WO2023249471A1 - Nouveau dérivé d'amide immunorégulateur, son procédé de préparation et son utilisation - Google Patents
Nouveau dérivé d'amide immunorégulateur, son procédé de préparation et son utilisation Download PDFInfo
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- WO2023249471A1 WO2023249471A1 PCT/KR2023/008838 KR2023008838W WO2023249471A1 WO 2023249471 A1 WO2023249471 A1 WO 2023249471A1 KR 2023008838 W KR2023008838 W KR 2023008838W WO 2023249471 A1 WO2023249471 A1 WO 2023249471A1
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Classifications
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- 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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to novel immunomodulatory amide derivatives and their preparation methods and uses.
- Thalidomide was a drug sold from the late 1950s to the 1960s to prevent morning sickness in pregnant women, but as teratogenic side effects were reported, its use and handling was prohibited for pregnant women, as well as people of childbearing age or those with the potential to become pregnant. However, interest in the drug increased again after thalidomide was found to be clinically effective in the treatment of erythema nodosum (ENL), HIV wasting syndrome, and various cancers.
- ENL erythema nodosum
- Anti-tumor necrosis factor alpha (anti-TNF- ⁇ ) activity was confirmed from mechanistic studies on ENL activity. Specifically, thalidomide increases the degradation of TNF- ⁇ RNA, thereby reducing its synthesis and secretion. Further studies have shown that it is a known co-stimulator of both CD8+ and CD4+ T cells and may also act as an angiogenesis inhibitor as an inhibitor of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the transcription factor NF- ⁇ B. It turned out that there was.
- bFGF basic fibroblast growth factor
- VEGF vascular endothelial growth factor
- TNF- ⁇ and its family members play a pivotal role in various physiological and pathological processes, including cell proliferation and differentiation, apoptosis, regulation of immune responses, and induction of inflammation.
- TNF- ⁇ acts through two receptors, TNFR1 and TNFR2, the former of which is expressed in all tissues and is the main signaling receptor for TNF- ⁇ . The latter is mainly expressed in immune cells and mediates more limited biological responses.
- the caspase cascade is activated, causing cells to die through apoptosis.
- the main cell surface molecules that can initiate apoptosis are the ligands and receptors of TNF family members.
- each death-inducing member of the TNF receptor family contains a cytoplasmic 'death domain' (DD), a protein-protein interaction motif that is important for binding to downstream components of the signaling machinery.
- DD cytoplasmic 'death domain'
- TRAIL a tumor necrosis factor-related apoptosis-inducing ligand
- TRAIL a tumor necrosis factor-related apoptosis-inducing ligand
- TNF- ⁇ has been implicated in many inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease, and Crohn's disease, and is known to further exacerbate dementias associated with ENL, septic shock, AIDS, and Alzheimer's disease (AD). .
- thalidomide-based treatments include thalidomide, bortezomib, lenalidomide, and pomalidomide.
- the injectable drug bortezomib is steadily maintaining its market and growing, and the oral drug is taking over the existing thalidomide position. Domide has replaced it and is recording high growth in the market.
- Lenalidomide is the next-generation drug of thalidomide and shows better therapeutic effects than thalidomide through more powerful cancer cell killing and immune regulation.
- the combined treatment of lenalidomide and dexamethasone is known to be quite effective, with a disease-free survival of 13.4 months and an overall survival of 38 months.
- Pomalidomide directly inhibits angiogenesis and myeloma cell growth, and this dual effect is centered on its activity in myeloma rather than on other pathways such as TNF- ⁇ inhibition.
- pomalidomide exhibits anti-angiogenic and anti-myeloma activities.
- thio compounds were newly synthesized using thalidomide derivatives, and it was confirmed that these thio compounds can regulate TNF- ⁇ activity and change the expression of immune cytokines by TCR-stimulated T cells.
- the present inventors have made diligent efforts to develop additional derivatives to improve the pharmaceutical effect of thalidomide, and as a result, compounds of [Formula 1], [Formula 2], and [Formula 3] have cereblon binding ability and suppress bone marrow cells.
- the present invention was completed by confirming that the immunomodulatory and antioxidant effects were strengthened without side effects such as reproductive toxicity, and the stability in plasma was improved, enabling development as a variety of therapeutic agents.
- the object of the present invention is to provide novel thalidomide derivatives, methods for their preparation and uses thereof.
- the present invention provides any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
- the present invention also provides a pharmaceutical composition for preventing or treating inflammatory diseases containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- the inflammatory disease may be selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease.
- any one compound selected from the group consisting of [Formula 1] to [Formula 3] may be characterized as being non-teratogenic.
- the present invention also provides a pharmaceutical composition for preventing or treating brain diseases containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- the brain disease includes traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's dementia, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke and multiple sclerosis. It may be characterized as being selected from the group consisting of.
- any one compound selected from the group consisting of [Formula 1] to [Formula 3] may be characterized as being non-teratogenic.
- the present invention also provides a method for preparing a compound of formula 1 comprising the following steps:
- the manufacturing method includes, after step (b),
- the present invention also provides a method for preparing a compound of formula 2 comprising the following steps:
- the manufacturing method includes, after step (b),
- the present invention also provides a method for preparing a compound of formula 3 comprising the following steps:
- the production method is after step (c),
- the novel immunomodulatory amide derivative developed in the present invention has excellent binding ability to Cereblon, has almost no cytotoxicity, has a low possibility of teratogenic side effects, and is capable of controlling the expression of TNF- ⁇ and pro-inflammatory cytokines, as well as neurotoxicity. It has protective and neuroinflammation inhibitory effects and is excellent for degenerative brain diseases such as Parkinson's disease, so it has the advantage of being developed as a treatment that can replace existing thalidomide derivatives.
- Figure 1a shows the results of comparing the cereblon binding activity of the compound of Formula 1 with pomalidomide through a competitive inhibition reaction in vitro .
- Figure 1b shows the results of comparing the cereblon binding activity of the compound of Formula 2 with lenalidomide through a competitive inhibition reaction in vitro .
- Figure 1c shows the results of comparing the cereblon binding activity of the compound of Formula 3 with pomalidomide through a competitive inhibition reaction in vitro .
- Figure 2a shows the results of evaluating the cytotoxicity of the compound of Formula 1 on the MM.1R cell line.
- Figure 2b shows the results of evaluating the cytotoxicity of the compound of Formula 2 to the MM.1S cell line.
- Figure 3a shows the results of treating MM.1S cells with the compound of Formula 1 and comparing the intracellular decomposition effects of Ikaros and Aiolos with those of pomalidomide by immunoblotting.
- Figure 3b shows the results of treating MM.1S cells with the compound of Formula 2 and comparing the intracellular decomposition effects of Ikaros and Aiolos with those of lenalidomide by immunoblotting.
- Figure 3c shows the results of treating MM.1S cells with the compound of Formula 3 and comparing the intracellular decomposition effects of Ikaros and Aiolos with those of pomalidomide by immunoblotting.
- Figure 4a shows the results of treating Tera-1 cells with the compound of Formula 1 and comparing the degree of intracellular SALL4 degradation with pomalidomide by immunoblotting.
- Figure 4b shows the results of treating Tera-1 cells with the compound of Formula 2 and comparing the degree of intracellular SALL4 degradation with that of lenalidomide by immunoblotting.
- Figure 4c shows the results of treating Tera-1 cells with the compound of Formula 3 and comparing the degree of intracellular SALL4 degradation with pomalidomide by immunoblotting.
- Figure 5a shows the inhibitory effect on the production of pro-inflammatory cytokines TNF- ⁇ , IL-1 ⁇ , IL-6, and IL-8 by treating PBMC cells with the compound of Formula 1 at the mRNA level using pomalidomide and RT-PCR. This is the result of comparison.
- Figure 5b shows the inhibitory effect on the production of pro-inflammatory cytokines, TNF- ⁇ , IL-1 ⁇ , IL-6, and IL-8, by treating PBMC cells with the compound of Formula 2 and lenalidomide and RT-PCR at the mRNA level. This is the result of comparison.
- Figure 5c shows the results of treating PBMC cells with the compound of Formula 2 and comparing the inhibitory effect of TNF- ⁇ , a pro-inflammatory cytokine, with lenalidomide at the protein level.
- Figure 6 shows the results of treating rat midbrain-derived primary culture cells with the compound of Formula 3 and confirming the protective effect from neurotoxin induced by alpha-synuclein and the anti-neuroinflammatory effect.
- Figure 7 shows the results of confirming the Parkinson's disease treatment effect of the compound of Formula 2 using a zebrafish animal model.
- the new compounds according to the present invention were confirmed to have excellent cereblon binding activity and low cytotoxicity, thereby demonstrating excellent in vivo safety.
- the new compounds according to the present invention reduce the expression of Aiolos and Ikaros, which are substrates of cereblon, and inhibit the degradation of SALL4, which causes teratogenic side effects, thereby reducing major side effects caused by thalidomide compounds. I was able to.
- the present invention relates to any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
- the compound of [Formula 1] may be named 6'-Monothio pomalidomide and may be represented by the chemical formula C 13 H 11 N 3 O 3 S, It can be characterized as having a molecular weight of 289.31.
- the compound of [Formula 1] can be abbreviated as 6-MP.
- the compound of [Formula 2] may be named 1-Monothio lenalidomide and may be represented by the chemical formula C 13 H 13 N 3 O 2 S, and has a molecular weight of It can be characterized as having 275.33.
- the compound of [Formula 2] can be abbreviated as 1-ML.
- the compound of [Formula 3] may be named 1-Monothio pomalidomide and may be represented by the chemical formula C 13 H 11 N 3 O 3 S, and has a molecular weight of 289.31. It can be characterized as having.
- the compound of [Formula 3] can be abbreviated as 1-MP.
- any one compound selected from the group consisting of [Formula 1] to [Formula 3] may be non-teratogenic.
- the new compounds according to the present invention were able to suppress the expression of various pro-inflammatory cytokines, exerted a neuroprotective effect against neurotoxins, and could also exert a therapeutic effect for Parkinson's disease.
- the present invention relates to a pharmaceutical composition for preventing or treating brain diseases containing a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof as an active ingredient:
- the inflammatory disease may be selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease, but is not limited thereto.
- the present invention includes the step of administering a compound selected from the group consisting of [Formula 1] to [Formula 3], or a pharmaceutically acceptable salt thereof, or a composition containing the same as an active ingredient, to a subject in need thereof. It relates to a method of preventing or treating inflammatory diseases, including.
- the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for preventing or treating inflammatory diseases.
- the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for the production of a drug for preventing or treating inflammatory diseases.
- the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases containing a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof as an active ingredient. :
- the brain disease includes traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's dementia, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke and multiple sclerosis. It may be characterized as being selected from the group consisting of, but is not limited to this.
- the present invention includes the step of administering a compound selected from the group consisting of [Formula 1] to [Formula 3], or a pharmaceutically acceptable salt thereof, or a composition containing the same as an active ingredient, to a subject in need thereof. It relates to a method of preventing or treating brain disease, including.
- the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for the prevention or treatment of brain disease.
- the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for the production of a drug for preventing or treating brain diseases.
- compositions of the present invention refers to a pharmaceutical agent, such as a diluent or carrier, that makes the novel compound of the present invention particularly suitable for in vivo or in vitro diagnostic or therapeutic use. It refers to a mixture containing acceptable excipients.
- a pharmaceutical composition containing the composition of the present invention may be provided by administering a therapeutically effective amount to a subject according to need.
- compositions of the present invention can be administered to humans.
- an effective amount refers to the amount of a compound or composition (e.g., a compound or composition of the invention) sufficient to achieve a beneficial or desired result. Refers to an amount.
- An effective amount may be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular agent or route of administration.
- the compound may be contained in an amount of 0.01 to 99.9% (w/w) based on the total weight of the pharmaceutical composition.
- “pharmaceutically acceptable salt” refers to an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.
- Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid, etc.
- sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.
- sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.
- amino acid salts such as lysine, arginine, and guanidine
- organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine.
- the compound according to the present invention can be converted into its salt by a conventional method, and the preparation of the salt can be easily performed by a person skilled in the art based on the chemical structure without separate explanation.
- compositions provided by the present invention relate in principle to pharmaceutical compositions for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. That is, the pharmaceutical composition according to the present invention is suitable for use in animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals. It can also be administered to other mammals such as rats, mice, guinea pigs, etc. A skilled veterinary pharmacologist with a good understanding of the modifications of pharmaceutical compositions for administration to various animals can design and/or perform such modifications, if necessary, simply by routine experimentation.
- livestock e.g., dogs, cats, etc.
- farm animals e.g., cows, sheep, pigs, horses, etc.
- laboratory animals e.g., cows, sheep, pigs, horses, etc.
- laboratory animals e.g., cows, sheep, pigs,
- compositions described in the present invention may be prepared by any method known in the field of pharmacology or as discussed later in the text. Generally, these methods for tableting involve the steps of associating the active ingredient with excipients and/or one or more other auxiliary ingredients, followed by shaping and/or packaging the product into the desired single- or multi-dose units, if necessary or desired. Includes steps.
- compositions of the present invention may be manufactured, packaged, and/or sold unpackaged as a single unit dose and/or multiple single unit doses.
- a “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient.
- the amount of active ingredient is generally equal to the dosage of active ingredient administered to the subject and/or a convenient fraction of such dosage such as, for example, one-half or one-third of the dosage.
- compositions of the invention will vary depending on the identity, size, and/or disorder of the subject being treated and the route by which the composition is administered. .
- the composition may include 0.001% to 100% (w/w) active ingredient.
- a pharmaceutically acceptable excipient is any solvent, dispersion medium, diluent, or other liquid vehicle, dispersion or suspension aid, surface active agent, isotonic agent, thickener or emulsifier suitable for the purpose of the particular dosage form; Contains preservatives, solid binders, lubricants, etc.
- Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, (Lippincott, Williams & Wilkins, Baltimore, MD, 2006) describes various excipients used in the preparation of pharmaceutical compositions and known methods for their preparation.
- any conventional carrier medium is incompatible with the substance or derivative thereof, for example by providing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition. and their uses are considered to be within the scope of the present invention.
- Pharmaceutically acceptable excipients are at least 95%, 96%, 97%, 98%, 99%, or 100% pure.
- the excipients are approved for human and veterinary use. In some embodiments, the excipient is approved by the Food and Drug Administration. In some embodiments, the excipient is pharmaceutical grade. In some embodiments, the excipient meets the standards of the United States Pharmacopeia (USP), European Pharmacopoeia (EP), British Pharmacopoeia, and/or International Pharmacopoeia (EP).
- USP United States Pharmacopeia
- EP European Pharmacopoeia
- EP British Pharmacopoeia
- EP International Pharmacopoeia
- compositions include, but are not limited to, inert diluents, dispersants and/or granulating agents, surface active agents and/or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and/or oils. Not limited.
- excipients may optionally be included in the formulations of the present invention.
- Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavors, and perfumers may be present in the composition at the discretion of the formulator.
- Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dried starch, Including, but not limited to, corn starch, powdered sugar, and combinations thereof.
- Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation-exchange resins.
- Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g.
- natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
- colloidal clays e.g. bentonite [aluminum silicate] and veeg
- stearyl alcohol cetyl alcohol, oleyl alcohol
- triacetin monostearate ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate
- polyvinyl alcohol polyvinyl alcohol
- carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymers
- carrageenans e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose
- sorbitan fatty acid esters e.g.
- polyoxyethylene monostearate [mirz 45]) , polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. cremophor), polyoxyethylene ethers, ( For example, polyoxyethylene lauryl ether [Brise 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl.
- Exemplary binders include starches (e.g. corn starch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); Natural and synthetic gums (e.g.
- acacia sodium alginate, extract of Irish moss, Farnwer gum, Shatty gum, Isapol Husk's slime, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl) cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (bigum), and lachi arabogalactan); alginate; polyethylene oxide; polyethylene glycol; inorganic calcium salt; silicic acid; polymethacrylate; wax; water; Alcohol; and combinations thereof.
- Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
- Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, bisulfite. Including, but not limited to, sodium sulfate, sodium metabisulfite, and sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, disodium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. .
- EDTA ethylenediaminetetraacetic acid
- citric acid monohydrate disodium edetate
- disodium edetate disodium edetate
- edetic acid fumaric acid, malic acid
- phosphoric acid sodium edetate
- tartaric acid tartaric acid
- trisodium edetate trisodium edetate.
- Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, Includes, but is not limited to, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
- Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
- Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
- Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
- preservatives include tocopherol, tocopherol acetate, deteroxyme mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluende (BHT), ethylenediamine, sodium lauryl sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), Sodium Bisulfite, Sodium Metabisulfite, Potassium Sulfite, Potassium Metabisulfite, Glydant Plus, Fenonib, Methylparaben, Low Mol 115, Germaben II, Neolon, Katon, and E Including, but not limited to, Uxil.
- the preservative is an antioxidant.
- the preservative is a chelating agent.
- Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluvionate, calcium gluceptate, calcium gluconate, D-gluconic acid, glycero.
- Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium. Including, but not limited to, lauryl sulfate, and combinations thereof.
- oils include almond, apricot kernel, avocado, babassu palm, bergamot, black currant seed, borage, cayenne, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee. , corn, cotton seed, emu, eucalyptus, evening primrose, fish, flax seed, geraniol, pumpkin, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litthea cucumber.
- oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil. , and combinations thereof.
- Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
- liquid dosage forms may contain inert diluents such as, for example, water or other solvents, solubilizers and emulsifiers commonly used in the art such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl.
- compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- novel compounds of the invention are mixed with solubilizing agents such as cremophor, alcohols, oils, denatured oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
- solubilizing agents such as cremophor, alcohols, oils, denatured oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
- Injectable preparations for example, sterile injectable aqueous or oily suspensions, may be prepared according to the known art using dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as solution in 1,3-butanediol.
- a non-toxic parenterally acceptable diluent or solvent such as solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are commonly employed as solvents or suspending media.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid have been used in the preparation of injectables.
- Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active ingredient may be combined with one or more inert pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b ) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch.
- inert pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid
- b binders
- alginic acid alginic acid, certain silicates, and sodium carbonate
- dissolution retarders such as paraffin
- absorption accelerators such as quaternary ammonium compounds
- humectants such as, for example, cetyl alcohol and glycerol monostearate
- absorbents such as kaolin and bentonite clay
- lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.
- dosage forms may contain buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like as such excipients.
- Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be compositions that release the active ingredient only, or preferentially, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like as such excipients.
- the active ingredient may be in micro-encapsulated form with one or more of the excipients described above.
- Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulation art.
- the active ingredient may be mixed with one or more inert diluents such as sucrose, lactose or starch.
- These dosage forms may contain additional substances other than inert diluents as in common practice, such as tablet lubricants and other tablet auxiliaries such as magnesium stearate and microcrystalline cellulose.
- dosage forms may also contain buffering agents.
- opacifying agents may optionally contain opacifying agents and may be compositions that release the active ingredient only, or preferentially, in a specific part of the intestinal tract, optionally in a delayed manner.
- embedding compositions include polymeric substances and waxes.
- Dosage forms for topical and/or transdermal administration of the novel compounds of the present invention or pharmaceutical compositions containing them may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. .
- the active ingredient is admixed under conditions of sterility with a pharmaceutically acceptable carrier and/or any necessary preservatives and/or buffering agents that may be required.
- the present invention contemplates the use of transdermal patches, which often have the additional advantage of providing controlled delivery of the active ingredient to the body.
- Such dosage forms can be prepared, for example, by dissolving and/or dispersing the active ingredient in a suitable medium.
- the rate may be controlled by providing a rate controlling membrane and/or dispersing the active ingredient in a polymer matrix and/or gel.
- Formulations for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments/or pastes, and/or solutions and/or suspensions.
- concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent
- topically-administrable formulations may also comprise, for example, from about 1% to about 10% (w/w) of the active ingredient.
- Formulations for topical administration may further comprise one or more additional ingredients described herein.
- novel compounds of the invention described herein or pharmaceutical compositions containing them are typically prepared in dosage unit form for easy administration and uniform administration.
- the total daily dosage of the composition of the present invention will be determined by the attending physician within the scope of sound medical judgment.
- the particular therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disease, disorder, or disorder being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; The subject's age, weight, general health, gender, and diet; the time of administration, route of administration, and rate of excretion of the particular active ingredient employed; duration of treatment; Drugs used in combination or simultaneously with the specific active ingredients employed; and factors well known in the medical field.
- novel compound of the present invention, its salt, or pharmaceutical composition may be administered by any route.
- the novel compound, salt thereof, or pharmaceutical composition thereof may be administered orally, intravenously, intramuscularly, intraarterially, intramedullarily, intrathecally, subcutaneously, intracerebroventricularly, transdermally, intradermally, rectally, intravaginally, intraperitoneally, Topically (by powder, ointment, cream, and/or drop), mucosal, nasal, oral, enteral, sublingual; endotracheal instillation, bronchial instillation, and/or inhalation; and/or administered by various routes, including oral spray, nasal spray, and/or aerosol.
- Particularly contemplated routes are permeable intravenous injection, local administration via the blood and/or lymphatic supply, and/or direct administration to the affected area.
- the most appropriate route of administration will depend on a variety of factors, including the properties of the agent (e.g., stability in the environment of the gastrointestinal tract), and the disorder of the subject (e.g., whether the subject can tolerate oral administration). will be.
- novel compound of the present invention or its salt may be included in an amount of 0.001 to 99.9% of the total weight of the pharmaceutical composition.
- the novel compounds of the present invention, salts thereof, or pharmaceutical compositions thereof are administered at a daily dose of about 0.001 mg/kg to about 1000 mg/kg, about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg of the subject's body weight.
- mg/kg to about 400 mg/kg, about 0.5 mg/kg to about 300 mg/kg, about 1 mg/kg to about 200 mg/kg, about 10 mg/kg to about 100 mg/kg, or about 3 mg. /kg to about 90 mg/kg may be administered at a dosage level sufficient to deliver once or more per day to achieve the desired therapeutic effect.
- the intended dosage may be delivered three times a day, twice a day, daily, every two days, every three days, weekly, every two weeks, every three weeks, or every four weeks.
- the desired dosage may be delivered via multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations). .
- the dosage ranges described herein provide guidance for administration of pharmaceutical compositions provided to adults.
- the amount administered to a child or adolescent may be determined by a physician or person skilled in the art, and may be less or the same as that administered to an adult.
- the exact amount of a compound according to the invention required to achieve an effective amount will vary from subject to subject, depending, for example, on the subject's species, age, and overall disorder, severity of side effects or disorders, identity of the specific compound, mode of administration, etc.
- novel compounds and pharmaceutical compositions of the present invention can be used in combination therapy.
- the particular combination of treatments (treatments or procedures) for use in combination therapy will take into account the desired therapeutic effect to be achieved and the suitability of the desired treatments and/or procedures.
- the pharmaceutical composition of the present invention can be administered alone or in combination with one or more therapeutically active agents.
- “combination” it is not intended to imply that the agents must be administered at the same time and/or be formulated for delivery together, although the following delivery methods are within the scope of the present invention.
- the composition may be administered concurrently with, prior to, or subsequent to one or more other therapeutic agents or medical procedures. Generally, each agent will be administered at a dose and/or time schedule established for that agent.
- the present invention provides a pharmaceutical form of the present invention in combination with agents capable of improving its bioavailability, reducing and/or modifying its metabolism, inhibiting its secretion, and/or modifying its distribution within the body. It encompasses delivering the composition. It will be further understood that the novel compound of the invention and the therapeutically active agent used in this combination may be administered together in a single composition or may be administered separately in different compositions.
- the particular combination used in combination therapy will take into account the desired therapeutic effect to be achieved and/or the suitability of the therapeutically active agent and/or procedure comprising the compound of the invention.
- the combination used may achieve the desired effect for the same disorder (e.g., a novel compound of the invention may be administered in combination with another therapeutically active agent (e.g., a second therapeutic agent) used to treat the same disorder. It will be understood that they may achieve different effects (e.g., control of any side effects), and/or they may achieve different effects (e.g., control of any side effects).
- therapeutically active agent refers to any substance used as a medicine to treat, prevent, delay, reduce or ameliorate a disorder, and refers to substances used in treatment, including prophylactic and curative treatments. .
- the pharmaceutical compositions of the invention treat, alleviate, ameliorate, alleviate, delay the onset, inhibit the progression, reduce the severity, and/or the incidence of one or more symptoms or characteristics.
- the present invention may be provided as a kit for treating any one or more diseases selected from the group consisting of inflammatory diseases and brain diseases to a subject suffering from such diseases.
- the kit includes i) instructions for administering the novel compound or pharmaceutical composition according to the invention to a subject suffering from the disease, and ii) the novel compound or pharmaceutical composition according to the invention. do.
- the kit may include one or more unit dosage forms containing a dose of the novel compound or pharmaceutical composition as described herein effective for treating the disease in a subject.
- the subject is a human patient.
- the kit further includes one or more selected from the group comprising a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.
- the present invention also provides a food composition containing any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
- the food may be a health functional food for alleviating or improving inflammation.
- the food may be a health functional food for assisting in the treatment of brain diseases.
- food composition of the present invention is used in a broad sense to encompass substances containing nutritional ingredients, such as beverages, tea, drinks, alcoholic beverages, vitamin complexes, prebiotics, probiotics, postbiotics, health supplements, health There are functional foods and health foods, and it not only includes all foods in the conventional sense, but is also used to include “food additives” or “food additive compositions” added to foods.
- the food composition may be characterized as a health functional (sexual) food that has the function of alleviating or improving brain disease.
- the term of the present invention is the same as food for special health use (FoSHU), and is a medical product processed to efficiently exhibit bioregulatory functions in addition to nutritional supply. It refers to foods with high medical effects.
- “function” means adjusting nutrients to the structure and function of the human body or obtaining useful effects for health purposes, such as physiological effects.
- the food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry.
- the formulation of the food can be manufactured without limitation as long as it is a formulation recognized as a food, and the health functional food according to the present invention may be in the form of powder, granules, tablets, capsules, or beverages.
- health food refers to food that has a more active health maintenance or promotion effect compared to general food
- health supplement food refers to food for the purpose of health supplementation.
- health functional food, health food, and health supplement are used interchangeably.
- the food composition may further include a physiologically acceptable carrier.
- a physiologically acceptable carrier is not particularly limited and any carrier commonly used in the art can be used.
- the composition may contain additional ingredients that are commonly used in food compositions to improve odor, taste, vision, etc.
- additional ingredients may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc.
- minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr).
- it may contain amino acids such as lysine, tryptophan, cysteine, and valine.
- composition contains preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), and antioxidants (butylhydroxyanisole (BHA), butylhydroxyanisole).
- preservatives potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.
- disinfectants bleaching powder, high bleaching powder, sodium hypochlorite, etc.
- antioxidants butylhydroxyanisole (BHA), butylhydroxyanisole).
- toluene BHT, etc.
- colorants tar color, etc.
- coloring agents sodium nitrite, sodium nitrite, etc.
- bleaching agents sodium sulfite
- seasonings MSG, etc.
- sweeteners dulcine, cyclemate, saccharin, sodium, etc.
- flavorings vanillin, lactones, etc.
- leavening agents alum, D-potassium hydrogen tartrate, etc.
- strengthening agents emulsifiers, thickeners (greasings), coating agents, gum base agents, anti-foam agents, solvents, improvers, etc.
- food additives food additives (food) additives) may be included.
- the additives can be selected depending on the type of food and used in an appropriate amount.
- a foodologically acceptable food auxiliary additive may be further included, and may be used together with other foods or food ingredients, and may be used appropriately according to conventional methods.
- the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
- “Individual,” “patient,” and “subject” are used interchangeably and refer to mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, and sheep. , horses, or any animal, including primates, including humans.
- treatment means reversing, alleviating, inhibiting the progression of, or preventing the disease or disease to which the term applies, or one or more symptoms of the disease or disease.
- treatment refers to the act of treating when “treating” is defined as above. Accordingly, “treatment” or “therapy” of a disease in a mammal may include one or more of the following:
- prevention means any action that suppresses or delays the onset of inflammatory disease or brain disease by administering the pharmaceutical composition according to the present invention.
- the present invention relates to a process for preparing a compound of formula 1, comprising the following steps:
- step (b) can be carried out at 70 to 90°C, and preferably at about 80°C.
- step (b) may be performed for 10 minutes to 6 hours, for example, 30 minutes to 3 hours, preferably about 1 hour.
- step (b) may be characterized in that pomalidomide is reacted with phosphorus pentasulfide at a molar ratio of about 1:0.5 to 2, preferably at a molar ratio of about 1:1. You can do this.
- the production method may further include, after step (b), (c) purifying by filtration and/or chromatography.
- step (c) filtration may be performed to remove the solid in step (b) and obtain a solvent, and the solvent may then be concentrated and purified by chromatography.
- the compound purified by chromatography can be solidified using dichloromethane.
- the present invention in another aspect, relates to a process for preparing a compound of formula 2 comprising the following steps:
- the production method may further include, after step (b), (c) purifying by chromatography.
- step (b) can be carried out at 90 to 110°C, and preferably at about 100°C.
- step (b) may be performed overnight.
- step (b) may be characterized by reacting lenalidomide with Lawesson's reagent at a molar ratio of about 1:0.5 to 2, preferably at a molar ratio of about 1:1. It can be characterized. In this case, Lawesson's reagent can be added in several installments.
- the present invention in another aspect, relates to a process for preparing a compound of formula 3 comprising the following steps:
- step (b) can be stirred at 50 to 70°C, and preferably at about 60°C.
- step (b) may be stirred for 10 to 30 hours, for example, 13 to 23 hours, preferably about 18 hours.
- step (b) may be, for example, producing a crude product by removing the solvent using a column filled with C 18 -SiO 2 .
- the production method is after step (c),
- the crude product may be subsequently concentrated and purified by chromatography.
- chromatography means a method for separation and purification for compounds of the invention, wherein a solution containing the compound of the invention is passed using a liquid stream over a stationary phase, and the components of the mixture are It is fractionated.
- the stationary phase is preferably the packing material in the chromatography column.
- the filling material hereinafter also referred to as the so-called gel material, preferably consists of a solid support material consisting of porous or non-porous particles of approximately equal size, on which functional groups that establish the mode of separation are covalently bonded.
- Support materials can be biopolymers such as, for example, agarose, cellulose and dextran (preferably Sepharose and Sephadex), or polymers such as, for example, methacrylates, polyvinylbenzene, polystyrene and polyacrylamide. It may be a synthetic polymer or an inorganic polymer such as, for example, silica or porous glass beads.
- the chromatography is selected from the group consisting of hydrophobic interaction chromatography (HIC), ion exchange chromatography (IEC), size exclusion chromatography (SEC), affinity chromatography, and reversed phase chromatography.
- HIC hydrophobic interaction chromatography
- IEC ion exchange chromatography
- SEC size exclusion chromatography
- affinity chromatography affinity chromatography
- reversed phase chromatography reversed phase chromatography
- the step of selectively performing ultrafiltration or diafiltration may be additionally included.
- a rotary evaporator may be used for concentration during the manufacturing process of the compound, but is not limited to this.
- Pomalidomide used as a control in the present invention is known as (R,S)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione, It may be characterized by being represented by [Chemical Formula I].
- Lenalidomide used as a control in the present invention is (R,S)-3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl)piperidine-2, It is known as 6-dione and can be characterized as being represented by the formula (II).
- 1,6'-Dithiothalidomide used as a material for synthesis in the present invention, can be represented by [Chemical Formula III].
- thalidomide derivatives While existing commercially available thalidomide derivatives have specific efficacy in the treatment of multiple myeloma, related effects can cause side effects such as bone marrow cell suppression. However, the derivatives according to the present invention minimize this effect and enhance immune regulation and antioxidant efficacy. It can be applied more safely as a treatment for immune-related diseases.
- the monothio compounds in the present invention have superior stability in plasma compared to dithio compounds, which is advantageous for actual biological application and drug action analysis.
- the compound of Formula 1 has a weak decomposition effect on the target protein related to the death of pomalidomide in multiple myeloma and a weak binding force to cereblon, so it reduces the toxicity of pomalidomide and can be used as a similar treatment for other effects such as inflammation control. .
- the compound of formula 2 has a better binding ability to cereblon than lenalidomide, its efficacy in killing multiple myeloma and decomposing related proteins is very weak, so it is relatively unlikely to have related toxicity. In particular, it is a gene related to developmental toxicity of the thalidomide series. There is little decrease in SALL4, so the possibility of developmental toxicity is low. In contrast, its inflammation control efficacy is similar to that of lenalidomide, and its efficacy was confirmed in a Parkinson's animal model, so it can be used as a treatment for Parkinson's disease.
- the formula 3 compound has excellent cereblon binding ability, but is less effective in degrading pomalidomide's target protein related to multiple myeloma death and the SALL4 gene related to developmental toxicity, and has a negative effect on neurons in alpha-synuclein toxicity tests on dopaminergic neurons using rat midbrain.
- the protective effect and inflammation protection effect were confirmed, so it can be applied as a treatment for Parkinson's disease.
- Pomalidomide (Combi Block, QB-4271) (2.00 g, 7.32 mmol) was dissolved in dioxane (SAMCHUN, D0654) (200 mL) and then dissolved in phosphorous pentasulfide (Aldrich, 232106). (P 2 S 5 ) (1.63 g, 7.32 mmol) was added dropwise and stirred at 80°C for 1 hour. After lowering the reaction temperature to room temperature, solids were removed using a filter (Advantec, F12-510-221), and the solvent was concentrated using a rotary evaporator (EYELA, N-1300) .
- Dimethylsulfoxide (Daejeong Chemical, 3047-4400) (250mL) and 1,6'-dithiopomalidomide (STAble, T0014) (1 ,6'-DT-POM) (500mg, 1.64mmol) solution was stirred at 60°C for 18 hours and cooled to room temperature.
- the solution was passed through a column filled with C 18 -SiO 2 to remove the solvent.
- the crude product captured at the top of the column was eluted with MeOH:THF (50%), and the solution containing the crude product was concentrated using a rotary evaporator (EYELA, N-1300).
- Thalidomide-based compounds are known to regulate the function of immune cells and exert various pharmacological effects by binding to Cereblon (CRBN), an E3 ligase, and decomposing the transcription factors Aiolos and Ikaros as its substrates. Accordingly, the cereblon binding ability of compounds of formula 1, formula 2, and formula 3, respectively, was compared with pomalidomide or lenalidomide in vitro .
- the binding force to Cereblon was measured using the 'AlphaScreen' method based on Fluorescence Resonance Energy Transfer (FRET), and the test was performed using the PROTAC Optimization kit for BET Bromodomain-Cereblon binding kit (#79770, BPS bioscience, CA USA). It was carried out according to the 'Competitive Inhibition of the PROTAC assay' written in the manual in the kit. All reagents except the candidate substance, DMSO, and Flag/Glutathione beads (#6765300, PerkinElmer, USA) were used as those included in the kit.
- FRET Fluorescence Resonance Energy Transfer
- MM.1R Human multiple myeloma cell lines, MM.1R and MM.1S cell lines, were treated with compounds of Formula 1 and Formula 2, respectively, at different concentrations, and cytotoxicity was evaluated.
- MM.1R is a cell line that acquired resistance to dexamethasone from MM.1S.
- MM.1S Human multiple myeloma cell lines, MM.1S (CRL-2974) and MM.1R (CRL-2975), were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA) and incubated with 10% fetal calf serum (Corning , MD, USA), 100 U/ml penicillin (Corning, MD, USA), and 100 ⁇ g/ml streptomycin (Corning, MD, USA) at 37°C using RPMI1640 medium (Corning, MD, USA). Cultured for 24 hours in a 5% CO 2 incubator. Cells were distributed in a 96-well plate at 1 The analysis was conducted according to the manufacturer's manual. As a control group, pomalidomide or lenalidomide was treated at the same concentration.
- the compound of formula 1 showed a similar level of cytotoxicity as pomalidomide, and as shown in Figure 2b, the compound of formula 2 showed no cytotoxicity (blood toxicity) compared to lenalidomide. I was able to confirm.
- Thalidomide-based compounds are known to regulate the function of immune cells by binding to Cereblon (CRBN), an E3 ligase, and decomposing the transcription factors Aiolos and Ikaros as its substrates.
- CRBN Cereblon
- E3 ligase an E3 ligase
- Compounds of Formula 1, Formula 2, and Formula 3 We sought to determine whether the expression of Aiolos and Ikaros was decreased.
- the MM.1S cell line was supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U/ml penicillin (Corning, MD, USA), and 100 ⁇ g/ml streptomycin (Corning, MD, USA).
- RPMI medium (Corning, MD, USA) was used and cultured at 37°C in a 5% CO 2 incubator. Cells were distributed in a 12-well plate at 1 Fisher Scientific), disrupted by adding RIPA buffer, and centrifuged at 4°C at 14,000 rpm for 15 minutes to obtain a cell extract. The same amount of cell extract was loaded, separated using SDS-PAGE, and transferred to a PVDF membrane.
- the protein-transferred membrane was blocked using skim milk, incubated with primary antibody at room temperature for 3 hours, and then incubated with HRP-attached secondary antibody at room temperature for 1 hour. Washed three times with TBS-T between each step. Detection was performed by applying a chemoluminescence reagent (Thermo Fisher Scientific) and confirmed using Chemidoc (iBright CL1500, Invitrogen, CA, USA). Aiolos (#15103), Ikaros (#9034), and GAPDH (#2118S) antibodies used as primary antibodies and secondary antibodies were purchased from Cell signaling technology (Danvers, MA, USA).
- Tera-1 cell line (HTB-105), a human embryonic carcinoma cell line, was purchased from American Type Culture Collection (ATCC, Manassas, VA, USA), 10% fetal bovine serum (Corning, MD, USA), DMEM medium (Corning, MD, USA) supplemented with 100 U/ml penicillin (Corning, MD, USA) and 100 ⁇ g/ml streptomycin (Corning, MD, USA) was used at 37°C in a 5% CO 2 incubator. Cultured.
- Cells were distributed at 5 ⁇ 10 5 cells/well in a 12-well plate and cultured for 24 hours, then treated with compounds of Formula 1, compounds of Formula 2, and compounds of Formula 3, respectively, at different concentrations and cultured for an additional 4 hours.
- Cells were disrupted by adding RIPA buffer containing protease inhibitor cocktail (Thermo Fisher Scientific), and centrifuged at 14,000 rpm for 15 minutes at 4°C to obtain cell extract. The same amount of cell extract was loaded, separated using SDS-PAGE, and transferred to a PVDF membrane. The protein-transferred membrane was blocked using skim milk, incubated with primary antibody at room temperature for 3 hours, and then incubated with HRP-attached secondary antibody at room temperature for 1 hour.
- Detection was performed by applying a chemoluminescence reagent (Thermo Fisher Scientific) and confirmed using Chemidoc (iBright CL1500, Invitrogen, CA, USA).
- SALL4 (#5850) and GAPDH (#2118S) antibodies used as primary antibodies and secondary antibodies were purchased from Cell signaling technology (Danvers, MA, USA).
- Immunomodulating agents pomalidomide or lenalidomide improve T cell-mediated immunity and natural killer (NK) cell-mediated immunity, and promote pro-inflammatory cytokines (e.g., TNF- ⁇ , It is known to inhibit the production of IL-1 ⁇ , IL-6, and IL-8). Therefore, the inhibitory effect of compounds of Formula 1 and Formula 2 on pro-inflammatory cytokine production was compared with pomalidomide or lenalidomide at the mRNA level.
- NK natural killer
- peripheral blood mononuclear cells PBMC, StemExpress, CA, USA
- PBMC peripheral blood mononuclear cells
- fetal bovine serum (Corning, MD, USA)
- RPMI1640 (Corning, MD, USA) medium containing 100 U/ml of penicillin/streptomycin (Corning, MD, USA) was used to stabilize the cells by culturing them in an incubator at 37°C and 5% CO 2 for one day.
- RNA prep was performed according to the kit manual using an RNA prep kit (Monarch Total RNA Miniprep kit, NEB, UK), and the concentration was measured using a Nanophotometer (NP80, Implen, Germany). Depending on the concentration of each RNA sample, an amount of RNA equivalent to 1 ⁇ g was added, and cDNA was synthesized according to the manual of the cDNA synthesis kit (LunaScript RT SuperMix kit, NEB, UK).
- the expression level of each cytokine in the synthesized cDNA was analyzed and compared using Real-Time PCR (StepOneTMUSA) equipment.
- 1 ⁇ l of cDNA, 10 pmol of forward and reverse primers for each gene, 8 ⁇ l of DW and 10 ⁇ l of SYBR green were added to each well of a 48-well plate (MicroAmp ® Fast Optical 48-well plate, Applied Biosystem, USA). (Luna®Mix, NEB, UK) was included.
- the PCR reaction was carried out according to the manual of the SYBR green kit, and the base sequences of the primers used are shown in Table 1.
- the C T value for each gene in each sample obtained through real-time PCR was normalized to the value of the internal control gene ( ⁇ -actin) of each sample, and the expression amount was inversely estimated by calculating 2 ⁇ C T , and the results for each group were The value was expressed as a relative quantification as a 100% value compared to the PHA treatment group alone.
- the chemical formula 2 compound was analyzed for differences in protein expression of TNF- ⁇ , a major inflammatory cytokine, during the test process.
- the protein was extracted with a protein extraction buffer (RIPA, 89900, Thermo) containing a protease inhibitor (Thermo).
- the protein amount of TNF- ⁇ was analyzed using the Human TNF alpha uncoated ELISA kit (88-7346-22, Invitrogen) according to the manufacturer's instructions.
- both compounds of Formula 1 and Formula 2 produced pro-inflammatory cytokines (e.g., TNF- ⁇ , IL-1 ⁇ ) at a similar level to pomalidomide or lenalidomide. , IL-6, and IL-8), and as shown in Figure 5c, the compound of Formula 2 was confirmed to inhibit TNF- ⁇ protein to a similar level as pomalidomide.
- pro-inflammatory cytokines e.g., TNF- ⁇ , IL-1 ⁇
- IL-6, and IL-8 pro-inflammatory cytokines
- the reaction was stopped by adding Dulbecco's modified Eagle's medium (DMEM, P04-03600, DUSTCHER) containing (0.5 mg/ml, P60-37780100, DUTSCHER) and 10% fetal calf serum (FCS). Afterwards, the cells were separated into three passages using a 10 ml pipette and centrifuged at 180g at 4°C for 10 minutes in the BSA (3.5%) layer of L15 medium.
- DMEM Dulbecco's modified Eagle's medium
- DUSTCHER Dulbecco's modified Eagle's medium
- FCS fetal calf serum
- the cell pellet was incubated with basic B27 (2%), L-glutamine (2mM, P04-80100, DUTSCHER) and 2% PS solution and brain-derived neurotrophic factor (BDNF, CB-1115002, DUTSCHER) for neuronal culture. ) and resuspended in medium (11570556, FISHER SCIENTIFIC) containing 10ng/ml and microglial nerve growth factor (GDNF) 1ng/ml. Viable cells were confirmed through trypan blue exclusion test using a Neubauer cell counter.
- Cells were cultured at a density of 225,000 cells/well in a 24-well plate (pre-coated with poly-L-lysine) and maintained in a humidified incubator at 5% CO 2 and 37°C. Half of the medium was replaced with fresh medium every two days.
- Human alpha-synuclein peptide (Watkinsville, GA) was dissolved in the medium at a concentration of 4 ⁇ M and shaken slowly for 3 days at 37°C in the dark to form alpha-synuclein.
- the compound of Formula 3 dissolved in the medium was treated 1 hour before alpha-synuclein to stabilize it.
- the dopaminergic neuron culture was treated with alpha-synuclein solution (250 nM, confirmed by automated western blotting to contain ⁇ 60% of oligomers) for 48 hours.
- the supernatant of the cells was separated and frozen (-80°C), and the cells were washed with PBS (L0615-1000, DUTSCHER).
- Tyrosine hydroxylase-dopaminergic neuron detection reaction was performed with rabbit-derived polyclonal TH antibody (Sigma Aldrich) diluted 1:2000 in PBS containing 1% FCS and 0.1% saponin for 2 hours at room temperature. Through this, it specifically binds to neurons that act on dopamine and was used to study the survival of neurons and the neurite network of neurons.
- Iba1-microglia They were reacted with mouse-derived monoclonal Iba-1 antibody (Sigma Aldrich) diluted 1:500 in PBS containing 1% FCS and 0.1% saponin for 2 hours at room temperature. Through this, a study on the activation of microglial cells was performed.
- ELISA was performed using the supernatant (100 ⁇ l/well) of dopaminergic neuron culture, and the test was performed according to the instructions in the product (Rat TNF-alpha ELISA kit, abcam, ab46070) manual. did.
- the test was conducted at Zefit Co., Ltd., a CRO specializing in zebrafish, and the zebrafish used in the test were AB strain zebrafish fry managed by Zefit.
- the AB strain is a strain commonly used in zebrafish for research in the United States and other countries, and is widely used in Parkinson's models.
- MPTP (Sigma-Aldrich, M0896) was prepared as a 100mM stock solution using dimethyl sulfoxide (DMSO) (Sigma-Aldrich, 276855), diluted in E3 medium to the final concentration immediately before use in the experiment, and incubated in zebrafish. Fry were exposed to a concentration of 200 ⁇ M for 4 days from 2dpf to 6dpf, and E3 medium (5mM NaCl, 0.17mM KCl, 0.33mM CaCl 2 , 0.33mM MgSO 4 , pH 7.0-7.2) was replaced at 24-hour intervals.
- DMSO dimethyl sulfoxide
- Rasagiline (Sigma-Aldrich, SML0124), used as a positive control, was exposed to zebrafish fry at a concentration of 1 ⁇ M by co-treatment with 200 ⁇ M MPTP for 4 days from 2 dpf to 6 dpf, and the E3 medium was replaced every 24 hours.
- Pomalidomide and the compound of Formula 2 used in the test were prepared as 10mM stock solutions using dimethyl sulfoxide (DMSO), diluted in E3 medium to the final concentration (0.03, 0.1, 0.3, 1 ⁇ M) immediately before use in the experiment, and grown in zebrafish.
- Fry were exposed to 200 ⁇ M MPTP and co-treatment for 4 days from 2 dpf to 6 dpf, and E3 medium was replaced at 24-hour intervals.
- the movements of the fry were tracked by setting a threshold, distinguishing them from the background. did. If the speed of a larvae that moved during 1 frame during 10 minutes of video analysis is less than 2 mm/s, it is judged as if the larvae is turning its body or floating in the water while shaking, rather than moving a distance, and moves at a speed of more than 2 mm/s. Only included in Total moved distance (mm).
- pomalidomide As a result of measuring the total distance traveled, pomalidomide was confirmed to have significant efficacy compared to the MPTP treatment group alone at 0.03 and 0.3 ⁇ M, but did not show concentration-dependent results, whereas the compound of Formula 2 showed concentration-dependent efficacy at 0.3 and 1 ⁇ M. Significant efficacy could be confirmed, making it possible to estimate relief of Parkinson's symptoms caused by MPTP toxicity by the substance.
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Abstract
La présente invention concerne un nouveau dérivé d'amide immunorégulateur, son procédé de préparation et son utilisation. Le nouveau dérivé d'amide immunorégulateur selon la présente invention a une excellente capacité de liaison au céréblon, a une faible cytotoxicité, a une faible possibilité d'effets secondaires tératogènes, peut réguler l'expression de TNF-α et de cytokines pro-inflammatoires, a des effets neuroprotecteurs et inhibiteurs de neuroinflammation et est très efficace sur des maladies cérébrales dégénératives telles que la maladie de Parkinson, et peut ainsi être développé en tant qu'agent thérapeutique qui peut remplacer un dérivé de thalidomide classique.
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KR20220055171A (ko) * | 2020-10-26 | 2022-05-03 | 주식회사 아이비스바이오 | 포말리도마이드로부터 3,6'-디티오포말리도마이드를 선택적으로 합성하는 방법 |
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