WO2023239694A1 - Molécules conjuguées de cannabinoïdes comprenant un composant d'avermectine - Google Patents

Molécules conjuguées de cannabinoïdes comprenant un composant d'avermectine Download PDF

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Publication number
WO2023239694A1
WO2023239694A1 PCT/US2023/024537 US2023024537W WO2023239694A1 WO 2023239694 A1 WO2023239694 A1 WO 2023239694A1 US 2023024537 W US2023024537 W US 2023024537W WO 2023239694 A1 WO2023239694 A1 WO 2023239694A1
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Prior art keywords
substituents
independently selected
group
linear
optionally substituted
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PCT/US2023/024537
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English (en)
Inventor
Paul HERSHBERGER
Philip ARLEN
William Fisher
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Diverse Biotech, Inc.
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Publication of WO2023239694A1 publication Critical patent/WO2023239694A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • This disclosure relates generally to multifunctional therapeutics.
  • This disclosure describes multifunctional conjugate molecules comprising at least one avermectin component and at least one cannabinoid component covalently attached by a linker:
  • embodiments of the disclosed conjugate molecules are designed to deliver more than one therapeutic benefit via more than one mechanism of action; this is achieved when the covalent binding of the avermectin component to its target may accompany or facilitate the release of the cannabinoid at or near the site of the avermectin component’s action, which can then effect a second therapeutic benefit. That is, these conjugate molecules are designed to deliver the therapeutic benefits of each of their components. In other embodiments, the avermectin component and the cannabinoid component are released to provide their respective therapeutic benefits via functionality of the linker.
  • Conjugate molecules comprise at least one avermectin component covalently linked via a linker to at least one cannabinoid component.
  • an avermectin component is covalently attached directly to a hydroxy or carboxylic acid group of a cannabinoid component.
  • cannabinoid conjugate components comprise an avermectin component and a cannabinoid component attached by means of a linker which is covalently attached at one end to the avermectin component and at the other end to a hydroxy or carboxylic acid group of the cannabinoid component.
  • the hydroxy group is an “aromatic hydroxy group;” i.e., a hydroxy group bonded directly to an aromatic hydrocarbon.
  • the hydroxy group is an “aliphatic hydroxy group;” i.e., a hydroxy group bound to a carbon that is not part of an aromatic ring.
  • conjugate molecules contain only one avermectin component.
  • conjugate molecules can contain two or more avermectin components, which can be the same or different.
  • the two or more linkers can be the same or different and, independently, the two or more avermectin components can be the same or different.
  • a cannabinoid component contains two or more hydroxy groups
  • the two or more hydroxy groups can be aliphatic or the two or more hydroxy groups can be aromatic, or, for example, a first hydroxy group can be aliphatic and a second hydroxy group can be aromatic.
  • conjugate molecules can contain two avermectin components which are both attached to a single linker.
  • the two avermectin components can be the same or different.
  • a conjugate molecule can contain an additional cannabinoid component.
  • Conjugate molecules can have one or more centers of asymmetry and can therefore be prepared either as a mixture of isomers (e.g., a racemic or diasteromeric mixture) or in an enantiomerically or diasteromerically pure form. Such forms include, but are not limited to, diastereomers, enantiomers, and atropisomers. Conjugate molecules can also include alkenes and can therefore be prepared either as a mixture of double bond isomers or independently as either an E or Z isomer. Isotopic variants of conjugate molecules can also be prepared.
  • Conjugate molecules can form salts.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base.
  • a metal ion e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J Pharm. Sci. 1977 Jan; 66(1): 1-19..
  • C1-C3 linear or branched alkyl means “methyl, ethyl, propyl, and isopropyl.”
  • C1-C3 linear or branched heteroalkyl means “a linear or branched heteroalkyl containing 1, 2, or 3 carbon atoms.”
  • C1-C8 linear or branched heteroalkyl means “each of a Cl, C2, C3, C4, C5, C6, C7, and C8 linear heteroalkyl and Cl, C2, C3, C4, C5, C6, C7, and C8 branched heteroalkyl.”
  • C1-C24 linear or branched heteroalkyl means each of a Cl, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cl l, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24 linear heteroalkyl and Cl, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cl l, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24 branched heteroalkyl.”
  • C1-C6 linear or branched alkoxy means “a linear or branched alkoxyl containing 1, 2, 3, 4, 5, or C carbon atoms.”
  • C1-C6 linear or branched alkylamino means “a linear or branched alkylamino containing 1, 2, 3, 4, 5, or 6 carbon atoms.”
  • C1-C6 linear or branched dialkylamino means “each linear or branched dialkylamino in which each alkyl independently contains 1, 2, 3, 4, 5, or 6 carbon atoms.”
  • C3-C6 cycloalkyl means “C3, C4, C5, and C6 cycloalkyl.”
  • R7 is H or is C1-C3 linear or branched alkyl or C1-C3 linear or branched heteroalkyl comprising an O, N, or S atom;
  • R7 is H or is C1-C3 linear or branched alkyl or C1-C3 linear or branched heteroalkyl comprising an O, N, or S atom;
  • R4 is H or C1-C3 linear or branched alkyl
  • R4 is H, R4 is methyl, R4 is ethyl, R4 is propyl, and R4 is isopropyl, respectively.
  • An “avermectin component” as used in this disclosure is that portion of an avermectin agent that is present in a conjugate molecule and covalently attached to a linker.
  • a number of avermectin agents can be used to provide an avermectin component of a conjugate molecule.
  • An “avermectin agent” is a member of the avermectin family or an active metabolite or derivative thereof. Examples of avermectin derivatives are described, for example, in Huang et al., Applied and Environmental Microbiology 81(16), 5325-34, 2015; Batiha et al., Pharmaceuticals (Basel) 13(8), 196, 2020.
  • the avermectin component is provided by avermectin:
  • the avermectin can be avermectin B 1a or avermectin B 1b .
  • the avermectin component is provided by ivermectin:
  • the ivermectin can be ivermectin B 1a or ivermectin B 1b .
  • the avermectin component is provided by emamectin:
  • the emamectin can be emamectin B 1a or emamectin B 1b .
  • the avermectin component is provided by moxidectin:
  • the avermectin component is provided by eprinomectin:
  • the avermectin component is provided by doramectin :
  • the avermectin component is provided by selamectin:
  • linkers can be used in the conjugate molecules. Examples are shown below. in which marks a bond attaching the linker to the avermectin component, # indicates a site of covalent attachment to the cannabinoid component, and in which:
  • Ar is either:
  • Re, Rf, and R g independently are selected from the group consisting of:
  • a “cannabinoid component” as used in this disclosure is that portion of a cannabinoid that is present in the conjugate molecule and covalently attached to a linker, as shown in the examples below.
  • cannabinoids include, but are not limited to, cannabigerol s, cannabichromenes, cannabidiols, tetrahydrocannabinols, cannabicyclols, cannabielsoins, cannabinols, cannabinodiols, cannabitriols, dehydrocannabifurans, cannabifurans, cannabichromanons, and cannabiripsols.
  • cannabichromenes include cannabichromenic acid (CBC), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), and cannabichromevarin (CBCV).
  • cannabidiols include cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), and cannabidiorcol (CBD-Ci).
  • cannabielsoins include cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), and cannabielsoin (CBE).
  • cannabitriols examples include cannabitriol (CBT), 10-ethoxy-9-hydroxy-A-6a- tetrahydrocannabinol, cannabitriolvarin (CBTV), and ethoxy-cannabitriolvarin (CBTVE).
  • Cannabifurans include dehydrocannabifuran (DCBF) and cannabifuran (CBF).
  • cannabinoids examples include cannabichromanon (CBCN), 10-oxo-A-6a- tetrahydrocannabinol (OTHC), cannabiripsol (CBR), and trihydroxy-A-9-tetrahydrocannabinol (triOH-THC).
  • CBCN cannabichromanon
  • OTHC 10-oxo-A-6a- tetrahydrocannabinol
  • CBR cannabiripsol
  • triOH-THC trihydroxy-A-9-tetrahydrocannabinol
  • a second avermectin component can be covalently attached to the second hydroxyl group by means of a second linker such that the conjugate molecule contains a first avermectin component and a second avermectin component covalently attached to the cannabinoid component by means of a first linker and a second linker, respectively.
  • conjugate molecules comprising two avermectin components
  • the avermectin components can be the same or different.
  • Conjugate molecules comprising a first avermectin component can comprise one, two, or three cannabinoid components.
  • a conjugate molecule comprises a first cannabinoid component, a second cannabinoid component, and a third cannabinoid component.
  • the first and second cannabinoid components are the same and the third cannabinoid component is different.
  • the second and third cannabinoid components are the same and the first cannabinoid component is different.
  • the first and third cannabinoid components are the same and the second cannabinoid component is different.
  • the first, second, and third cannabinoid components are the same.
  • the first, second, and third cannabinoid components are different.
  • each cannabinoid component can be the same or different, and, when linkers are used, each linker can be the same or different.
  • linkers when linkers are used, each linker can be the same or different.
  • Any of the three OH groups may be linked in the general fashion shown in these Examples using linkers as defined.
  • the following Examples show a conjugate with either one or two linked cannabinoids. Any of the three OH groups may be linked in the general fashion shown in these Examples using linkers as defined.
  • Anti-viral activity has been reported, for example, for ivermectin; see Martin et al., Trends in Parasitology 37(1), 48-64, 2021 (summarizing experiments demonstrating activity in vitro against the RNA viruses dengue virus, West Nile virus, and Venezuelan equine encephalitis virus; activity in vitro and in vivo against the DNA virus pseudorabies virus; and, at high concentrations, activity in vitro against SARS-CoV-2- infected Vero/hSLAM cells).
  • Anti-tumor activity has also been reported, for example, for example, for ivermectin; see Liu, 2020 (summarizing experiments demonstrating activity in vitro against multiple cancers including breast, colon, gastric, glioblastoma, leukemia, melanoma, and ovarian).
  • An advantage of conjugate molecules is that a cannabinoid can be delivered directly to the site of action of the avermectin agent, where the released cannabinoid can provide further therapeutic benefits.
  • the therapeutic benefits and potential benefits of cannabinoids are well known. For example, see Dzierzanowski, Cancers 11, 129-41, 2019 (oncology and palliative care); Urits et al., Pain Ther.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des molécules conjuguées multifonctionnelles dans lesquelles au moins un agent avermectine est lié de manière covalente à au moins un cannabinoïde au moyen d'un lieur. Les molécules conjuguées décrites sont conçues pour fournir des avantages thérapeutiques de composants des molécules conjuguées.
PCT/US2023/024537 2022-06-08 2023-06-06 Molécules conjuguées de cannabinoïdes comprenant un composant d'avermectine WO2023239694A1 (fr)

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US63/350,074 2022-06-08

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100144859A1 (en) * 2008-12-04 2010-06-10 Meng Charles Q Dimeric avermectin and milbemycin derivatives
US20170119807A1 (en) * 2015-10-28 2017-05-04 City Of Hope Macrocyclic lactones and uses thereof as modulators of purinergic receptors
WO2020263888A1 (fr) * 2019-06-24 2020-12-30 Diverse Biotech, Inc. Molécules conjuguées de cannabinoïdes
WO2021076197A1 (fr) * 2019-10-15 2021-04-22 Diverse Biotech, Inc. Molécules conjuguées

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100144859A1 (en) * 2008-12-04 2010-06-10 Meng Charles Q Dimeric avermectin and milbemycin derivatives
US20170119807A1 (en) * 2015-10-28 2017-05-04 City Of Hope Macrocyclic lactones and uses thereof as modulators of purinergic receptors
WO2020263888A1 (fr) * 2019-06-24 2020-12-30 Diverse Biotech, Inc. Molécules conjuguées de cannabinoïdes
WO2021076197A1 (fr) * 2019-10-15 2021-04-22 Diverse Biotech, Inc. Molécules conjuguées

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