WO2020096372A1 - Nouveau dérivé de pipéridine-2,6-dione et utilisation associée - Google Patents

Nouveau dérivé de pipéridine-2,6-dione et utilisation associée Download PDF

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WO2020096372A1
WO2020096372A1 PCT/KR2019/015061 KR2019015061W WO2020096372A1 WO 2020096372 A1 WO2020096372 A1 WO 2020096372A1 KR 2019015061 W KR2019015061 W KR 2019015061W WO 2020096372 A1 WO2020096372 A1 WO 2020096372A1
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compound
dioxopiperidin
oxo
urea
methyl
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PCT/KR2019/015061
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Korean (ko)
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황종연
하재두
조성윤
김필호
김현진
이정옥
박지훈
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한국화학연구원
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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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 a novel piperidine-2,6-dione derivative and use thereof, and more specifically, piperidine-2 showing the effect of preventing or treating leprosy, chronic graft-versus-host disease, inflammatory disease or cancer. , 6-dione derivatives.
  • Thalidomide includes the trade names thalamide (THALOMID®) and ⁇ - (N-phthalimido) glutarimide or 2- (2,6-dioxo-3-piperidinyl) -lH-isoindole-1, It is a racemic compound sold under the chemical name of 3 (2H) -dione. Thalidomide was originally developed to treat morning sickness (morning sickness), but was discontinued due to its teratogenic effect. Thalidomide is currently approved in the United States for the treatment of leprosy nodules in humans (Korean Patent No. 10-0671366).
  • thalidomide has been reported to be used in patients with leprosy, chronic graft-versus-host disease, rheumatoid arthritis, sarcoidosis, some inflammatory skin diseases, and inflammatory bowel disease. It has been reported that it can be combined with other drugs (U.S. Patent No. 05643915).
  • thalidomide has been used to treat certain types of cancer. This includes refractory multiple myeloma, brain, melanoma, breast, colon, mesothelioma and renal cell carcinoma. It has been reported that thalidomide is further used to prevent the expression of chronic cardiomyopathy caused by doxorubicin in rats. Other reports of the use of thalidomide in the treatment of certain cancers include use with carboplatin in the treatment of glioblastoma multiforme.
  • thalidomide is also used as an analgesic in the treatment of astrocytoma (Costa, PT et al., Blood, 92 (Suppl 1, Pt 2), 235b, 1998; Marx, GM et al., Proc Am Soc Clin Oncol. , 454a, 1999; Singhal, S. et al., N Engl J Med., 341 (21), 1565-1571, 1999; Zwart, D., Arzneistoffforschung, 16 (12), 1688-1689, 1966).
  • thalidomide has been used in various ways for the prevention or treatment of lupus nephritis, fibromyalgia, schizophrenia, central nervous system disease, diabetes, and inflammatory diseases. It has a history of being withdrawn from the horse market.
  • the present inventors have made efforts to develop novel derivative compounds without the side effects of thalidomide while maintaining the physiological activity indicated by thalidomide, and in particular, develop new thalidomide derivatives based on piperidine-2,6-dione And evaluating its activity to complete the present invention.
  • an object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.
  • X is nitrogen (N) or carbon (C);
  • R 1 is-(CH 2 ) n NH 2 ,-(CH 2 ) m NH (CO) NHR 4 ,-(CH 2 ) m NH (CS) NHR 4 and-(CH 2 ) m NH (CO) R 4 Is selected from the group consisting of;
  • R 2 is hydrogen, deuterium or C 1 -C 6 alkyl
  • R 3 is hydrogen, C 1 -C 6 alkyl, -CH 2 OCOR 5 , -CH 2 OCOOR 5 , -CH 2 OCONR 6 R 7 or Is selected from the group consisting of;
  • R 4 is hydrogen, halogen, hydroxy, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted Substituted with one or more substituents selected from the group consisting of substituted C 1 -C 10 arylalkyl or C 4 -C 10 heteroaryl,
  • the substituted alkyl, cycloalkyl, aryl or arylalkyl is hydrogen, halogen, hydroxy, CF 3 , S-CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclo Substituted with one or more substituents selected from the group consisting of alkyl or C 4 -C 10 aryl;
  • R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 heterocycloalkyl or-(CH 2 CH 2 O) n CH 3 is substituted with one or more substituents selected from the group consisting of,
  • the substituted alkyl, cycloalkyl or heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, acetamino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy ;
  • R 6 and R 7 are each independently hydrogen, hydroxy, amino, acetamino, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of,
  • substituted alkyl, alkoxy, cycloalkyl or heterocycloalkyl is one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, acetamino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy. Substituted;
  • R 8 is substituted with one or more substituents selected from the group consisting of hydrogen, C 1 -C 6 alkyl,-(CH 2 ) m -imidazole, amino acid residue or derivatives thereof;
  • n is an integer from 1 to 5;
  • n is an integer from 0 to 5; to be.
  • X is nitrogen (N) or carbon (C);
  • R 1 is-(CH 2 ) n NH 2 ,-(CH 2 ) m NH (CO) NHR 4 ,-(CH 2 ) m NH (CS) NHR 4 and-(CH 2 ) m NH (CO) R 4 Is selected from the group consisting of;
  • R 2 is hydrogen
  • R 3 is hydrogen, C 1 -C 6 alkyl, -CH 2 OCOR 5 , -CH 2 OCOOR 5 , -CH 2 OCONR 6 R 7 or Is selected from the group consisting of;
  • R 4 is hydrogen, halogen, hydroxy, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted Substituted with one or more substituents selected from the group consisting of substituted C 1 -C 10 arylalkyl or C 4 -C 10 heteroaryl,
  • the substituted alkyl, cycloalkyl, aryl or arylalkyl is hydrogen, halogen, hydroxy, CF 3 , S-CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclo Substituted with one or more substituents selected from the group consisting of alkyl or C 4 -C 10 aryl;
  • R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 heterocycloalkyl or-(CH 2 CH 2 O) n CH 3 is substituted with one or more substituents selected from the group consisting of,
  • the substituted alkyl, cycloalkyl or heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, acetamino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy ;
  • R 6 and R 7 are each independently hydrogen, hydroxy, amino, acetamino, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of,
  • substituted alkyl, alkoxy, cycloalkyl or heterocycloalkyl is one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, acetamino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy. Substituted;
  • R 8 is substituted with one or more substituents selected from the group consisting of hydrogen, C 1 -C 6 alkyl or-(CH 2 ) m -imidazole;
  • n is an integer from 1 to 3;
  • n is an integer from 0 to 3; to be.
  • X is nitrogen (N);
  • R 1 is-(CH 2 ) n NH 2 ,-(CH 2 ) m NH (CO) NHR 4 ,-(CH 2 ) m NH (CS) NHR 4 and-(CH 2 ) m NH (CO) R 4 Is selected from the group consisting of;
  • R 2 is hydrogen, deuterium or C 1 -C 6 alkyl
  • R 3 is hydrogen, C 1 -C 6 alkyl, -CH 2 OCOR 5 , -CH 2 OCOOR 5 , -CH 2 OCONR 6 R 7 or Is selected from the group consisting of;
  • R 4 is hydrogen, halogen, hydroxy, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted Substituted with one or more substituents selected from the group consisting of substituted C 1 -C 10 arylalkyl or C 4 -C 10 heteroaryl,
  • the substituted alkyl, cycloalkyl, aryl or arylalkyl is hydrogen, halogen, hydroxy, CF 3 , S-CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cyclo Substituted with one or more substituents selected from the group consisting of alkyl or C 4 -C 10 aryl;
  • R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 heterocycloalkyl or-(CH 2 CH 2 O) n CH 3 is substituted with one or more substituents selected from the group consisting of,
  • the substituted alkyl, cycloalkyl or heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, acetamino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy ;
  • R 6 and R 7 are each independently hydrogen, hydroxy, amino, acetamino, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of,
  • substituted alkyl, alkoxy, cycloalkyl or heterocycloalkyl is one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, acetamino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy. Substituted;
  • R 8 is substituted with one or more substituents selected from the group consisting of hydrogen, C 1 -C 6 alkyl,-(CH 2 ) m -imidazole, amino acid residue or derivatives thereof;
  • n is an integer from 1 to 5;
  • n is an integer from 0 to 5; to be.
  • Halogen in the present invention means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • alkyl used in the present invention means a single-bonded straight-chain or branched-chain hydrocarbon group. Examples are methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, and the like.
  • alkoxy used in the present invention refers to a single bond straight or branched chain saturated hydrocarbon group. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, and the like.
  • cycloalkyl used in the present invention refers to a cyclic, single bond, saturated hydrocarbon group.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. are mentioned.
  • aryl used in the present invention refers to an aromatic substituent having at least one ring having a covalent py electron system, for example, phenyl, benzyl, and the like.
  • arylalkyl used in the present invention means an aryl group substituted with an alkyl group, and aryl and alkyl are as described above.
  • heterocycloalkyl refers to a ring-shaped, single bond, saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and is not dependent on the number and type of heteroatoms included in the ring and the number of carbon atoms.
  • heteroaryl refers to an aromatic cyclic compound containing one or more heteroatoms such as N, O, or S, depending on the number and type of heteroatoms contained in the ring, and the number of carbon atoms, pyrrolyl, furanyl, pyridine And work, pyrimidinyl, and pyranyl.
  • the pharmaceutically acceptable salt means a salt or complex of Formula 1 having desirable biological activity.
  • examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid , Salts formed with organic acids such as benzoic acid, tannic acid, palmic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid and poly-galacturonic acid.
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carbohydrate Carboxylates (e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate And diphenyl acetate).
  • Carboxylates e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate And diphenyl acetate.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic acid or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure and drying to crystallize under an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc.
  • bases can be used to make pharmaceutically acceptable metal salts.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • a suitable silver salt eg, silver nitrate
  • the compound of Formula 1 of the present invention may include all salts, hydrates, solvates and prodrugs that can be prepared by conventional methods, as well as pharmaceutically acceptable salts.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms, and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.
  • R 1 is-(CH 2 ) n NH 2 ,-(CH 2 ) m NH (CO) NHR 4 ,-(CH 2 ) m NH (CS) NHR 4 or-(CH 2 ) m NH It is substituted with a substituent selected from the group consisting of (CO) R 4 .
  • the solvent used in step (a) of the present invention is not particularly limited as long as it is a solvent that dissolves the starting material and does not inhibit the reaction.
  • tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether or di Ether-based solvents such as oxane
  • Aromatic hydrocarbon-based solvents such as benzene, toluene or xylene
  • Amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone
  • Organic solvents such as dimethyl sulfoxide
  • Alcohol solvents such as methanol, ethanol, propanol, n-butanol or t-butanol
  • a mixture of these or a mixed solvent of the above solvent and water may be used.
  • dimethylformamide may be used, but is not limited thereto.
  • an appropriate base in order to facilitate the reaction in the step (a), an appropriate base can be used.
  • the base include sodium hydride, potassium t-butoxide, sodium methoxide, sodium ethoxide, N, N-diisopropylamine, diisopropylethylamine 2,4-diaminobutyl acid ( DBU), and the like, and preferably diisopropylethylamine, but is not limited thereto.
  • step (a) the reaction molar ratio of the compound of Formula 2 and the compound of Formula 3 may be 1: 3 to 5, and most preferably, the reaction proceeds at a molar ratio of 1: 4.
  • the step (b) is a step of proceeding a cyclization reaction by adding sodium nitride to the compound of Formula 4 produced in the step (a), and it is preferable to proceed the reaction under weakly acidic and room temperature conditions.
  • the method for preparing a compound represented by Formula 1 according to the present invention shown in the above preparation method should be understood as an example of a method for preparing the compound of the present invention, and the compound represented by Formula 1 prepared by the present invention is prepared. If possible, it is included in the present invention without limitation.
  • the method presented in the specification of the present invention and a manufacturing method that can be easily changed and modified by a person skilled in the art from the present invention are also included in the scope of the present invention, which will be apparent to those skilled in the art. It can be understood as.
  • the present invention relates to a pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory disease or cancer, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • CRBN protein is a type of E3 ubiquitin ligase, which binds thalidomide and its analogues, pomalidomide, lenalidomide, and the like, to activate the activity of attaching ubiquitin to substrate proteins such as Ikaros / Aiolos protein and GSPT1 protein. It is known to have.
  • the cancer may include breast cancer, colon cancer, lung cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anus near rectum cancer, colon cancer, Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic Or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma, but is not particularly limited thereto. It does not work.
  • compositions according to the present invention can be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not cause an allergic or similar reaction, such as gastrointestinal disorder, dizziness, etc., when administered to a human.
  • the composition may be formulated and used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., according to a conventional method.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil may be included, but is not limited thereto.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in the compounds of the present invention, for example, starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose and hypromellose. Also, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions, syrups, etc.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
  • non-aqueous solvents and suspensions propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • injectable esters such as ethyl oleate
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized and / or an auxiliary agent such as a preservative, stabilizer, hydrating agent or emulsifying accelerator, salt and / or buffer for osmotic pressure control, And other therapeutically useful substances, mixed with water to prepare a solution or suspension, which can be prepared in ampoules or vials.
  • an auxiliary agent such as a preservative, stabilizer, hydrating agent or emulsifying accelerator, salt and / or buffer for osmotic pressure control, And other therapeutically useful substances, mixed with water to prepare a solution or suspension, which can be prepared in ampoules or vials.
  • the pharmaceutical composition provides a pharmaceutical composition comprising the compound of Formula 1 and excipients.
  • the compound may be added in an amount of preferably 0.001% by weight to 50% by weight, more preferably 0.001% by weight to 40% by weight, and most preferably 0.001% by weight to 30% by weight relative to the total weight of the total composition.
  • the pharmaceutical composition comprising the compound of formula 1 disclosed in the present invention as an active ingredient can be administered to various mammals, such as rats, livestock, humans. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracranial injection.
  • the dosage is the age, gender, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the type of other drug used and the prescriber's It will depend on the judgment.
  • Dosage determination based on these factors is within the level of those skilled in the art, and dosages generally range from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferred dosage is 1 mg / kg / day to 500 mg / kg / day.
  • the administration may be administered once a day, or may be divided into several times. The above dosage does not limit the scope of the present invention in any way.
  • the compound of formula 1 according to the present invention specifically binds to the CRBN protein and is involved in its function. Therefore, the compound of the present invention can be usefully used for the prevention or treatment of leprosy, chronic graft-versus-host disease, inflammatory disease or cancer by the action of CRBN protein.
  • FIG. 1 shows the degradation activity for GSPT1 and Aiolos when the compounds 1, 2, 110 and 143 of the present invention were treated for 6 hours or 24 hours.
  • Ikaros / Aiolos protein (Chamberlain, PP et al.) That is degraded by CRBN protein when combined with thalidomide and its analogs to confirm that the compound of the present invention can specifically inhibit CRBN function by specifically binding to CRBN (celebron).
  • Nat Struct Mol Biol., 21 (9), 803-809, 2014) or GSPT1 protein (Matyskiela, ME et al., Nature, 535 (7611), 252-257, 2016) The impact was investigated.
  • OCI-LY3 cells were seeded 5 ⁇ 10 5 cells in a 12-well plate, and then each compound was treated in each well at a predetermined concentration. After 6 or 24 hours, cell lysate was collected using TBSN buffer. Ikaros / Aiolos proteolytic activity was assessed by Western blot using an antibody against Aiolos protein, and GSPT1 proteolytic activity using an antibody against GSPT1 protein. For this purpose, each well of 4-15% gradient gel was used. After loading the same amount of protein in the electrophoresis, the protein was transferred to the PVDF membrane, and bound to the primary antibody for each protein. Subsequently, a secondary antibody to which HRP was attached was bound and developed using an HRP substrate.
  • Each cancer cell (TMD8, KG-1, OCI-LY3, OCI-LY19, NALM6, Molt-4, HL-60, NB-4, MOLM-13, Tanoue, Caco-2) in a 96-well plate 10,000 per well
  • each of the Example compound of the present invention and the comparative compound of Table 1 below was treated for each predetermined concentration.
  • WST-1 reagent was added, and after 1 hour, the degree of cancer cell death was measured by measuring the absorbance at 450 nm using a spectramax spectrophotometer. Using the measured values, IC 50 ( ⁇ M) values were calculated using the graphpad prism program and are shown in Tables 2 to 4.
  • the compounds of the present invention have sufficient cytotoxicity in cancer cells, and in particular, unlike the comparative compounds 1 and 2, the compounds of the present invention in which urea derivatives are substituted have more cytotoxicity against cancer cells. Excellent was confirmed.
  • the compounds 1 and 2 of the present invention showed cytotoxicity against various types of cancer cells, and although not shown in Table 4, the remaining compounds excluding compounds 1 and 2 of the present invention also have ICs for 9 cancer cells
  • the 50 value was 0.0001 to 0.1 ⁇ M, and it was confirmed that the compound of the present invention has excellent cytotoxicity against cancer cells.

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Abstract

La présente invention concerne un nouveau dérivé de pipéridine-2,6-dione et son utilisation et, plus particulièrement, un composé dérivé de pipéridine-2,6-dione ayant la structure d'un analogue de thalidomide. La présente invention concerne également un composé de formule chimique 1 qui se lie de manière spécifique à la protéine CRBN, et qui est impliqué dans ses fonctions. Par conséquent, le composé selon la présente invention peut être utilisé de manière bénéfique dans la prévention ou le traitement de la lèpre, d'une maladie chronique du greffon contre l'hôte, d'une maladie inflammatoire ou d'un cancer qui sont provoqués par des actions de la protéine CRBN.
PCT/KR2019/015061 2018-11-09 2019-11-07 Nouveau dérivé de pipéridine-2,6-dione et utilisation associée WO2020096372A1 (fr)

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WO2023001028A1 (fr) * 2021-07-19 2023-01-26 南京明德新药研发有限公司 Composé hétéroaryle-3-pipéridinedione et son utilisation

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