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WO2023150057A1 - Molécules conjuguées de cannabinoïdes - Google Patents

Molécules conjuguées de cannabinoïdes Download PDF

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Publication number
WO2023150057A1
WO2023150057A1 PCT/US2023/011680 US2023011680W WO2023150057A1 WO 2023150057 A1 WO2023150057 A1 WO 2023150057A1 US 2023011680 W US2023011680 W US 2023011680W WO 2023150057 A1 WO2023150057 A1 WO 2023150057A1
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Prior art keywords
molecule
conjugate
conjugate molecule
formula
group
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Inventor
Paul M. HERSHBERGER
Yinghui Liu
Kirk William HERING
Ramanathan S. Lalgudi
James Bernard Kramer
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Akos Biosciences Inc
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Akos Biosciences Inc
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Priority claimed from US17/982,859 external-priority patent/US11660348B1/en
Priority claimed from US17/982,779 external-priority patent/US11883499B2/en
Application filed by Akos Biosciences Inc filed Critical Akos Biosciences Inc
Publication of WO2023150057A1 publication Critical patent/WO2023150057A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present disclosure relates to conjugate molecules containing an active agent and a cannabinoid moiety. It finds particular application in conjunction with medical applications, and will be described with particular reference thereto. However, it is to be appreciated that the present disclosure is also amenable to other like applications.
  • the present disclosure relates generally to conjugate molecules formed from an active agent which is linked to a cannabinoid moiety through a specified linker.
  • the active agent is a COX-2 inhibitor moiety
  • the cannabinoid moiety is a cannabidiol moiety.
  • FIG. 1A is the first part of a synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1 B is the second part of a synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1C is an illustration of a modified part of the synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1 D is another illustration of a modified part of the synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1 E is another illustration of a modified part of the synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1 F is another illustration of a modified part of the synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1G is another illustration of a modified part of the synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 1 H is another illustration of a modified part of the synthetic route for preparing a conjugate molecule, in some embodiments.
  • FIG. 2A and FIG. 2B illustrate a first comparative synthetic route which was not successful in producing the desired conjugate molecule.
  • FIG. 3 illustrates a second comparative synthetic route which was not successful in producing the desired conjugate molecule.
  • the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context. When used in the context of a range, the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the range of “from about 2 to about 10” also discloses the range “from 2 to 10.”
  • the term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11 %, and “about 1” may mean from 0.9-1 .1 .
  • compositions of the present disclosure means a sufficient amount of the compound to treat the subject and obtain the desired therapeutic benefit at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician or other care provider within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the seventy of the disorder; medical history of the patient, age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, the duration of the treatment, other drugs being taken by the patient, and the like. A single administration may be sufficient to produce a therapeutic effect, but it is contemplated that multiple administrations will be used over a substantial period of time to assure continued response.
  • the present disclosure relates to conjugate molecules which are contemplated to be useful in the treatment of various medical conditions, such as for pain management, or for inflammatory conditions, or for arthritis.
  • Compositions including these conjugate molecules are also contemplated, as well as methods of making and using these conjugate molecules.
  • the conjugate molecules are formed from an active agent which is linked to a cannabinoid moiety through a specified linker. It is contemplated that both the active agent and the cannabinoid will have a therapeutic effect when delivered to the desired location.
  • the conjugate molecule can remain intact, or a covalent bond can be broken so that the active agent and the cannabinoid become two separate molecules.
  • Such conjugate molecules are illustrated in Formula (I) below:
  • the linker may comprise an alkyl chain with heteroatomic end groups.
  • heteroatomic end groups can include an ester group and an amide group.
  • the active agent may be any agent that can be used to treat a medical condition.
  • Some non-limiting examples of active agents may include celecoxib or diclofenac, which can be used for pain management.
  • the active agent has an acidic hydrogen atom attached to a nitrogen atom, for example a primary or secondary amino group.
  • the linker can be reacted to remove the acidic hydrogen atom and form a covalent bond with the nitrogen atom.
  • the active agent also does not have any hydroxyl groups, so that the reaction of the linker is directed to the nitrogen atom.
  • the active agent has a carboxylic acid group.
  • the linker can also be reacted to form a covalent bond with the non-carbonyl oxygen atom.
  • the active agent also does not contain any primary or secondary amino groups, or does not contain any acidic hydrogen atom attached to a nitrogen atom.
  • the active agent is a COX-2 inhibitor moiety.
  • the COX-2 inhibitor moiety targets cyclooxygenase-2 (COX-2).
  • COX-2 inhibitor moieties may include celecoxib; cimicoxib; etoricoxib; lumiracoxib; parecoxib; polmacoxib; rofecoxib; valdecoxib; bromfenac; etodolac; ketorolac tromethamine; meloxicam; nabumetone; oxaprozin; and diclofenac.
  • COX-2 inhibitor moieties may take any form, such as salts, acids, esters, analogs, derivatives, or prodrugs thereof, etc.
  • the cannabinoid moiety can be any cannabinoid or derivative thereof.
  • the cannabinoid can be a cannabidiol, cannabigerol, cannabichromene, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabitriol, dehydrocannabifuran, cannabifuran, cannabichromanon, or cannabiripsol.
  • cannabidiols include cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), and cannabidiorcol (CBD-Ci).
  • CBDA cannabidiolic acid
  • CBD cannabidiol
  • CBD cannabidiol
  • CBD cannabidiol
  • CBDDM cannabidiol monomethylether
  • CBD-C4 cannabidiol-C4
  • CBDVA cannabidivarinic acid
  • CBDDV cannabidivarin
  • CBD-Ci cannabidiorcol
  • cannabigerols examples include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethyleither (CBGM), cannabigerovarinic acid (CBGVA), and cannabigerovarin (CBGV).
  • cannabichromenes examples include cannabichromenic acid (CBC), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), and cannabichromevarin (CBCV).
  • CBC cannabichromenic acid
  • CBC cannabichromene
  • CBCVA cannabichromevarinic acid
  • CBCV cannabichromevarin
  • tetrahydrocannabinols include D-9-tetrahydrocannabinolic acid A (THCA-A), D-9-tetrahydrocannabinolic acid B (THCA-B), D-9-tetrahydrocannabinol (THC), D-9-tetrahydrocannabinolic acid-C4 (THCA-C4), A-9-tetrahydrocannabinol-C4 (THC-C4), D-9-tetrahydrocannabivarinic acid (THCVA), D-9-tetrahydrocannabivarin (THCV), D-9-tetrahydrocannabiorcolic acid (THCA-Ci), D-9-tetrahydrocannabiorcol (THC-Ci), D-7 -cis-tetrahydrocannabivarin, D-8-tetrahydrocannabinolic acid (A 8 -THCA), and D-8-tetrahydrocannabin
  • cannabicyclols examples include cannabicyclolic acid (CBLA), cannabicyclol (CBL), and cannabicyclovarin (CBLV).
  • cannabielsoins examples include cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), and cannabielsoin (CBE).
  • cannabinols and cannabinodiols include cannabinolic acid (CBNA), cannabinol (CBN), cannabinol-C4 (CBN-Cr), cannabivarin (CBV), cannabinol- C2 (CBN-C2), cannabiorcol (CBN-Ci), cannabinodiol (CBND), and cannabinodivarin (CBVD).
  • cannabitriols examples include cannabitriol (CBT), 10-ethoxy-9-hydroxy-A- 6a-tetrahydrocannabinol, cannabitriolvarin (CBTV), and ethoxy-cannabitriolvarin (CBTYE).
  • Cannabifurans include dehydrocannabifuran (DCBF) and cannabifuran (CBF).
  • DCBF dehydrocannabifuran
  • CBF cannabifuran
  • cannabinoids include cannabichromanon (CBCN), 10-oxo- A-6a-tetrahydrocannabinol (OTHC), cannabiripsol (CBR), and trihydroxy -D-9- tetrahydrocannabinol (triOH-THC).
  • Derivatives of such cannabinoids may be used as the cannabinoid moiety as well.
  • the hydroxyl, methyl, and olefinic groups can be modified to enhance binding affinity to cannabinoid receptors CB1 or CB2.
  • the groups may be modified through acetylation, methylation, or neutralization to form salts. Examples of such derivatives are illustrated in structures (CM-1 ) through (CM-5): [0044]
  • the hydroxyl groups in derivatives (CM-1 ) and (CM-2) are acetylated, and (CM-2) is also carboxylated.
  • the hydroxyl groups in derivative (CM-3) have been methylated.
  • the sodium and potassium salts of CBD are illustrated in derivatives (CM- 4) and (CM-5).
  • Other salts, such as lithium or cesium, are also contemplated.
  • the linker of Formula (I) has the structure of Formula (L-1 ):
  • the wiggly lines indicate the presence of a covalent bond. It can be seen that the linker of Formula (L-1 ) includes an ester end group on the left side, and an amide end group on the right side.
  • the resulting conjugate molecule has the structure of Formula (l-a):
  • the active agent is a celecoxib moiety
  • the cannabinoid moiety is a cannabidiol (CBD) moiety.
  • Conjugate molecules of this structure are illustrated in Formula (II) below:
  • Formula (II) wherein L is alkyl or substituted alkyl; and wherein R is hydrogen, alkyl, or substituted alkyl.
  • the celecoxib moiety is on the left-hand side of Formula (II), and the CBD moiety is on the right-hand side of Formula (II).
  • the linker contains an ester group which is covalently bonded to the nitrogen atom in the amino group of the celecoxib moiety.
  • the linker also contains an amide group which is covalently bonded to an oxygen atom of the CBD moiety.
  • alkyl refers to a radical composed entirely of carbon atoms and hydrogen atoms which is fully saturated.
  • the alkyl radical may be linear, branched, or cyclic.
  • the alkyl radical has the ability to form a single bond to one or two different nonhydrogen atoms, depending on the context. For example, the formulas -CH2-CH3 and - CH2-CH2- should both be considered alkyl.
  • an alkyl group has from 1 to about 8 carbon atoms.
  • amino refers to a radical of the formula -NR 1 R 2 , where R 1 and R 2 are independently hydrogen, alkyl, or substituted alkyl. This includes monosubstituted radicals (i.e. where R 2 is hydrogen) and disubstituted radicals (where neither R 1 nor R 2 are hydrogen).
  • heteroatom ic refers to the end group containing at least one oxygen, nitrogen, or sulfur atom.
  • esteer refers to a radical of the formula -O-CO-.
  • amide refers to a radical of the formula -CO-NR-, where R is hydrogen, alkyl, or substituted alkyl.
  • substituted refers to at least one hydrogen atom on the named radical being substituted with another functional group.
  • An exemplary substituted alkyl group is a perhaloalkyl group, wherein one or more hydrogen atoms in an alkyl group are replaced with halogen atoms.
  • An alkyl group can be substituted with a hydroxyl or halogen group.
  • hydroxyl refers to -OH.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • carboxylic acid refers to a radical of the formula -COOH. Although the carboxylic acid contains a hydroxyl group, they participate in reactions differently, and so a carboxylic acid group should not be considered a hydroxyl group, and a hydroxyl group should not be considered a carboxylic acid group.
  • L is alkyl containing from 1 to about 8 carbon atoms.
  • L contains 3 to 5 carbon atoms, and in an even more specific embodiment is n-propyl (i.e. 3 carbon atoms arranged linearly).
  • the conjugate molecule has the structure of Formula (ll-a):
  • R is hydrogen or alkyl.
  • R is alkyl containing from 1 to about 8 carbon atoms.
  • L contains 1 to 3 carbon atoms, and in an even more specific embodiment is a methyl group (-CH3).
  • the conjugate molecule has the structure of Formula (lll-a) or Formula (lll-b):
  • the active agent is illustrated as a celecoxib moiety.
  • the cannabinoid moiety is the acetylated derivative (CM-1 ), now mono-acetylated or having an acetoxy substituent.
  • CM-1 acetylated derivative
  • CM-2 mono-acetylated or having an acetoxy substituent.
  • the derivatives of (CM-2)-(CM-5) can also be used.
  • the cannabinoid moiety is cannabigerol
  • Formula (IV-c) the cannabinoid moiety is cannabichromene.
  • FIG. 1A and FIG. 1B illustrate one method for synthesizing the molecules of Formula (II), using the conjugate molecules of Formula (lll-a) and Formula (lll-b) as an example.
  • molecule 1 is a 3-aminopropan-1-ol (or more broadly, an aminohydroxyalkane) in which one hydrogen atom on the amino group has been replaced with a t-butyloxycarbonyl (Boc) protecting group. It is noted that the molecule 1 must have at least one hydrogen atom. Again, R can be hydrogen, alkyl, or substituted alkyl.
  • the addition of the Boc protecting group is typically performed in a solvent such as water, water/THF, THF, acetonitrile, dioxane, or methanol at room temperature or moderate heat (40°C) in the presence of a base.
  • Common bases include sodium hydroxide, 4-dimethylaminopyridine (DMAP) and sodium bicarbonate.
  • DMAP 4-dimethylaminopyridine
  • first intermediate molecule 2 a chloroformate group to form first intermediate molecule 2, a 3-aminopropyl chloroformate, or more generally an aminoalkyl chloroform ate.
  • the first intermediate molecule 2 is then reacted with celecoxib (or more broadly, an active agent having an acidic hydrogen atom attached to a nitrogen atom).
  • the chloroformate group of molecule 2 reacts with the amino group of the celecoxib molecule, forming a covalent bond and releasing HCI in the process to obtain second intermediate molecule 3.
  • the Boc protecting group is then removed to obtain primary intermediate molecule 4.
  • the removal is performed in an acidic environment in water or an organic solvent such as toluene, dichloromethane, or ethyl acetate.
  • Concentrated hydrochloric acid (HCI) or trifluoroacetic acid (TFA) can be used.
  • the reaction usually occurs at room temperature.
  • the cannabinoid broadly contains at least one hydroxyl group.
  • CBD is reacted with TBDPSCI (t-butyl- diphenylchlorosilane) to replace the hydrogen atom on one of the hydroxyl groups with a TBDPS protecting group and obtain third intermediate molecule 5.
  • third intermediate molecule 5 is reacted with phosgene to convert the second hydroxyl group to a chloroformate group to obtain secondary intermediate molecule 6.
  • the use of the protecting group is optional, with the recognition that the resulting conjugate molecule will not correspond to the structure Formula (II) because both hydroxyl groups are free to react in subsequent steps.
  • tertiary intermediate molecule 7 The chloroformate group of molecule 6 reacts with the amino group of molecule 4, forming a covalent bond and releasing HCI again.
  • the tertiary intermediate molecule 7 is then reacted with TBAF (tetra-n-butylammonium fluoride) and AcOH (acetic acid) in THF (tetrahydrofuran) to remove the TBDPS protecting group, resulting in the molecule of Formula (II), which is labeled 8 in FIG. 1B.
  • TBAF tetra-n-butylammonium fluoride
  • AcOH acetic acid
  • THF tetrahydrofuran
  • conjugate molecule should be construed as also including the molecule in the form of a salt, for example by replacing a hydrogen atom with a metal ion such as sodium (Na) or potassium (K).
  • a method for synthesizing a conjugate molecule of the present disclosure begins with an aminoalkyl chloroformate having a protecting group on the amino group (e.g. the first intermediate molecule 2).
  • the amino group and the chloroformate group are at opposite ends of the alkyl chain.
  • the aminoalkyl chloroformate is then reacted with an active agent having an acidic hydrogen atom attached to a nitrogen atom.
  • a covalent bond is formed between the chloroformate and the nitrogen atom to obtain a second intermediate molecule.
  • the protecting group is removed from the amino group to obtain a primary intermediate molecule comprising the active agent.
  • a secondary intermediate molecule comprising a cannabinoid having a chloroformate group is then reacted the primary intermediate molecule with the secondary intermediate molecule to obtain the conjugate molecule.
  • the secondary intermediate molecule can prepared by reacting a cannabinoid with, for example, TBDPSCI, to form a protecting group on a hydroxyl group of the cannabinoid and obtain the secondary intermediate molecule. This controls the reaction between the primary intermediate molecule and the secondary intermediate molecule. The protecting group on the secondary intermediate molecule can then be removed from the conjugate molecule.
  • FIG. 1C illustrates what is believed to be a general reaction between the first intermediate molecule 2 and a secondary amide group, illustrated here using meloxicam to obtain a second intermediate molecule 3a. The conjugate molecule can then be formed continuing the process as illustrated in FIG. 1A and FIG. 1B.
  • FIG. 1D illustrates what is believed to be a general reaction between the first intermediate molecule 2 and a carboxylic acid chloride group, illustrated here using ketorolac tromethamine to obtain a second intermediate molecule 3b.
  • the conjugate molecule can then be formed continuing the process as illustrated in FIG. 1A and FIG. 1B
  • FIG. 1E illustrates what is believed to be a first general reaction for obtaining a second intermediate molecule for etoricoxib.
  • Etoricoxib is reacted with protected aminohydroxyalkane 1 in the presence of cesium carbonate, dimethyl sulfoxide (DMSO), and heat to obtain second intermediate molecule 3c.
  • DMSO dimethyl sulfoxide
  • the aminohydroxyalkane reacts with the chloride atom instead of a nitrogen atom.
  • the conjugate molecule can then be formed continuing the process as illustrated in FIG. 1A and FIG. 1B.
  • FIG. 1F illustrates what is believed to be a second general reaction for obtaining a second intermediate molecule for etoricoxib.
  • Etoricoxib is first reacted in the presence of lithium bis(trimethylsilyl)amide, bromine, and 1 ,4-dioxane to obtain what is labeled here as etoricoxib-Br.
  • This molecule includes a bromine atom on the methyl group next to the sulfonyl group.
  • the etoricoxib-Br is then reacted with protected aminohydroxyalkane 1 in the presence of cesium carbonate, dimethyl sulfoxide (DMSO), and heat to obtain second intermediate molecule 3d.
  • DMSO dimethyl sulfoxide
  • the aminohydroxyalkane reacts with the bromine atom.
  • the conjugate molecule can then be formed continuing the process as illustrated in FIG. 1A and FIG. 1B.
  • FIG. 1G illustrates what is believed to be a general reaction for obtaining a second intermediate molecule for rofecoxib.
  • This reaction is essentially the same as that illustrated in FIG. 1F, but using rofecoxib instead of etoricoxib.
  • the first intermediate is labeled here as rofecoxib-Br, which is then reacted with protected aminohydroxyalkane 1 to obtain second intermediate molecule 3e.
  • the conjugate molecule can then be formed continuing the process as illustrated in FIG. 1A and FIG. 1B
  • FIG. 1H illustrates what is believed to be a general reaction for obtaining a second intermediate molecule using nabumetone.
  • Nabumetone is reacted in the presence of hydrogen iodide and heat to replace the methoxy group with a hydroxyl group, obtaining a molecule that is labeled here as nabumetone-OH.
  • the nabumetone- OH is then reacted with the first intermediate molecule 2 to obtain second intermediate molecule 3f.
  • the conjugate molecule can then be formed continuing the process as illustrated in FIG. 1A and FIG. 1B.
  • protecting groups may be applied to direct the reaction towards only one of the reactive groups.
  • lumiracoxib, bromfenac, and etodolac each have an amino group and a carboxylic acid group.
  • An appropriate protecting group could be applied, for example, to the amino group to direct the reaction of the first intermediate molecule 2 towards the carboxylic acid group, or vice versa. The protecting group could then be removed at an appropriate step in the synthesis of the conjugate molecule.
  • conjugate molecule should be construed as also including the molecule in other forms such as a salt, for example by replacing a hydrogen atom with a metal ion such as sodium (Na) or potassium (K), or an acid, an ester, an analog, or a derivative.
  • a metal ion such as sodium (Na) or potassium (K)
  • the conjugate molecules of the present disclosure can be used in a pharmaceutical composition suitable for being administered to a subject such as a human or animal.
  • the composition should contain a pharmaceutically effective amount of the conjugate molecule.
  • the pharmaceutically effective amount may range from about 0.1 to about 1000 milligrams per milliliter of the composition (w/v).
  • the pharmaceutical composition may be administered via topical, transdermal, oral, nasal, intravenous, intra-arterial, intradermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intrapleural, vaginal, intraurethral, intratumoral, intravesicular, intrathecal, intracranial, intraspinal, sublingual, buccal, or rectal routes, as appropriate or feasible for the given medical condition.
  • the dose used in a particular formulation or application may be determined by the requirements of the particular state of disease and the constraints imposed by the characteristics or capacities of the carrier materials. It contemplated in that in the most desirable form, the composition will be administered topically.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier.
  • the carrier acts as a vehicle for delivering the conjugate molecule.
  • pharmaceutically acceptable carriers include liquid carriers like water, oil, and alcohols, in which the conjugate molecule can be dissolved or suspended.
  • the pharmaceutical composition may also include excipients.
  • excipients include buffering agents, surfactants, preservative agents, bulking agents, polymers, and stabilizers, which are useful with these molecular antagonists.
  • Buffering agents are used to control the pH of the composition.
  • Surfactants are used to stabilize proteins, inhibit protein aggregation, inhibit protein adsorption to surfaces, and assist in protein refolding.
  • Exemplary surfactants include Tween 80, Tween 20, Brij 35, Triton X- 10, Pluronic F127, and sodium dodecyl sulfate.
  • Preservatives are used to prevent microbial growth. Examples of preservatives include benzyl alcohol, m-cresol, and phenol.
  • Hydrophilic polymers such as dextran, hydroxyl ethyl starch, polyethylene glycols, and gelatin can be used to stabilize proteins. Polymers with nonpolar moieties such as polyethylene glycol can also be used as surfactants.
  • Protein stabilizers can include polyols, sugars, amino acids, amines, and salts. Suitable sugars include sucrose and trehalose. Amino acids include histidine, arginine, glycine, methionine, proline, lysine, glutamic acid, and mixtures thereof. Proteins like human serum albumin can also competitively adsorb to surfaces and reduce aggregation of the protein-like molecular antagonist. It should be noted that particular molecules can serve multiple purposes. For example, histidine can act as a buffering agent and an antioxidant. Glycine can be used as a buffering agent and as a bulking agent.
  • the pharmaceutical composition may be in the form of a powder, injection, solution, suspension, or emulsion. It is more particularly contemplated that the composition will be delivered by injection or by topical administration.
  • the conjugate molecule may be lyophilized using standard techniques known to those in this art. The lyophilized conjugate molecule may then be reconstituted with, for example, suitable diluents such as normal saline, sterile water, glacial acetic acid, sodium acetate, combinations thereof and the like.
  • Dose will depend on a variety of factors, including the therapeutic index of the drugs, disease type, patient age, patient weight, and tolerance.
  • the dose may broadly be chosen to achieve serum concentrations from about 0.1 pg/ml to about 100 pg/ml in the patient.
  • the dose of a particular patient can be determined by the skilled clinician using standard pharmacological approaches in view of the above factors.
  • the response to treatment may be monitored by analysis of blood or body fluid levels of the patient, or by other appropriate means. The skilled clinician will adjust the dose based on the response to treatment revealed by these measurements.
  • a single administration may usually be sufficient to produce a therapeutic effect, but it is contemplated that multiple administrations will be used to assure continued response over a substantial period of time.
  • compositions of the present disclosure can be used to treat any appropriate medical condition.
  • the term “treat” is used to refer to a reduction in progression of the medical condition, a regression in the medical condition, and/or a prophylactic usage to reduce the probability of presentation of the medical condition.
  • Such medical conditions might include inflammatory conditions such as arthritis, or pain management, or cancer, or neuropsychiatric disorders. This may include any form of arthritis, such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or gout, whether in adult or juvenile patients.
  • Non-limiting examples of pain that could be treated might include acute pain, painful menstruation, or pain after surgery.
  • Nonlimiting examples of cancers include colorectal adenomas, pre-cancerous growths, familial adenomatous polyposis, neuroblastoma, or breast cancer. Any neuropsychiatric disorder might be treatable, including for example major depressive disorder or schizophrenia.
  • Additional examples of medical conditions for which some COX-2 inhibitors have been approved for use include acute and sub-acute bursitis; age related macular degeneration; allergic conjunctivitis; ankylosing spondylitis (Bekhterev's disease); anterior segment inflammation; anterior uveitis; arthritis pain; back pain; blepharitis; cancer pain; colorectal cancer; conjunctivitis; cystoid macular edema; dental abscess; dental pain (toothache/tooth pain); depression; dysmenorrhea; familial adenomatous polyposis; frozen shoulder syndrome; gouty arthritis (gout); juvenile arthritis; juvenile rheumatoid arthritis; low back pain; migraine; myalgia (muscle pain); ocular inflammation; ocular pain (eye pain); osteoarthritis; osteoarthritis pain; pain; polyarticular arthritis; post-operative pain; primary dysmenorrhea; renal colic; rheumatoid
  • the pharmaceutical compositions I formulations of the present disclosure are intended to be applied topically to the skin of the user I patient. This results in the active ingredient being delivered to local tissue.
  • the formulations may also operate transdermally, delivering the active ingredient across the skin and into systemic circulation.
  • the topical formulation may be in the form of a cream, gel, hydrogel, liquid, lotion, or ointment.
  • the topical formulation may be applied manually, sprayed, or by syringe, applicator, or other dispensing means.
  • the topical formulation could alternatively be provided in the form of a matrix-type delivery system, where the formulation is absorbed or suspended in a matrix that is then adhered to a backing membrane (commonly referred to as a bandage or a patch).
  • the conjugate molecules of the present disclosure may be administered singly, or in combination with other pharmaceutical therapies.
  • the pharmaceutical composition may also contain a second therapeutic agent which operates by a distinct mechanism of action or through another pathway.
  • the second therapeutic agent could include acetaminophen; a non-steroidal anti-inflammatory drug (NSAID) such as aspirin, ibuprofen, or naproxen; a COX-2 inhibitor; or an opioid such as codeine, oxycodone, hydrocodone, buprenorphine, or tramadol.
  • NSAID non-steroidal anti-inflammatory drug
  • COX-2 inhibitor a COX-2 inhibitor
  • an opioid such as codeine, oxycodone, hydrocodone, buprenorphine, or tramadol.
  • the conjugate molecule and the second therapeutic agent are individually present in less-than-pharmaceutically effective amounts, but together obtain the desired therapeutic effect, and might act together synergistically as well.
  • kits comprising a pharmaceutical composition as described above, which may also contain any or all of an applicator, such as a pad, utensil, spatula, sprayer or droplet dispenser; and / or a bandage, such as a dermal patch, wrap or other form of bandage and instructions for use thereof.
  • an applicator such as a pad, utensil, spatula, sprayer or droplet dispenser
  • a bandage such as a dermal patch, wrap or other form of bandage and instructions for use thereof.
  • the second intermediate molecule (3) was mixed with 1 N HCI in ethyl acetate (3 mL) at room temperature, but the reaction was very slow, so was rotary evaporated and then switched to 4N HCI in dioxane (3 mL) at room temperature overnight. After additional concentration, the remainder was loaded onto a column to obtain the primary intermediate molecule (4) (480 mg). The identity of (3) was verified using NMR and MS. Further experiments increased the product yield, so that 320 mg of celecoxib would yield 280 mg of the primary intermediate molecule (4).
  • CBD (5.1 grams) was mixed with TBDPS-chloride (10.2 grams) in imidazole (2.7 grams) and anhydrous THF (100 mL) overnight at 60°C to obtain the third intermediate molecule (5).
  • TBDPS-chloride (10.2 grams) in imidazole (2.7 grams) and anhydrous THF (100 mL) overnight at 60°C to obtain the third intermediate molecule (5).
  • a mixture of deionized water and ethyl acetate was added, and the organic phase was collected and concentrated, then run through a column with DCM to collect the third intermediate molecule (5) (5.63 grams).
  • the third intermediate molecule (235 mg, 0.425 mmol) was then reacted with phosgene (365 microliters) in anhydrous DCM and pyridine (50 mg), then underwent workup and a chromatographic purification prior to concentration to obtain the secondary intermediate molecule (6) (95 mg). The mixture was rotary evaporated to dryness.
  • the primary intermediate molecule (4) (164 mg, 0.34 mmol) was dissolved in DCM (3 mL) and treated with phosgene solution (365 microliters) and pyridine (50 mg). TLC indicated incomplete reaction, so an additional portion of phosgene solution was added (50 microliters) and the reaction mixture was then concentrated to dryness. This was combined with the secondary intermediate molecule (6) (235 mg, 0.425 mmol) and N,N-diisopropylethylamine (iPr2NEt, 175 mg) in anhydrous DMF (5 mL), stirring until completion. The reaction was partitioned between ethyl acetate and deionized water and the organic phase concentrated for purification.
  • FIGS. 2A-2B An alternative synthesis reaction was attempted for conjugate molecule (8), as illustrated in FIGS. 2A-2B.
  • the CBD chloroformate (6) was reacted with 3-amino-1 -propanol to obtain intermediate (A), then reacted with phosgene and ammonia to obtain intermediate (B).
  • the sulfonyl chloride of celecoxib (Cxb-SO2CI) was prepared by the reaction of two starting reactants (C, D) in HCI to obtain intermediate (E), then chlorinating with PCIs.
  • intermediate (B) and the Cxb-So2CI were then reacted together to obtain the conjugate molecule (8).
  • the linker formed from the 3-amino-1- propanol
  • conjugate molecule (8) Another alternative synthesis reaction was attempted for conjugate molecule (8), as illustrated in FIG. 3.
  • the primary intermediate molecule (4A) was converted into an isocyanate (4B) using a phosgene solution and an aqueous NaHCOs DCM solution, although there was some possibility of forming a urea byproduct (G).
  • the isocyanate could then be reacted directly with protected or unprotected CBD in triethylamine and DCM to obtain the conjugate molecule (8).

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Abstract

Des molécules conjuguées formées à partir d'un agent actif qui est lié à un fragment cannabinoïde par l'intermédiaire d'un lieur spécifié ayant des groupes terminaux ester et amide sont divulguées. L'agent actif peut être un fragment inhibiteur de COX-2, et le fragment cannabinoïde peut être un fragment cannabidiol. Ces molécules conjuguées sont envisagées pour être potentiellement efficaces dans le traitement d'états médicaux.
PCT/US2023/011680 2022-02-01 2023-01-27 Molécules conjuguées de cannabinoïdes Ceased WO2023150057A1 (fr)

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US202263321319P 2022-03-18 2022-03-18
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US63/321,319 2022-03-18
US63/321,341 2022-03-18
US17/982,859 US11660348B1 (en) 2022-02-01 2022-11-08 Cannabinoid conjugate molecules
US17/982,779 2022-11-08
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WO2019159168A1 (fr) * 2018-02-13 2019-08-22 Beetlebung Pharma Ltd. Dérivés et conjugués de cannabinoïdes et leurs utilisations
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