At higher pH, for example, values of 8 or above, maleimides react more readily with amine groups (Brewer & Riehm, Anal. Biochem. 18, 248, 1967).
2. Poly-His tag
[00232] A, "protein tag,” or “protein functional group," refers to an amino acid sequence that provides new characteristics when joined to a psychoactive compound, for example, to assist in purification, identification, activity, affinity and so on. A common protein tag used in purification is a poly-His tag where a series of about six to about nine histidine (His) residues are added to a base compound which enables a conjugate to bind to purification matrices chelated to metal ions, such as, nickel or cobalt, which is bound by the His tag. Other functional groups used as tags in purification schemes include Strep tag (about 8 amino acids which bind specifically avidin or streptavidin), chitin binding protein, maltose binding protein,
glutathione-S-transferase, FLAG-tag (a synthetic octapeptide bound by monoclonal antibodies (mAb’s); and so on. Tags such as, "epitope tags," confer a psychoactive compound with affinity to a cognate antibody. Common antibody epitope tags include, V5-tag, Myc-tag, HA-tag and so on, see, for example, US Pat. No. 9,951,108.
[00233] 3. Glycosylation
[00234] Glycosides may serve as prodrugs with a therapeutic effect. Glycoside prodrugs may improve bioavailability; may improve pharmacokinetics; may enable site-specific or tissue-specific PAI delivery; may yield sustained or delayed release forms; and so on. Glycosylation may enhance stability or survival in the acidic stomach environment. Glycosides have greater bulk and weight. Glycosides have different properties. A sugar moiety of a glycoside can be one member of a binding pair, for example, the other member of the binding pair may be an antibody or a lectin.
[00235] Glycosidases may enable specific delivery of a glycoside. By removal of a sugar functional group to yield an active psychoactive compound where a glycosidase resides. Glycosidases are present in the gut so liberation of a sugar from a glycosylated psychoactive compound to yield a biologically active psychoactive compound can occur in the gut. Glycosidases are present in different tissues so glycosides enable delivery by modes that bypass the digestive tract and colon. For example, intravenous administration may enable targeted delivery to other cells and tissues where a glycosidase is resident or is expressed. A psychoactive agent functionalized with other modifications can be manufactured to carry modified psychoactive compounds to targets sites in the body for directed delivery.
[00236] Glucose residues of glycosides commonly are acid-hydrolyzed in the stomach or are cleaved by a glycosidase, for example, in the intestinal tract, including by a-glycosidases and P-glycosidases, which are expressed by intestinal microflora across different regions of the intestine. Accordingly, ingested glycosides are hydrolyzed to release the aglycone, the psychoactive compound, in the intestines.
[00237] On parenteral administration of a glycoside prodrug to a subject, the aglycone is liberated by a glycosidase at, near or in a target tissue.
[00238] Glycosides can enhance purification. A conjugate or derivative can have different physical properties, which can be exploited, for example, by chromatography, precipitation and so on. A conjugate is heavier, which may be
exploited for separation. A sugar moiety can be a target for purification. For example, an entity that binds a sugar, such as, a lectin, can be used for affinity separation.
[00239] Conjugation or functionalization of a psychoactive compound using a sugar as the functional group can occur by use of a variety of chemical reactions. Chemical adding of a carbohydrate to a psychoactive compound can be known as glycation.
[00240] In embodiments, a method of producing a psychoactive agent glycoside comprises incubating an aglycone with one or more sugar donors in presence of a glycosyltransferase under conditions that allow for glycosylation.
[00241] Glycosyltransferases are common in plants (Srivatava et al., JBC 297(3)101045, 2021; Lim & Bowles, EMBO J 23:2915-2922, 2004; Hansen et al., Front Plant Sci 3:59, 2012; and Ross et al., Genome Biol 2(2):reviews, 3004.1-3006.6, 2001), animals and microbes (Breton et al., Glycobiol 16:29R-37R, 2006; and Yakovliev & Walvoort, ACS Chem Biol 15:3-16, 2020), and enzymes are available commercially. Some enzymes are specific as to substrate and sugar donor, other are less specific, less discriminate or are degenerate by acting on more than one substrate or can utilize more than type of sugar donor, for example, where the vehicle for carrying the sugar can vary or the enzyme can accept and join different sugars.
[00242] Abundance of glycosyltransferases, and commercial availability thereof, enable one to identify an enzyme to glycosylate a base compound of interest, such as, a psychoactive compound, for any of a variety of reasons, including those disclosed herein.
[00243] For example, River Stone Biotech (Copenhagen, DK) provides glycosyltransferase libraries for screening (Gly-Kit). Different enzymes are isolated in wells of a microtiter plate; a sugar donor, such as, UDP-glucose, is added in a reaction mixture to a well containing a psychoactive compound., The plate is incubated and then the reaction mixtures are assessed for glycosylation, for example, by HPLC or other screening assay. Reaction conditions may need to be altered, such as, reagent amount, sugar donor, reaction conditions and so on, to obtain glycosylation. Once suitable enzyme or enzymes are identified, reaction conditions can be optimized and scaled.
[00244] c. Donor/ Adduct Reagent
[00245] 1. Glucose
[00246] In embodiments, a sugar donor can be a nucleotide sugar, such as, UDP-glucose, UDP-glucuronic acid, UDP-mannose, UDP-fructose, UDP -xylose, UDP -rhamnose, UDP-fluoro-deoxyglucose, combinations thereof; and so on.
[00247] ii. Mannose
[00248] Mannose can be joined to a hydroxyl group of a psychoactive compound. Mannosyl transferase with an appropriate sugar donor can be used to join a mannose residue to a psychoactive compound. Mannose is a reducing sugar that can be reacted with an amine as taught herein.
[00249] iii. Fucose
[00250] Fucose can be joined to a hydroxyl group of a psychoactive compound. Fucosyl transferase with an appropriate sugar donor, such as, GDP-fucose, can be used to join a fucose residue to a psychoactive compound.
[00251] 4. Protein A
[00252] Protein A binds to a site on the heavy chain Fc portion of immunoglobulins, primarily IgG. Protein G binds to both the Fab and Fc portions of immunoglobulins. Protein L binds light chain of immunoglobulins (Ig).
[00253] Those immunoglobulin-binding proteins, or Ig-binding portions thereof, can be used as one member of a binding pair, for example, in affinity chromatography to isolate a psychoactive compound.
[00254] 5. Halogen
[00255] Fluorine substituted cannabinoids were created through synthetic chemical reaction, see, for example, WO2014108899. That reference provides a roadmap for fluorinating a psychoactive compound.
[00256] D. Linkers
[00257] The term, "linker moiety," “linking molecule,” “linker,” “bridge,” “bridging molecule,” synonyms thereof, as well as grammatic forms thereof, refers to a molecule that joins two or more other molecules together. A linker can contain two different reactive or functional groups to provide directional reactivity with the two or more other molecules. Hence, a linker moiety can comprise at least one ester or amide linkage, and other linker moi eties include ethers, thioethers, thioamides, thioesters, amines and so on, US Pat. No. 9,968,683.
[00258] A linker moiety may include atoms, such as, carbon, hydrogen, oxygen and/or nitrogen, US Pat. No. 10,188,719. A linker can overcome poor reactivity of a psychoactive compound by introducing a reactive functional group, can provide distance, for example, minimizing steric hindrance or interference, or minimizing reactivity of an introduced functional group with the psychoactive compound and so on, between a functional group and the psychoactive compound and so on.
[00259] For example, conjugation of a saccharide or a polysaccharide and a psychoactive compound can occur by coupling a sugar to a linker to form a sugar-linker intermediate (or an activated sugar) in which a free terminus of the linker bears a functional group, such as, an ester group; and then reacting the intermediate, for example, the ester group, with, for example, a primary amine group in the psychoactive compound to form a sugar-linker-psychoactive compound conjugate (a functionalized psychoactive compound) in which the linker is coupled to the psychoactive compound via an amide linkage.
[00260] In embodiments, a sugar can be coupled to the linker using a primary amine group in an amino sugar, or an amine group introduced into a sugar. Hence, a linker that can be used has an ester group at both termini.
[00261] Such a linker can be homobifunctional where the two termini are chemically the same. The ester groups can be separated by an intermediate portion of the linker that can be of varying length and complexity. Hence, in the case of a linear stretch between the ester termini, the intermediate portion can comprise a straight chain alkyl with 1 to more than 10 carbon atoms. A terminal group can be N- oxysuccinimide. An intermediate portion can comprise a four carbon chain, such as, adipic acid N-hydroxysuccinimide diester.
[00262] The first coupling with one of the ester groups with the primary amine group of the sugar occurs by nucleophilic acyl substitution.
[00263] In embodiments, an additional linker can be used to derivatize the sugar prior to joining to the linker. Hence, a sugar can be coupled to the additional linker, for example, at a carbonyl group at the reducing terminus of the sugar or polysaccharide. Hence, the additional linker can have a primary amine group at both termini, thereby allowing one of the primary amine groups to react with the carbonyl
group in the sugar or polysaccharide by reductive amination. For example, a hydrazide or a hydroxylamino group can be used in the additional linker. The same primary amine group can be present at both termini of the additional linker. The reaction results in a sugar/polysaccharide-additional linker intermediate via a C— N linkage.
[00264] In embodiments, the additional linker can be coupled to a carboxyl group. An additional linker can have a primary amine group at both termini, thereby allowing coupling of the additional linker to the carboxyl group of the sugar or polysaccharide by carbodiimide activation. A primary amine group can be one that is reactive with a carbodiimide-activated carboxyl group in the sugar or polysaccharide. A hydrazide group can be used. The same primary amine group can be present at both termini of the additional linker. The result is a sugar/polysaccharide-additional linker intermediate in which the sugar/polysaccharide is coupled to the additional linker via an amide linkage.
[00265] The free terminus of the additional linker can be a primary amine group and reacted with a linker as described herein or as known in the art. The additional linker can be coupled to the linker via an amide linkage. Hence, the additional linker is a bifunctional linker that provides a first primary amine group for reacting with the carbonyl (or carboxyl) group in the sugar/polysaccharide and a second primary amine group for reacting with one of the ester groups in the linker. A suitable terminal group of the additional linker is an --NHNH2 group with an intermediate portion as described above. Thus, a suitable additional linker can be adipic acid dihydrazide.
[00266] Then, the ester group at the free terminus of the linker in the sugar/polysaccharide-linker intermediate is reacted with a primary amine group in the psychoactive compound. That can occur by nucleophilic acyl substitution to form a sugar/polysaccharide-linker-carrier molecule conjugate in which the linker is coupled to the carrier molecule via an amide linkage.
[00267] After conjugation, free and conjugated sugar/polysaccharide can be separated, for example, by hydrophobic interaction chromatography, tangential flow filtration, size exclusion chromatography, countercurrent chromatography and other known separation methods.
[00268] Carrying a sugar, the conjugate generally is soluble in water and/or in an aqueous or physiologic buffer.
[00269] In embodiments, coupling can occur by reductive amination of a carbonyl group at the reducing terminus of a polysaccharide. The conjugation can involve a suitably functionalized additional linker as provided herein.
[00270] Reductive amination is known and can be achieved by combining the sugar/polysaccharide with the primary amine group in the presence of a reducing agent (for example, cyanoborohydrides, such as, sodium cyanoborohydride; borane-pyridine; sodium triacetoxyborohydride; borohydride exchange resin; and so on) see, for example, US Pat. No. 9,358,284.
[00271] A suitable sugar for conjugation has a reducing terminus, which can be activated. Methods are known for random activation of a polysaccharide chain (for example, with cyanogen bromide (CNBr) or l-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP)) prior to conjugation with a linker or a psychoactive compound (Watson et al., Infect Imm 60(11)4679-4686, 1992; Konadu et al., Infect Imm 7:2709-2715, 1996.) Other methods are more selective, involving a specific residue on the chain (for example, a 2-keto-3-deoxyoctanoic acid (KDO) residue, found, for example, in certain bacterial saccharides) (Chu et al., Infect Imm 59(12)4450-4458, 1991; Taylor et al., Infect Imm 61(9)3678-3687, 1993).
[00272] Hence, a sugar can comprise a reducing end. That reducing end can be a KDO subunit, which comprises a carbonyl group. The carbonyl group can be used for coupling the sugar to the linker or the carbonyl group takes part in the reductive amination process. Other sugars that comprise a carbonyl group at the reducing termini can be used. The KDO subunit also comprises a carboxyl group that can be reacted as taught herein or as known in the art.
[00273] IV. Purification
[00274] After synthesis (or purchased), a functionalized group reagent can be purified by conventional methods and reacted with a psychoactive compound, for example, containing a nucleophilic site capable of bonding with an electrophilic functional group reagent os using an enzyme and sugar donor, while maintaining at least some activity associated with the unmodified psychoactive compound.
[00275] A modified psychoactive compound may be isolated and purified by, for example, affinity chromatography; applied to various commercial schemes and reagents; and so on. A modified compound may be restored and reconstituted by, for example, an enzymic reaction, such as, using a glycosidase or an esterase, or a chemical reaction.
[00276] A psychoactive compound with a pharmacologic activity can be described as, "biologically active." The term, however, is not limited to physiologic or pharmacologic activities as a psychoactive compound can be used, for example, for recreational purposes. A modified psychoactive compound may or may not be biologically active. A key feature of conjugates or modified psychoactive compounds is that at least some portion of activity associated with the unmodified psychoactive compound is maintained or can be restored when the modification is removed.
[00277] A. Chromatography
[00278] Chromatography, no matter the mode, such as, paper, solid phase, column, batch, affinity liquid-liquid, countercurrent and so on, can be used for separation of molecules.
[00279] Affinity chromatography can be used for purification. Affinity chromatography relies on a binding pair reaction, for example, a lectin and a cognate carbohydrate; an antibody and a cognate antigen, epitope or determinant; a factor and a cofactor; an enzyme and a substrate; and so on. For example, one member of a binding pair is immobilized or coupled to a solid phase or support. That derivatized phase or support is exposed to a mixture that contains a functionalized psychoactive compound carrying the other of the binding pair (which may be the functional group). The functionalized psychoactive compound binds to and is immobilized on the functionalized solid phase or support. Non-binding elements and non-specific binding elements present with the derivatized psychoactive compound are separated and removed in the mobile phase. The bound modified psychoactive may be eluted or displaced from the solid phase or support by, for example, a competing member of the binding pair, altering the environment, such as, changing the pH; and so on to displace or to disrupt the binding pair bond.
[00280] In biotechnology, biotin has found use to label, to detect and to purify target molecules. The uses are based on affinity between biotin and the
proteins, avidin and streptavidin. The dissociation constant of biotin and avidin or streptavidin is about 10'15 M, one of the strongest known interactions between a protein and a ligand. While all parts of the biotin molecule contribute to that tight binding, hydrogen bonding donation by the ureido nitrogens is considered a major contributor.
[00281] Countercurrent chromatography is a cost effective, gentle, discriminating method for separating molecular species. The process is continuous. The process does not require costly solid phase or regeneration of solid phase. The separation is gentle without the need for harsh reagents. The method can be used, for example, to separate carbon nanotubes, mAb, nucleic acids, see, for example, US Pat. Nos. 9,713,778 and 8,597,509; viruses, see for example, US Pat. No. 10,851,349; and cannabinoids, see, for example, WO 2020/180759.
[00282] 1. Ligand
[00283] Entities that can be affixed or immobilized on or to a solid phase, such as, a paper, a resin, such as, a bead, a plastic, such as, a surface of a well, and so on, include, a lectin, a chelated metal ion, avidin/streptavidin, one member of a binding pair and so on. Once a modified psychoactive compound is bound to a derivatized solid phase by an affinity interaction, the functionalized psychoactive compound is separated from other reagents, compounds and medium. The functionalized then can be recovered by dissociating the bound psychoactive compound from the support, for example, by altering the binding environment, such as, changing a salt concentration, changing pH, exposure to a detergent, surfactant, amphiphile and so on. Those methods of desorption are known. However, the high binding affinity of biotin and streptavidin commands different methods.
[00284] US Pat. No. 7,279,285 teaches a method for dissociating biotin from avidin. The exact mode of action of the aqueous solution on biotin dissociation from avidin/streptavidin is not known. However, without wishing to be bound by theory, it is believed that the mechanism behind the reversible dissociation is due to a conformational change in the biotin-binding compound that results in release of the bound biotin. That theory is supported by the observation that dissociation between the biotin-binding compound and biotin is completely reversed when salt is added.
[00285] Release, disruption or dissociation of biotin and avidin/ streptavidin is effected by incubation in a substantially aqueous solution, such as, purified or distilled water. Purified water is obtained or obtainable by passing water, such as, distilled water, through an appropriate ion-exchange matrix or system, for example an appropriate Milli-Q matrix or system, which is commercially available (Millipore Sigma, MA) and standard in the art. Distilled water is passed through a Milli-Q system using a Millipore Purification Pak, QPAK1. The resulting water is generally at approximately 18.2 MQ. Such methods of purifying water and equivalent methods are known and standard in the art. Such purified water also is sometimes referred to as Milli-Q water.
[00286] Incubation times may vary depending on temperature used and may readily be determined by those skilled in the art for any given temperature condition. Incubation times can range up to about 10 minutes, up to about 5 minutes, up to about 2 minutes, up to about 1 minute.
[00287] Incubation can occur at a temperature in the range of from about 20 to about 95° C., from about 50 to about 90° C., from about 60 to about 90° C. from about 70 to about 90° C. Incubation can be at a temperature of about 80° C. Incubation can be conducted with a gradual or stepped increase in temperature from ambient to the desired temperature at which incubation is to take place. For example, temperature may be stepped by +1° C. every 2 seconds.
[00288] Reagents can be stored and reactions conducted in aqueous solutions. Solutions generally have a low content of dissolved solids (for example, Mg2+, Ca2+, Na+, Li+, monovalent and divalent ions in general, chlorides, sulfates and so on). The solutions can be purified using conventional purification techniques, such as, distillation or ion-exchange, and will be substantially free from chemical impurities. The aqueous solution can be substantially free of ammonia or an amine.
[00289] The aqueous solution can be substantially free of any monovalent and divalent salts, for example, sodium chloride, lithium chloride and magnesium chloride.
[00290] pH can be in the range from about 5 to about 7.
[00291 ] Chelating agents, such as, ethylene diamine tetraacetic acid (EDTA), in the incubating solution can decrease efficiency of complex dissociation.
[00292] A biotin conjugate can be disrupted under relatively mild conditions such that the structure of both the biotin compound and the biotin-binding compound remain intact. Appropriate reaction conditions are selected in which both components of the conjugate are stable, see, for example, US Pat. No. 7,279,285.
[00293] 2. Batch or column
[00294] As provided herein, and as known in the art, chromatography can be practiced to separate, to separate, to purify and so on, a modified psychoactive compound of interest. Chromatography can be practiced in a variety of format, such as, paper, countercurrent centrifugation, column, batch and so on. Chromatography capitalizes on physical differences of a target compound, such as, size, shape, charge, specific binding and so on for separation.
[00295] B. Filtration
[00296] Filtration enables separation of molecules differing in, for example, mass, shape and so on. One format employs cross-linked polymer gels, such as, dextran, polyacrylamide, for example, which can be in the shape of beads. The degree of cross linking can provide a sieving action. In embodiments, a cross-linked gel can be provided in the form of a slab. Molecules can be sieved and separated with a mobile phase under the influence of gravity, an applied electric current or field, and so on.
[00297] 1. Differential precipitation
[00298] Differential precipitation is a means for separation that depends on altering the solvation potential of a solvent, lowering solubility of a solute by addition of a reagent, such as, ammonium sulfate. Trichloroacetic acid (TCA) also can be used when TCA disrupts hydrogen-bonded water molecules.
[00299] 2. Recrystallization
[00300] Recrystallization is s known method for purifying a compound. Impurities and a modified psychoactive compound of interest are dissolved in a solvent in which with impurities or compound of interest dissolve leaving the other behind. Alternatively, both species may dissolve in solvent at an elevated temperature and on cooling to allow the compound of interest to crystallize. Crystallization may be benefited by seeding. The crystals can be isolated by filtration with disposal of the solvent.
[00301] V. Precursor/Prodrug
[00302] The term, "prodrug," refers to a precursor of a biologically active psychoactive compound (drug) where the psychoactive compound is functionalized. Prodrugs undergo chemical or metabolic conversion or reaction to become the biologically active pharmaceutic agent. A prodrug can be converted ex vivo to the biologically active pharmaceutic agent by a transformative process. In vivo, a prodrug generally is converted to the biologically active pharmaceutic agent by action of a metabolic process; an enzymatic process; a degradative process; a particular environment; and so on that removes the prodrug moiety (the functional group) to form the biologically active, base psychoactive compound.
[00303] VI. Pharmaceutics
[00304] As used herein the term, "composition," or "pharmaceutic composition," refers to combination of an API and other inert ingredients in any physical form including, but not limited to, a mixture, a complex or the like, which renders the composition suitable for ingestion, administration or instillation.
[00305] The term, "active pharmacologic ingredient," or, "API," as used herein is intended to refer to any compound capable of inducing a biologic, physiologic or pharmacologic response (for example, a sopoforic effect, a hypnotic effect and so on) in a warm-blooded animal, including, human. Synonyms include, “pharmaceutically active agent,” drug, “pharmacologically active agent,” “lead compound,” and so on.
[00306] When dealing with psychoactive compounds, there can be a need to develop forms that cannot be or are not abused or diverted. Hence, an API can be delivered to a patient for prescribed medical use, but is diversion-resistant and/or abuse-resistant to, at least, deter illicit use of the API. For example, see US Pat. No. 9,649,282, herein incorporated by reference in entirety, which teaches a pharmaceutic composition containing an API and an additive, which prevents effective separation of the API by conventional separation techniques and/or prevents the administration of the API for a non-therapeutic or non-medical effect.
[00307] Compositions may be formulated in whole or in part as pharmaceutic compositions, whether prophylactic or therapeutic Pharmaceutic compositions include two or more components. For example, a pharmaceutic
composition may include two or more compositions including two or more different therapeutic and/or prophylactic modified psychoactive compounds. Pharmaceutic compositions may include one or more pharmaceutically acceptable excipients or accessory ingredients, such as, those known or described herein. General guidelines for formulation and manufacture of pharmaceutic compositions and agents are available and are known. Conventional excipients and accessory ingredients may be used in a pharmaceutic composition, except insofar as any conventional excipient or accessory ingredient may be incompatible with one or more components and/or functions of a modified psychoactive compound composition of interest.
[00308] In embodiments, one or more accessory ingredients may make up greater than about 50% of total mass or volume of a pharmaceutic composition. For example, one or more accessory ingredients may comprise up to about 50%, about 60%, about 70%, about 80%, about 90% or more of a pharmaceutic composition.
[00309] In embodiments, a, “pharmaceutically acceptable,” ingredient is at least about 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% pure. In embodiments, a, “pharmaceutically acceptable accessory ingredient,” is approved for use in human and perhaps also for veterinary use. In embodiments, a pharmaceutically accessory ingredient is approved by the United States Food and Drug Administration (FDA). A pharmaceutically acceptable ingredient or entity may be generally regarded as safe (GRAS).
[00310] An, “accessory ingredient,” is a compound that can be included in a pharmaceutic composition as an additive for a particular purpose, such as, a buffer, a flavorant, a glidant and so on. An accessory ingredient can be a diluent, an excipient or a carrier. An accessory ingredient generally does not have a biologic activity or a biologic activity of a psychoactive compound.
[00311] A pharmaceutic composition of interest includes one or more modified psychoactive compounds of interest and pharmaceutically acceptable excipients, diluents and/or carriers.
[00312] A pharmaceutic composition of the instant disclosure is formulated to be compatible with an intended route of administration. Examples of routes of administration include subcutaneous, oral, inhalable, intramuscular, subcutaneous, nasal, buccal, vaginal, transmucosal, rectal and so on.
[00313] The term, "systemic administration," refers to administration of a therapeutically effective or pharmacologically effective (synonymous terms) agent for distribution in much of the body of an individual in effective amounts and develops a biologic or pharmacologic effect. For example, an agent may develop a desired effect by delivery in blood and/or reaches a desired site of action via the vascular or circulatory system. Typical systemic routes of administration include administration into the vascular or circulatory system, or oral, pulmonary or intramuscular administration wherein an agent is adsorbed, enters the vascular or circulatory system and is carried to one or more desired site(s) of action in a body via blood or lymph and the circulatory system.
[00314] A pharmaceutic composition is generally applied in a, "pharmaceutically effective amount," “pharmacologically,” “biologically,” or, " pharmaceutically effective amount," are considered synonyms herein and are used equivalently herein, refers to non-toxicity of a material which does not interact with function or action of a psychoactive compound component of a pharmaceutic composition and comprises various additives with generally no adverse impact on or in a recipient. In context of the US and EU, an entity that is pharmaceutically acceptable is one approved for use in food or drug preparations by the FDA and European Medicines Agency (EMA), respectively.
[00315] A pharmaceutically effective amount is one that yields a desired biologic endpoint or effect of a psychoactive compound of interest.
[00316] In embodiments, a composition can comprises one or more detergents (for example, Tween 20, Tween 80, Pluronic F68, bile acid salts and so on), protease inhibitors, surfactants (for example, sodium lauryl sulfate and so on), permeation enhancers, solubilizing agents (for example, glycerol, polyethylene glycerol and so on), stabilizers (for example, hydroxypropyl cellulose, hyroxypropylm ethyl cellulose and so on), viscosity increasing agents (for example, carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum and so on), sweeteners (for example, aspartame, citric acid and so on), flow aids (for example, colloidal silicon dioxide and so on), plasticizers (for example, diethyl phthalate, triethyl citrate and so on), emulsifiers (for example, carbomer, hydroxypropyl cellulose, sodium lauryl sulfate and so on), polymer coatings (for example, poloxamers, poloxamines
and so on), coating and fdm forming agents (for example, ethyl cellulose, acrylates, polymethacrylates and so on) and so on.
[00317] A pharmaceutic composition of interest may contain salts, buffers, preserving agents, carriers, optionally, other therapeutic agents, and so on. A pharmaceutic composition of the instant invention can comprise one or more pharmaceutically acceptable carriers, diluents, excipients and so on.
[00318] The term, "excipient," can indicate substances, such as, binders, lubricants, thickeners, surface active agents, preservatives, emulsifiers, buffers, flavoring agents, colorants and so on.
[00319] The term, "diluent," relates to a diluting, a thinning agent and so on. Diluent includes any one or more of fluid, liquid or solid, a mixing medium and so on. Examples of suitable diluents include ethanol, glycerol, water and so on.
[00320] Other examples of diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar and so on, and/or combinations thereof in solid or liquid form, such as, dissolved or suspended in a fluid, such as, a saline, a buffer, a water and so on.
[00321] The term, "carrier," relates to one or more compatible solid or liquid fdlers or diluents, which are suitable for administration to a human. Carrier relates to a natural or synthetic organic or inorganic component that is combined with an active component to facilitate application or administration of the active component. Carriers can be sterile liquids, such as, a water, an oil, including those which are derived from mineral oil, animals or plants, such as, peanut oil, soy bean oil, sesame oil, sunflower oil and so on; and other natural or synthetic transporting materials. Salt solutions and aqueous dextrose and glycerin solutions also may be used as aqueous carriers. Other examples of suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like, in solid or liquid form, for example, suspended or dissolved in an aqueous, organic or oleaginous fluid.
[00322] Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are known in the pharmaceutic art, and are described in, for example, Remington's Pharmaceutical Sciences.
[00323] Antibacterial agents include benzyl alcohol, a paraben, chlorobutanol, phenol, ascorbic acid and the like. Examples of antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol and so on. Examples of antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid and so on. Examples of alcohol preservatives include ethanol, polyethylene glycol, a phenolic compound, bisphenol, hydroxybenzoate, phenylethyl alcohol and so on. Examples of acidic preservatives include vitamin A, vitamin E, [3-carotene, citric acid, acetic acid, dehydroascorbic acid, sorbic acid, phytic acid and so on. Other preservatives include tocopherol, tocopherol acetate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite and so on.
[00324] Antioxidants, such as, ascorbic acid, sodium bisulfite, sodium metabisulfite, butylated hydroxyanisole and so on, can be included. Examples of antioxidants include a-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium sulfite and so on.
[00325] Granulating and dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, a clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, a wood product, natural sponge, a cation exchange resin, calcium carbonate, a silicate, sodium carbonate, polyvinyl pyrrolidone (PVP) (which may be crosslinked), sodium carboxymethyl starch, carboxymethyl cellulose, methyl cellulose, microcrystalline starch, water insoluble starch, calcium
carboxymethyl cellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds and so on, and combinations thereof.
[00326] Examples of suitable binders include starch, gelatin, a natural sugar, such as, glucose and so on; anhydrous lactose, |3-lactose, a com sweetener, a natural gum, a synthetic gum, such as, acacia, tragacanth, sodium alginate and so on; carboxymethyl cellulose, polyethylene glycol, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, PVP and so on.
[00327] Disintegrants include cornstarch, potato starch, alginic acid, silicon dioxide, guar gum and so on.
[00328] Surface active agents and/or emulsifiers include a natural emulsifier (for example, acacia, agar, alginic acid, sodium alginate, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, lecithin and so on), a colloidal clay (for example, bentonite [aluminum silicate], magnesium aluminum silicate and so on), a long chain amino acid derivative, a sorbitan fatty acid ester, a sucrose fatty acid ester, a polyethylene glycol fatty acid ester, a polyoxyethylene ether, PVP, diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium and so on, and combinations thereof.
[00329] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, a hydrogenated vegetable oil, polyethylene glycol (PEG) and so on, and combinations thereof.
[00330] Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, tartaric acid and so on.
[00331] Buffers include acetates, citrates, phosphates; an aminoethane buffer, a Good buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, gluconic acid, calcium glycerophosphate, calcium lactate, calcium lactobionate, propanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, dibasic potassium phosphate, monobasic
potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, an aminosulfonate buffer, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and so on, and combinations thereof, including solutions of any of the above.
[00332] In embodiments, a pharmaceutic composition of the disclosure has a pH value between about 7 and 8 (for example, 6.8 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0, between 7.5 and 8 or between 7 and 7.8).
[00333] Isotonicfiers and agents for adjustment of tonicity, such as, sodium chloride; dextrose; a sugar; a polyalcohol, such as, mannitol, sorbitol and so on; and the like, can be included in the composition.
[00334] The pH can be adjusted with an acid or a base, such as, HC1, NaOH and so on.
[00335] Controlled or delayed release can be brought about by including in a composition, an agent that delays absorption, for example, a coating of aluminum monostearate, a gelatin and so on.
[00336] In embodiments, amodified psychoactive compound is prepared with carriers that protect a compound against rapid elimination from a body, such as, inclusion in implants, depots and so on. Biodegradable, biocompatible polymers can be used, such as, ethylene vinyl acetate, a polyanhydride, polyglycolic acid, collagen, a polyorthoester, polylactic acid and so on.
[00337] Liquid dosage forms for oral and parenteral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and so on. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art, such as, water, other solvents and so on; solubilizing agents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as, cottonseed, groundnut, corn, germ, olive, castor oil, sesame oil and so on), glycerol, tetrahydrofurfuryl alcohol, a polyethylene glycol, a fatty acid ester of sorbitan and so on; and mixtures thereof.
[00338] Oral compositions can include additional agents, such as, wetting agents, emulsifying and suspending agents, sweeteners, flavorants, odorants and so on.
[00339] In embodiments for parenteral administration, compositions can be mixed with solubilizing agents, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and so on; and combinations thereof.
[00340] Oral compositions generally include an inert diluent, flavorant, odorant, an edible carrier and so on. A composition can be enclosed in gelatin capsules or compressed into tablets or troches.
[00341] The term, "parenteral administration," refers to administration of a therapeutically effective amount of a modified psychoactive compound such that the active ingredient does not pass the intestine. Parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration and so on.
[00342] Solutions or suspensions used for parenteral, such as, intramuscular application, can include a sterile diluent, such as, water for injection, a saline, an oil, a polyethylene glycol, ethanol, glycerine, a polyol, such as, propylene glycol and so on; other solvent and so on. A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic as an article of manufacture.
[00343] A composition generally is sterile and is fluid to the extent that syringability or delivery success exists. Proper fluidity can be maintained, for example, by use of a coating, such as, a lecithin and so on; by maintenance of required particle size in the case of a dispersion, use of a thickener and so on; by use of surfactants and so on.
[00344] Sterile injectable solutions can be prepared by incorporating a modified psychoactive compound in a required amount of an appropriate solvent with one or a combination of accessory ingredients enumerated herein, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating a modified psychoactive compound in a sterile vehicle that contains a basic dispersion medium and required other ingredients, as known in the art.
[00345] In the case of a sterile powder for preparation of a sterile injectable solution, a solution of a modified psychoactive compound can he treated by, for example, lyophilization, vacuum drying, freeze drying and so on, to yield a dry powder of finely divided modified psychoactive compound plus any additional accessory ingredients from the previously sterile-filtered solution. A preparation of interest can be stored and reconstituted with a suitable liquid for use.
[00346] An injectable formulation can be sterilized, for example, by filtration through a filter and/or by incorporating sterilizing agents in the form of sterile, solid compositions that are dissolved or dispersed in sterile water or other sterile injectable medium, such as, a water, a buffer, a salt solution and so on prior to use.
[00347] Tablets, pills, troches and the like can contain a binder, such as, microcrystalline cellulose, gum tragacanth, gelatin and so on; an excipient, such as, starch, lactose and so on; a disintegrating agent, such as, alginic acid, com starch and so on; a lubricant, such as, magnesium stearate and so on; a glidant, such as, colloidal silicon dioxide and so on; a sweetening agent, such as, sucrose, saccharin and so on; a flavoring agent, such as, peppermint, methyl salicylate, a flavoring; and so on.
[00348] Oral compositions also can be prepared using a fluid carrier to yield a syrup or liquid formulation for injection, or for use as a mouthwash, wherein a solution comprising a modified psychoactive compound in a fluid carrier is applied orally, swished and expectorated or swallowed.
[00349] A pharmaceutic composition may be suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may include, for example, 0.1% to 20% (wt/wt) active ingredient and so on, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the accessory ingredients described herein. Alternatively, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any accessory ingredients described herein.
[00350] A buccal preparation can include a flavorant, an odorant and so on.
[00351] For administration by inhalation, a compound can be delivered in the form of, for example, a wet or dry aerosol spray, for example, from a pressurized container or dispenser that can contain a suitable propellant, for example, a gas, such as, carbon dioxide and so on; a nebulizer; a mister; and so on, see, for example, US Pat. No. 6,595,202, the content of which is incorporated by reference herein in entirety.
[00352] In general, inhalation is meant to encompass delivery of a substance to blood via a respiratory system, such as, lungs and so on; wherein delivery takes place across a respiratory tract, such as, pulmonary epithelium and so on. Inhalation can be via mouth, nose or intratracheal. Absorption can occur in any part of a respiratory system, including, mouth, throat and so on.
[00353] A variety of aerosolization systems have been proposed to disperse pharmaceutic formulations. For example, US Pat. Nos. 5,785,049 and 5,740,794 (the disclosure of each of which herein is incorporated by reference in entirety) describe powder dispersion devices that utilize a compressed gas to aerosolize a powder.
[00354] Other types of aerosolization systems include those that have a drug stored in a propellant; nebulizers that aerosolize liquids using a compressed gas and the like.
[00355] Pharmaceutic compositions formulated for pulmonary delivery may provide a modified psychoactive compound ingredient in the form of droplets of a solution and/or a suspension. Such formulations may be an aqueous and/or a dilute alcoholic solution and/or a suspension, optionally sterile, comprising a modified psychoactive compound composition, and may be administered using any nebulization and/or atomization device. Such formulations may comprise one or more accessory ingredients including a flavoring agent, such as, saccharin sodium and so on; a volatile oil, a buffering agent, a surface active agent; a preservative, such as, methylhydroxybenzoate and so on; and the like. Droplets provided by that route of administration may have an average diameter in the range from about 1 nm to about 200 nm.
[00356] A liquid inhaler may deliver about 50 pl/puff (at 20 mg/ml). Generally, about 65% of an inhaled composition arrives at lungs, which, at the above concentration, can be about 650 pg. A dry inhaler may deliver up to 25-30 mg/puff. Generally, about 50% of an inhaled composition gets to lungs, which can be about 15 mg.
[00357] Formulations described herein as useful for pulmonary delivery also may be used for intranasal delivery.
[00358] A formulation for intranasal administration may be a coarse powder comprising active ingredients and having an average particle size of from about 0.2 pm to about 500 pm. Such a formulation may be administered in a manner in which snuff is taken, that is, by rapid inhalation through a nasal passage from a container of powder held close to a nostril.
[00359] Formulations suitable for nasal administration, including a nasal spray and so on, may, for example, comprise from about as little as about 0.1% (wt/wt) to as much as about 100% (wt/wt) of active ingredient and so on, and may comprise one or more of additional ingredients described herein. A fine mist is generated by a handheld device and a user inhales by nose as a spray is generated.
[00360] A pharmaceutic composition may be prepared for ophthalmic administration. Such a formulation may, for example, be in a form of eye drops including, for example, an about 0.1/1.0% (wt/wt) solution and/or suspension of active ingredient and so on in an aqueous or oily liquid excipient. Such drops may comprise buffering agents, salts, one or more other accessory ingredients and so on, as described herein or as known in the art.
[00361] Other ophthalmically-administrable formulations that are useful include those that comprise active ingredient in microcrystalline form and/or in an ointment.
[00362] For mucosal exposure, for example, in a digestive or reproductive tract, such as, rectum, vagina and so on, for example, a modified psychoactive compound of interest can be delivered as a suppository, a foam, a fluid, such as, an enema and so on; and the like.
[00363] A liquid can be prepared as described herein for other liquid formulations. A liquid can be applied rectally using a reservoir, and a liquid carrying a
modified psychoactive compound of interest can be retained or discharged after a certain period.
[00364] A foam may be used for delivery. A foam can contain water and/or an oleaginous base, a polymer, a surfactant, a gelling agent, a foam stabilizing agent and so on, along with, when used with a canister for foam production, a liquid or compressed gas propellant, see, for example, US Pat. Nos. 6,818,204 and 9,539,208. A modified psychoactive compound is mixed with liquid ingredients, mixed with propellant and encased in a pressurized container. Alternatively, a foam may be produced by a manually operated device, such as one finger actuated, without need for a propellant.
[00365] A modified psychoactive compound also can be prepared as a suppository (for example, with conventional suppository bases, such as, cocoa butter, glycerides and so on). Compositions for rectal or vaginal administration can be suppositories prepared by mixing compositions with suitable non-irritating excipients, such as, polyethylene glycol, a suppository wax and so on which are solid at ambient temperature but liquid at body temperature and therefore melt in rectum or vagina and release active ingredient therein. Suppositories can be administered manually or with a dedicated device, see, for example, US Pat. No. 10,653,623.
[00366] In embodiments, a formulation comprises a pharmaceutically acceptable oleaginous base or substance. An oleaginous base can be naturally occurring, semi-synthetic or synthetic. In embodiments, an oleaginous base includes glycerides (for example, monoglycerides, diglycerides, triglycerides and so on); and so on. For example, an oleaginous base can include a mixture of monoglycerides, diglycerides, triglycerides and so on, in a variety of ratios. In embodiments, an oleaginous base includes triglycerides (for example, more than about 50% of glyceride content can be triglycerides and so on).
[00367] Other suitable oleaginous bases include, for example, theobroma oil/cocoa butter, triglycerides from vegetable oils, hydrogenated coco-glycerides, trilaurin triglycerides (for example, glyceryl tridodecanoate, glycerin trilaurate and so on), lecithin and hydrogenated lecithin, synthetic or semi-synthetic triglycerides and so on; and mixtures thereof. Tn embodiments, a formulation includes triglycerides from a hydrogenated vegetable oil. The vegetable oil can be, for example, a palm oil, a palm
kernel oil, a cottonseed oil, a soybean oil, a rapeseed oil, a coconut oil, a peanut oil, a sunflower seed oil, an olive oil and so on. In embodiments, an oleaginous base is a semi-synthetic glyceride base comprising saturated Cs-Cis triglyceride fatty acids, lecithin and so on.
[00368] Fatty acids, for example, those with aliphatic or hydrocarbon chains of about 8 to about 18 carbons in length can be used a modifying groups or in pharmaceutic formulations. Fatty acids can enhance bioavailability, can enhance stability and delivery of a modified psychoactive compound and so on.
[00369] Phospholipids also can find use as a modifying group or can be used in an administrable formulation. Examples include phosphatidyethanolamine, phosphatidylserine and so on.
[00370] A lecithin, inositol, ethanolamine, cholesterol and other lipids can be used as a modifying group or in a formulation.
[00371] Suppository formulations generally are semi-solid or solid. In embodiments, a formulation has a melting temperature in a range of about 35° C. to about 41° C., of about 37° C. to about 39° C.; and so on.
[00372] Other polymers, such as, gelatin and so on, may be incorporated to make a suppository more rigid to enable insertion digitally or with an applicator without breaking or fracturing.
[00373] In embodiments, a suppository can have a weight of about
2 grams (g), although weight can range from about 500 mg to about 5 g.
[00374] In embodiments, a suppository can have an oblong shape. In embodiments, an oblong shape further comprises a cylindrical shape. In embodiments, a suppository has a shape that allows contact between an outer surface of a suppository and a rectal mucosal membrane when a suppository is situated in a rectum.
[00375] Suppositories can have a (dry) density of about 0.001 to about 0.1 gm/cc, as such suppositories dissolved readily while being sturdy, yet soft and flexible. That provides a suppository that is comfortable to a user and yet does not readily break or fracture on insertion.
[00376] Such a formulation can be used as a vaginal suppository.
[00377] Alternatively, a rectal delivery vehicle or a vaginal delivery vehicle can be a foam, can be a lyophilized foam, see, for example, US Pat. No. 5,863,553.
[00378] Thus, an aqueous dispersion is made comprising at least one or several, water-soluble polymers, and a modified psychoactive compound of interest. The term, "aqueous dispersion," is meant to include dispersions (including solutions) in which a solvent is water or a water miscible liquid.
[00379] Cellulose, cellulose ethers, derivatives thereof, polymers of the type disclosed in US Pat. No. 4,615,697 can be used. Other suitable polymers include polycarboxylated vinyl polymers, polyacrylic acid polymers, polysaccharide gums (such as, natural plant exudates including karaya gum, ghatti gum and the like), seed gums (including, for example, guar gum, locust bean gum, psigllium seed gum and the like); and so on can be used.
[00380] Other suitable polymers include polyurethanes, gelatins, celluloses and cellulose ethers, including hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxypropyl ethylcellulose and so on; carbopol, polyvinyl alcohol and derivatives thereof, dextran, chitosan and derivatives thereof, starch and derivatives thereof, polyacrylamides, poly acrylates, agar, collagen, fibronectin, alginic acid, pectin, hyaluronic acid and so on, or mixtures thereof.
[00381] Cellulose ethers and hydroxypropylmethylcellulose can provide liquid foams that are stable with structural integrity, and dry foams with desirable softness.
[00382] Polymer is added to a dispersion at a concentration of about 1% to about 20% (by weight of total dispersion). At lower concentrations, there may be insufficient polymer to prepare a sturdy foam, whereas at higher concentrations, a dispersion may be too viscous to foam under normal conditions.
[00383] To ensure an aqueous dispersion will foam, viscosity of a dispersion can be maintained at about 4500 to 7000 cPs, as measured on a Brookfield viscometer at 32° C. using a number 4 spindle at 20 rpm. It may be necessary to cool a dispersion to about 32 to 35° C. by mixing to maintain desired viscosity.
[00384] After all materials are blended into an aqueous dispersion having adequate viscosity for foaming, that dispersion then is transferred to a continuous, enclosed mixer, such as an, "Oakes," foamer used to manufacture, for example, creamy, smooth food products, such as, ice cream and marshmallows, see, for example, US Pat. Nos. 2,572,049, 2,600,569, 2,679,866, and 3,081,069.
[00385] An Oakes foamer is comprised of an electrical system, an air system and a product section. Generally, such a device comprises a pump; a mixing chamber; a head assembly having a rotor; a gas inlet; an outlet for a foamed dispersion; means to measure pump speed, rotor speed, flow rate and pressure of an incoming gas; and means to measure back pressure of a foamed dispersion.
[00386] A product section consists of a positive displacement pump; speed reducer; inlet piping; a back pressure gauge to monitor back pressure; and a mixing chamber. A gauge is isolated from product by a diaphragm seal assembly.
[00387] A liquid dispersion is fed to a pump, transmitted through a line to a mixing chamber wherein a liquid is combined with air, under pressure, and mixed by a head assembly with a rotor.
[00388] In a mixing chamber, a dispersion is foamed, and air and dispersion are blended into a substantially uniform, homogeneous mixture. From a mixing chamber, a foamed dispersion then is sent to an outlet pipe.
[00389] Increasing pressure and/or airflow rate into a fixed volume of dispersion can produce a more flexible, faster dissolving suppository. Changing pump speed or rotor speed also changes liquid density of a foamed liquid dispersion.
[00390] Foams of varying liquid density can be produced by varying flow rate of incoming gas.
[00391] Density of a liquid foamed dispersion can range from about 0.1 to about 1.0 gm/cc.
[00392] A foamed dispersion can be lyophilized to yield a foamed suppository of interest carrying a modified psychoactive compound of interest.
[00393] To obtain shaped dry foams, a foamed liquid dispersion is placed into a receptacle having a known volume ("unit dosage"). Since liquid density of a foam and volume of a receptacle are known, foam weight of each unit dosage can
be determined. Liquid can be extruded through a tubing into a mold. Various aluminum, plastic and release liner covered molds can be employed.
[00394] Foam is extruded into compartmentalized trays whereby volume of one compartmental unit equals volume of a resulting suppository. The mold may be constructed in size and shape of a suppository. The foam is allowed to dry.
[00395] In embodiments, a modified psychoactive compound of interest can be configured into small particles, which can be coated with a hydrophilic and degradable layer or shell. Such a configuration confers stability to a modified psychoactive compound when carried and stored in oleaginous carriers and diluents, such as, those used in suppositories. On melting, a modified psychoactive compound of interest is exposed to an in vivo aqueous environment where that hydrophilic layer or shell dissolves exposing a modified psychoactive compound of interest to tissues and cells of mucosa.
[00396] In embodiments, a mucosal formulation comprises a water soluble, water miscible base. Examples of water-soluble miscible bases include glycerinated gelatins, polyethylene glycol (PEG) polymers (for example, PEG 300, PEG 1450, PEG 3350, PEG 6000, PEG 8000 and the like); and so on.
[00397] In embodiments, a mucosal formulation further comprises an accessory ingredient including adsorbents, surface acting agents (for example, mucosal adhesives, such as, xanthan gum, lisinopril, hydroxypropyl methylcellulose, carboxy methylcellulose, chitosan and so on), viscosity-influencing agents, suspending/dispersing agents, plasticizers (for example, diethylhexyl phthalate and so on), melting point-adjusting agents (for example, white wax and so on), antimicrobial agents, antioxidants and so on.
[00398] "Mucosa," refers to mucosal tissue of a host including respiratory passages (including bronchial passages, lung epithelium, nasal epithelium and so on), genital passages (including vaginal mucosa, penile mucosa, anal mucosa and so on), urinary passages (for example, urethra, bladder and so on), mouth, eyes, vocal cords and so on.
[00399] Mucosal administration can be accomplished, for example, through use of nasal sprays, eye drops, nebulizers, inhalers, atomizers, foams, suppositories and so on. Administration can be to nose, trachea, lung and so on.
[00400] In embodiments, a mucolytic agent can be administered together with a modified psychoactive compound composition of interest or at about the same time a modified psychoactive compound composition is administered to thin a mucus. For example, a mucolytic can be administered before a modified psychoactive compound composition is administered. Examples of a mucolytic includes acetyl cysteine, ammonium chloride, ammonium carbonate, DNase I and so on.
[00401] The term, "pharmaceutically effective amount," refers to an amount that achieves a desired reaction or a desired effect in vivo alone or with further doses. In the case of treatment of a particular disease, a desired reaction relates to inhibition or diminution of a symptom or course of a disease. That can comprise slowing down progress of disease and/or interrupting or reversing progress of disease. A desired reaction in treatment of disease also may be delay of onset or prevention of onset of said disease or said condition.
[00402] An effective amount of a modified psychoactive compound described herein can depend on condition to be treated, severity of disease, individual parameters of a patient, including age, physiologic condition, size and weight; duration of treatment, type of an accompanying therapy (if present), specific route of administration and so on. Efficacy can manifest at different levels, such as, reduction of one symptom, removal of one symptom, reduction of plural symptoms, reduction of plural symptoms, improvement of a disease state, cure from a disease and so on.
[00403] A modified psychoactive compound can be used in topical form, such as, gels, creams, ointments, lotions, unguents, other cosmetics and the like. A modified psychoactive compound can be carried in a formulation comprising emollients, bleaching agents, antiperspirants, moisturizers, scents, colorants, pigments, dyes, antioxidants, oils, fatty acids, lipids, inorganic salts, organic molecules, opacifiers, vitamins, pharmaceutics, keratolytic agents, UV blocking agents, tanning accelerators, depigmenting agents, deodorants, perfumes, insect repellants and the like.
[00404] Other formulations include liquid and/or semi liquid preparations, such as, liniments, lotions, oil in water emulsions, water in oil emulsions, such as, pastes and like; and so on. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (wt/wt) modified psychoactive
compound, although concentration of active ingredient may be as high as solubility limit of a modified psychoactive compound in a solvent.
[00405] Another method of administration comprises addition of a compound of interest into or with a food or drink, such as, a food supplement, an additive and so on. A modified psychoactive compound can be encapsulated into forms that survive passage through a gastric environment. Such forms are commonly known, for example, as enteric formulations.
[00406] In the case that reaction in a patient is insufficient with an initial dose, follow on doses, higher doses (or effectively higher doses achieved by a different, more localized route of administration), repeated doses and so on may be used.
[00407] It can be advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form,” as used herein refers to physically discrete units suited as unitary dosages for a subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce a desired therapeutic endpoint.
[00408] As used herein, a, "unit dose," is a discrete amount of a pharmaceutic composition comprising a predetermined amount of each modified psychoactive compound. Amount of active ingredient generally is equal to dosage of an active ingredient which would be administered to a subject; a convenient fraction of such a dosage, such as, for example, one-half, one-third and so on of such a dosage; and so on is administered to a subject.
[00409] Dosages, for example, preferred routes of administration and amounts are obtainable based on empiric data obtained from preclinical and clinical studies, practicing methods known in the art. Dosage and delivery form can be dictated by and can be dependent on characteristics of a modified psychoactive compound, particular biologic or therapeutic effect to be achieved, characteristics and condition of a recipient and so on. For repeated administration over several days or longer, depending on condition, treatment can be sustained until a desired endpoint is attained.
[00410] Amount of a modified psychoactive compound, one or more pharmaceutically acceptable accessory ingredients, and/or any additional ingredients in
a pharmaceutic composition in accordance with the instant disclosure may vary, depending on, for example, identity, size, and/or condition of a subject treated and further depending on route by which a composition is administered. By way of example, a pharmaceutic composition may comprise between about 0.1 mg and about 1000 mg of a modified psychoactive compound.
[00411] In embodiments, compositions of interest are administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 10 mg/kg from about 0.0001 mg/kg to about 5 mg/kg, from about 0.0001 mg/kg to about 2.5 mg/kg, from about 0.0001 mg/kg to about 1 mg/kg, from about 0.0001 mg/kg to about 0.25 mg/kg or greater of a modified psychoactive compound. A dose may be administered one or more times per day, in same or a different amount, to obtain a desired level of a therapeutic or prophylactic effect.
[00412] In embodiments, a unit dose or a single dose of a composition of interest can comprise from about 1 pg to about 500 pg, from about 1 pg to about 400 pg, from about 1 pg to about 300 pg, from about 1 pg to about 200 pg, from about 1 pg to about 100 pg, from about 3 pg to about 500 pg, from about 3 pg to about 400 pg, from about 3 pg to about 300 pg, from about 3 pg to about 200 pg, from about 3 pg to about 100 pg, from about 5 pg to about 500 pg, from about 5 pg to about 400 pg, from about 5 pg to about 300 pg, from about 5 pg to about 200 pg, from about 5 pg to about 100 pg, from about 7 pg to about 500 pg, from about 7 pg to about 400 pg, from about 7 pg to about 300 pg, from about 7 pg to about 200 pg, from about 7 pg to about 100 pg, from about 10 pg to about 500 pg, from about 10 pg to about 400 pg, from about 10 pg to about 300 pg, from about 10 pg to about 200 pg, from about 10 pg to about 100 pg, or in an amount outside of those ranges as needed to attain a desired biologic endpoint, to attain a desired pharmacologic endpoint or other desired result.
[00413] An effective amount of a modified psychoactive compound may include amounts between: 0.01 mg to 0.1 mg; 0.01 mg to 0.5 mg; 0.01 mg to 1 mg; 0.01 mg to 5 mg; 0.01 mg to 10 mg; 0.01 mg to 25 mg; 0.01 mg to 50 mg; 0.01 mg to 75 mg; 0.01 mg to 100 mg; 0.01 mg to 125 mg; 0.01 mg to 150 mg; 0.01 mg to 175 mg; 0.01 mg to 200 mg; 0.01 mg to 225 mg; 0.01 mg to 250 mg; 0.01 mg to 275 mg; 0.01 mg to 300 mg; 0.01 mg to 225 mg; 0.01 mg to 350 mg; 0.01 mg to
375 mg; 0.01 mg to 400 mg; 0.01 mg to 425 mg; 0.01 mg to 450 mg; 0.01 mg to
475 mg; 0.01 mg to 500 mg; 0.01 mg to 525 mg; 0.01 mg to 550 mg; 0.01 mg to
575 mg; 0.01 mg to 600 mg; 0.01 mg to 625 mg; 0.01 mg to 650 mg; 0.01 mg to
675 mg; 0.01 mg to 700 mg; 0.01 mg to 725 mg; 0.01 mg to 750 mg; 0.01 mg to
775 mg; 0.01 mg to 800 mg; 0.01 mg to 825 mg; 0.01 mg to 950 mg; 0.01 mg to
875 mg; 0.01 mg to 900 mg; 0.01 mg to 925 mg; 0.01 mg to 950 mg; 0.01 mg to
975 mg O;* 0.01 mg o to 1000 mg; 0.01 mg o to 2000 mg; 0.01 mg o to 3000 mg; 0.01 mg o to
4000 mg; 01 mg to 5000 mg; 0.01 mg to 0.1 mg/kg; 0.01 mg to 0.5 mg/kg; 01 mg to 1 mg/kg; 0.01 mg to 5 mg/kg; 0.01 mg to 10 mg/kg; 0.01 mg to 25 mg/kg; 0.01 mg to 50 mg/kg; 0.01 mg to 75 mg/kg; and 0.01 mg to 100 mg/kg.
[00414] In embodiments, formulations also may be constructed to locate passively or actively to different cell types in vivo, including, but not limited to particular sites in a body, such as, hepatocytes, brain cells and so on. Such targeting can occur as taught hereinabove, by employing particular modifications or functional groups and so on, which targeting can be active or passive.
[00415] For example, adeno-associated virus 9 may traverse the BBB (Merkel et al., J Neurochem. 140(2)216-230, 2017) and can infect brain cells (Dayton et al., Expert Opn. Biol. Therap. 12(6)757-766, 2012; Foust et al., Nat. Biotech. 27(1)56-95, 2009). Hence, AAV9 virus-like particles (VLP) can be made (Le et al., Sci. Rep. 9:18631, 2019; Womer et al., Nat. Comm. 12: 1642, 2021) and the particles can be made to carry a modified psychoactive compound. Moreover, AAV9 capsid proteins can self-reconstitute particles and are available commercially, Creative Biolabs, Shirley, NY. Hence, AAV9 packaging components are mixed a modified psychoactive compound and allowed to form particles, which will entrap the modified psychoactive compound within. The VLP’s are introduced into the circulatory system and home to the brain, where the VLP’s can fuse with brain cells and release the modified psychoactive compound.
[00416] An example of targeting a formulation to brain cells relies on a modified psychoactive compound contained within a delivery vehicle, such as, a liposome, a lipid nanoparticle and so on, and on the surface of the delivery vehicle is exposed or displayed a molecular entity that attracts the delivery vehicle, and hence, the modified psychoactive compound, to a particular site in the body, such as,
endothelial cells of capillaries of the blood-brain barrier (BBB). Formulations also can be selectively targeted through expression of different ligands or one of a binding pair on a surface of a modified psychoactive compound delivery vehicle, as exemplified by, for example, an antibody targeted approach, wherein a targeting antibody is attached to a delivery vehicle, wherein that antibody specifically binds an organ-specific molecule, a tissue-specific molecule, a cell-specific molecule and so on, see, for example, Curr Drug Discov Technol 2011, 8:197-206; Front Biosci 2011, 16:1388-1412; Mol Membr Biol 2010, 27:286-298; Crit Rev Ther Drug Carrier Syst 2008, 25: 1-61; Biomacromol 2011, 12:2708-2714; Expert Opin Drug Deliv 2008, 5:309-319; Mol Ther 2010, 18: 1357-1364; Methods Mol Biol 2012, 820: 105-116; Meth Mol Biol 2012, 757:497-507; J Cont Rel 20:63-68, 2010; PNAS 2007, ] 04:4095-4100, 2007; Meth Mol Biol 201 1 , 721 :339-353; Mol Ther 2010, 18:2028-2037; Nat Biotechnol 2005, 23:709-717; Sci 2008, 319:627-630; and Gene Ther 2011, 18: 1127-1133, the content of each of which is incorporated herein by reference in entirety); and so on.
[00417] Drug delivery vehicles, such as, liposomes, lipid nanoparticles, dendrimers, micelles, hydrogels, nanotubes, quantum dots, virus-like particles, cyclodextrins and so on are known and commercially available.
[00418] Liposomes can be made from phospholipids, such as phosphatidylcholine. A modified psychoactive compound suspended/dissolved in an aqueous, polar medium is mixed with a lipid suspended/dissolved in a volatile organic or non-polar solvent. The mixture can be sonicated or organic solvent evaporated to form liposomes.
[00419] Lipid nanoparticles (LNP) are another delivery form. A hydrophilic core carrying a modified psychoactive compound is encased with a boundary/layer comprised, for example, with an ionizable cationic lipid, a phospholipid and cholesterol, and optionally, a PEGylated lipid. An LNP can be prepared by mixing organic and aqueous solutions carrying the reagents using high shear homogenization and ultrasound, microemulsion-forming methods and so on.
[00420] For example, for targeted delivery to brain, LAT1 (large amino acid transporter-1 , also known as CD98) is expressed on many cells, but there is high expression in brain capillary endothelial cells (Boado et al., PNAS 96:12079-12084,
1999). The amino acid sequence of LAT1 is known (UniProt Q96QB2 or Q01650) and can be purchased (Solvo Biotech, SF, CA; and Novus Biol, Centennial, CO). Hence, mAh’s can be made as known in the art or purchased (AbCam, Shirley, NY).
[00421] Drug delivery vehicles carrying a modified psychoactive compound within can be constructed to express on the surface thereof an antibody or antigen binding portion thereof which specifically binds LAT1. Those vehicles could be administered directly to a vessel that supplies the brain (because LAT1 is not specific to the brain) to maximize exposure of the targeting vehicle to the capillary endothelium. Although LAT1 is not brain specific, the targeting vehicles may be administered by any mode as delivery of a modified psychoactive compound to sites other than brain may not be detrimental.
[00422] The terms, “therapeutic,” and, “prophylactic,” can be used interchangeably herein with respect to features and embodiments of the instant disclosure.
[00423] A modified psychoactive compound may be used in combination with one or more other therapeutic or prophylactic agents. By, "in combination with," is not intended to imply agents must be administered at the same time and/or formulated for delivery together, although methods of such delivery are within the scope of the instant disclosure. For example, two or more modified psychoactive compound may be administered in combination. Compositions can be administered concurrently with, prior to, or subsequent to one or more other desired therapeutics or medical procedures.
[00424] Such an other agent that is not a psychoactive compound may be, for example, an anti-inflammatory compound, a steroid (for example, a corticosteroid and so on), a statin, an analgesic and so on.
[00425] A pharmaceutic composition can be included in a container, pack or dispenser together with instructions for administration, forming a kit, an article of manufacture. A kit can comprise a unit dosage form, a multiple unit dosage form, a bulk container for dispensing unit doses and so on. A kit can include a device for delivering a dose, such as, a syringe, a suppository applicator or insertion device; and so on. A kit can include a liquid diluent.
[00426] A pharmaceutic composition including a modified psychoactive compound composition may be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing an active ingredient into association with one or more other accessory ingredients, and then, if desirable or necessary, dividing, shaping, packaging and so on a product into a desired single-dose or multi -dose unit as an article of manufacture.
[00427] Pharmaceutic compositions may be prepared in a variety of forms suitable for a variety of routes and methods of administration. For example, pharmaceutic compositions may be prepared in liquid dosage forms (for example, emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, elixirs and so on), injectable forms, solid dosage forms (for example, capsules, tablets, pills, powders granules and so on), dosage forms for topical and/or transdermal administration (for example, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, patches and so on), suspensions, powders; and other forms.
[00428] In embodiments, modified psychoactive compound compositions and/or pharmaceutic compositions of the disclosure are refrigerated or frozen for storage and/or shipment (for example, stored at a temperature of about 4° C., or lower, about 0° C. In embodiments, a modified psychoactive formulation can be stored at normal room temperatures (RT) of about 20-22° C. Compositions and/or pharmaceutic compositions disclosed herein are stable for about at least 1 week, about at least 2 weeks, about at least 3 weeks, about at least 4 weeks, about at least 5 weeks, about at least 6 weeks, about at least 1 month or longer, for example, at RT or at a temperature of about 4° C. or lower.
[00429] In embodiments, a modified psychoactive composition formulation of interest is desiccated to a dry powder, for example, by freeze drying, lyophilization and so on, practicing methods and material known in the art.
[00430] "Stability," "stabilized," "stable," and grammatic forms thereof refer to resistance of compositions and/or pharmaceutic compositions disclosed herein to chemical or physical change (for example, degradation, particle size change, aggregation and so on) under given manufacturing, preparation, transportation, storage and/or in use conditions.
[00431] Compositions are suitable for administration to any other animal, such as, a mammal. Modification of compositions suitable for administration to various animals is understood by a veterinarian or veterinary pharmacologist using ordinary and routine measures.
[00432] a. Bioavailability
[00433] “Bioavailability,” of a modified psychoactive compound can be enhanced by functionalization of a psychoactive compound. For example, a psychoactive compound may be hydrophobic. While that property may enhance cell uptake of that psychoactive compound, hydrophobic compound may not survive long in vivo after administration, for example, being captured by circulating protein, such as, albumin. Thus, modifying a psychoactive compound with a hydrophilic modification group can enhance aqueous solubility and stability of that modified psychoactive compound in circulation.
[00434] Generally, bioavailability means percentage of an administered compound that enter the circulatory system following administration.
[00435] A synonymous term is, “absorption,” although absorption can be viewed as going further than bioavailability to include travel from the site of administration to the site of action.
[00436] 1. Solubility
[00437] As discussed herein, functionalization can endow aqueous solubility on a psychoactive compound of interest. Hydrophilicity can enhance use as a deliverable formulation to a subject. For example, glycosylation can enhance solubility as carbohydrates are water soluble.
[00438] 2. Tissue penetration
[00439] As discussed herein, a functionalized or modified psychoactive compound may have enhanced access to an organ, tissue or cell. A modification or functional group may target a psychoactive agent to a particular organ tissue of cell. For example, as discussed herein, a formulation of interest may be used to locate and to traverse a tissue barrier, such as, the blood-brain barrier.
[00440] 3. Cell penetration
[00441 ] A modified psychoactive compound of interest can have affinity to a cell membrane through the psychoactive compound, through the modification or
both. A hydrophobic modified psychoactive compound or a hydrophobic psychoactive compound with a modification removed can have affinity with a cell membrane, facilitating entry into a cell.
[00442] In embodiments, a psychoactive compound in proximity to a cell or delivered to a cell by a modification attached thereto, and which engages a cell surface receptor, can have an enhanced biologic effect.
[00443] b. Toxicity
[00444] In embodiments, a modification can reduce or temper toxicity of a psychoactive compound of interest, thereby making such compound available for administration to a subject. In embodiments, toxicity can be reduced or tempered by encapsulating a psychoactive compound of interest, for example, in a liposome or an I.NP.
[00445] c. Dose/Half-life
[00446] Often drugs exhibit a short half-life in circulation, being rapidly excreted by the kidneys; reacting with opsonins for destruction or inactivation by triggering the immune system, adsorbed by the reticuloendothelial system (RES) and other tissues; and so on. To enhance persistence in vivo, larger doses are not always the solution as that might increase cost, can lead possibly to toxicity, can lead to an immune response thereto thereby potentially reducing efficacy of future administrations; and so on.
[00447] Hydrophilicity or greater hydrophilicity may reduce likelihood a modified psychoactive compound being recognized or taken up by tissues and being catabolized. Hydrophilicity can be conferred, for example, by pendant carboxyl groups, hydroxyl groups, amines, sulfates and so on.
[00448] Terminal galactose residues might be avoided because such can be recognized by galactose receptors on hepatocytes and Kuppfer cells and may therefore be cleared more readily from circulation.
[00449] Often, a proportion of an administered modified psychoactive compound is rapidly taken into the bloodstream and the remainder is eliminated, usually at steady rate. Half-life of a compound following initial rapid uptake can be an indicator of suitability of a modified psychoactive compound for prolonged circulation times and/or stability of a modified psychoactive compound and/or reduced
immunogenicity. Generally, longer half-life can be beneficial. Also, proportion of compound eliminated in the first rapid step can be an indicator of utility, useful compounds would have none or only a small proportion of compound removed from circulation in the first step.
[00450] A functionalized psychoactive compound can be one in which less than about 50%, less than about 25%, less than about 20%, or less is removed from circulation following intravenous administration, for example, within a period of about 15 minutes, from about 10 minutes, from about 5 minutes from injection. A functionalized psychoactive compound can have a half-life following the rapid removal stage of at least about 10 hours, at least about 20 hours, at least about 30 hours, or more. A compound comprising a larger molar ratio of functional group to psychoactive compound can have a longer half-life. Compounds displaying larger functional groups, such as, a branched sugar, may have prolonged half-life.
[00451] The instant invention is further defined and exemplified in the following non-limiting Examples. It should be understood that the Examples, while indicating embodiments of the invention, are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt to various uses and conditions.
EXAMPLES
Example 1
[00452] Methoxypoly(ethylene glycol) (m-PEG) (mw=2,000) is obtained from Molecular Depot, San Diego, CA. Solvents are obtained from Sigma-Aldrich.
[00453] Methoxy-poly (ethylene glycol)-N-succinimidyl carbonate
(SC-PEG) is prepared as described in US Pat. No. 5,122,614, using the m-PEG described above. m-PEG-N-acyl-thiazolidine is prepared as described in US Pat. No. 5,349,001.
[00454] Structure of each of the products is confirmed by carbon13 nuclear magnetic resonance (NMR).
[00455] A branched PEG is prepared by adding 100 mg (1.1 mmol) of l,3-diamino-2-propanol to a solution of 10.0 g (2 mmol) of SC-PEG in 50 mL of methylene chloride. The mixture is stirred for 18 hours at room temperature then filtered. Excess solvent is removed by distillation in vacuo. The residue is recrystallized from 2-propanol to yield 7.1 g of product (70% yield).
Example 2
[00456] Glycosylation reactions consist of 50 mM KPO4 pH 7.2, 3 mM MgCh, 0.005% psilocin, 2.5% purified UDP-glycosyltransferase and 2.5 mM UDP-glucose. Buffers are degassed and tubes are purged with nitrogen. Reactions are protected from light and are incubated at 28° C. with 180 rpm agitation for 18 hours. Reactions then are extracted 3 times with an equal volume of ethyl acetate, evaporated to dryness and dissolved in a half volume of HPLC grade methanol. A sample, 50 pl, is injected on a reverse phase C18 column and eluted with a gradient of acetonitrile starting at 10% and increasing to 99%.
[00457] Glycosylated psilocin is recovered.
Example 3
[00458] One pg of morphine (1 pl of a 1 mg/ml solution dissolved in methanol, 0.016 mM final concentration) is added to 200 pl of a mixture containing 50 mM potassium phosphate buffer (pH 7.2), 3 mM magnesium chloride (MgCb), 2.5 mM uridine diphosphate glucose (UDPG) as the sugar donor and 10 ml of a 50% UDP-glycosyltransferase glycerol stock solution (1.5 mg/ml stock solution, 1.44 pM final protein concentration). The reaction mixtures are incubated at 28° C with shaking at 180 rpm for 18 hrs. To stop the reaction, the reaction mixture is extracted three times with 200 pl of ethyl acetate each time. The organic layers containing morphine glycosides and any unreacted substrate are combined, and the ethyl acetate is removed under vacuum. Then, the samples are redissolved in 100 pl of 50% MeOH by volume. Reaction products re analyzed by RP-HPLC on a Dionex 3000 LC system using a Phenomenex Kinetex 5 pm XB-C18 IOOA column (150 x 4.6 mm). The conditions are: injection volume of 50 pl; column temperature 30° C; autosampler 8° C; flow of 1 ml/min; running time 25 min; solvent A deionized water; solvent B acetonitrile (ACN); gradient elution 10-99% ACN.
[00459] Glycosylation reaction is scaled up proportionally to 100 ml to obtain an adequate amount of glycosylated morphine for characterization by LC-MS and LH NMR. Enzyme is deactivated and precipitated from the glycosylation reaction mixture by treatment at 95° C for 10 minutes. The clarified reaction mixture is obtained by centrifugation.
Example 4
[00460] In a 25 mL round bottom flask with 130 mm fractionating column, still head, magnetic stirrer and N2 inlet are placed 25.48 g of morphine, terephthalic acid, 1.92 g tert-butyl acetoacetate (tBAA) and 35 mL n-butyl acetate. The solution is warmed to reflux and solvent removed until the head temperature reaches 110° C. (approximately 45 minutes).
[00461 ] NMR spectroscopic analysis of the resulting concentrated solution shows approximately 60% of the end groups are acetoacetylated.
Example 5
[00462] Glycosides are purified to homogeneity by Cl 8 solid phase extraction using a 100 mg Hypersep C18 column (Thermo) hydrated in methanol, rinsed with 50% methanol in water and rinsed with water. Glycosylation reactions are passed through the column, washed with water, washed with 10%, 20%, and 30% methanol, and the glycoside products are eluted with 45 and 60% methanol in water. Eluates are dried, extracted with ethyl acetate and dried to completion to yield >95% pure morphine-glycosides.
Example 6
[00463] For maleimide conjugation, mescaline is conjugated to maleimide-activated polyethylene glycol (PEG) (Creative PEGWorks, Chapel Hill, NC) at a 1 : 1 molar ratio of mescaline to PEG at a pH of 9 to facilitate reaction with the mescaline free amine group by mixing on a rocker platform for 2 hours at room temperature, followed by dialysis against phosphate-buffered saline (PBS) at 4° C.
[00464] PEG conjugates are isolated by gel chromatography.
Example 7
[00465] For a Michael addition reaction to the ketone group of cathinone, to a 250-mL round bottom flask containing a stir bar are added 150 millimoles of cathinone and 45 g of MeOH. The mixture is made homogeneous and
cooled to 4° C. under N2 atmosphere. To the stirred mixture are added 10 millimoles of trimethylolpropane triacrylate (Aldrich) in 20 g of MeOH over about 10 minutes using a dropping funnel. The mixture is stirred at 4° C. for one hour, then for one hour at 25° C. The mixture is evaporated of volatiles on a rotary evaporator. The resulting residue is dissolved in chloroform and extracted with water (4 x 20 mb). The organic layer is dried over sodium sulfate, filtered and evaporated of volatiles to give the desired conjugate cathinone product.
Example 8
[00466] The method of Example 7 is practiced but with ketamine as the ketone acceptor.
[00467] The conjugated ketamine is isolated.
Example 9
[00468] Indole (Sigma-Adrich) is mixed with oxalyl chloride (Sigma- Aldrich). To that mixture then is added dimethylamine (Sigma-Aldrich). The carbonyl groups are reduced with lithium aluminum hydride (Sigma- Aldrich) to form dimethyl tryptamine (DMT).
[00469] Three millimoles of phenylmethane sulfonyl chloride (Sigma- Aldrich) are dissolved in dry benzene (45 ml) under nitrogen. Five millimoles of DMT in 5 ml of dry benzene are added to the sulfonyl solution from a syringe with rapid stirring. The resulting mixture is stirred for one hour. Solvent is removed under reduced pressure and the residue extracted with ether, washed with 3 M HC1, drying over magnesium sulfate and again dried under reduced pressure.
[00470] The residue is chromatographed to reveal three species of conjugate, with addition of the phenylmethyl sulfonyl group to the tertiary amine, the indole amine or both.
[00471] All references cited herein are herein incorporated by reference in entirety.
[00472] It will be appreciated that various changes and modifications can be made to the teachings herein without departing from the spirit and scope of the disclosure.
Claims
1. A composition comprising a psychoactive compound and a modification thereto or attached thereto, said composition administrable to a subject.
2. The composition of claim 1, wherein said psychoactive compound comprises an alkaloid compound.
3. The composition of claim 1, wherein said psychoactive compound comprises an opioid compound.
4. The composition of claim 1 , wherein said psychoactive compound comprises a tropane group, an isoquinoline group, a phenanthrene group or a purine group.
5. The composition of claim 1, wherein said psychoactive compound comprises a phenethyl amine group.
6. The composition of claim 1, wherein said psychoactive compound comprises a tryptamine group.
7. The composition of claim 1, wherein said psychoactive compound comprises an indole group.
8. The composition of claim 1, wherein said psychoactive compound comprises a 2C compound.
9. The composition of claim 1, wherein said psychoactive compound comprises a mescaline.
10. The composition of claim 1, wherein said psychoactive compound comprises a psilocybin or psilocin.
11. The composition of claim 1, wherein said psychoactive compound binds a dopamine receptor.
12. The composition of claim 1, wherein said psychoactive compound binds a serotonin receptor.
13. The composition of claim 1, wherein said psychoactive compound binds a serotonin family 5 receptor.
14. The composition of claim 1, wherein said modification comprises one member of a binding pair.
15. The composition of claim 1, wherein said modification comprises a sugar, an amino acid, a nucleic acid, a lipid or a vitamin.
16. The composition of claim 1, wherein said modification comprises a linear polysaccharide of a branched polysaccharide.
17. The composition of claim 1, wherein said modification comprises glucose.
18. The composition of claim 1, wherein said modification comprises a biotin or a folate.
19. The composition of claim 1, wherein said modification is removable.
20. The composition of claim 1, comprising more than one modification.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030202981A1 (en) * | 2002-04-26 | 2003-10-30 | Kream Richard M. | Chimeric hybrid analgesics |
US20050089524A1 (en) * | 2002-03-01 | 2005-04-28 | Sanderson Sam D. | Compositions and compounds for use as molecular adjuvant for a nicotine vaccine |
US20080280937A1 (en) * | 2005-08-19 | 2008-11-13 | Christopher Paul Leamon | Ligand Conjugates of Vinca Alkaloids, Analogs, and Derivatives |
WO2011133151A1 (en) * | 2010-04-21 | 2011-10-27 | Pharmacofore, Inc. | Compositions comprising enzyme-cleavable phenol-modified opioid prodrugs and inhibitors thereof |
US20130023553A1 (en) * | 2010-01-12 | 2013-01-24 | Nektar Therapeutics | Pegylated opioids with low potential for abuse and side effects |
US20130072438A1 (en) * | 2011-09-20 | 2013-03-21 | The United States Government As Represented By The Department Of Veterans Affairs | Opioid peptide esters and methods of use |
-
2023
- 2023-05-03 WO PCT/US2023/020756 patent/WO2023215335A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050089524A1 (en) * | 2002-03-01 | 2005-04-28 | Sanderson Sam D. | Compositions and compounds for use as molecular adjuvant for a nicotine vaccine |
US20030202981A1 (en) * | 2002-04-26 | 2003-10-30 | Kream Richard M. | Chimeric hybrid analgesics |
US20080280937A1 (en) * | 2005-08-19 | 2008-11-13 | Christopher Paul Leamon | Ligand Conjugates of Vinca Alkaloids, Analogs, and Derivatives |
US20130023553A1 (en) * | 2010-01-12 | 2013-01-24 | Nektar Therapeutics | Pegylated opioids with low potential for abuse and side effects |
WO2011133151A1 (en) * | 2010-04-21 | 2011-10-27 | Pharmacofore, Inc. | Compositions comprising enzyme-cleavable phenol-modified opioid prodrugs and inhibitors thereof |
US20130072438A1 (en) * | 2011-09-20 | 2013-03-21 | The United States Government As Represented By The Department Of Veterans Affairs | Opioid peptide esters and methods of use |
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