WO2023274418A1 - Composé chimère ciblant la protéolyse - Google Patents

Composé chimère ciblant la protéolyse Download PDF

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WO2023274418A1
WO2023274418A1 PCT/CN2022/103762 CN2022103762W WO2023274418A1 WO 2023274418 A1 WO2023274418 A1 WO 2023274418A1 CN 2022103762 W CN2022103762 W CN 2022103762W WO 2023274418 A1 WO2023274418 A1 WO 2023274418A1
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compound
reaction
pharmaceutically acceptable
acceptable salt
independently selected
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PCT/CN2022/103762
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English (en)
Chinese (zh)
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黄婧婕
于涛
谭冶
李泽许
吴成德
陈曙辉
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南京明德新药研发有限公司
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a class of protein degradation targeting chimera compounds and their application in the preparation of drugs for treating related diseases, specifically disclosing the compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • BRD4 (Bromodomain-containing protein 4) is a protein encoded by the BRD4 gene in humans.
  • BRD4 is a member of the BET family, which also includes BRD2, BRD3 and BRDT. Similar to other BET family members, BRD4 contains two bromodomains that recognize acetylated lysine residues. BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.
  • BRD4 can bind to acetylated histones or non-histones, thereby regulating gene replication and transcription, affecting cell cycle, cell differentiation, signal transduction and other processes.
  • the upregulation of BRD4 expression is closely related to the malignant development of various tumors. Inhibiting or degrading BRD4 can effectively control the malignant progression and distant metastasis of tumors. Therefore, BRD4 is a promising tumor epigenetic target.
  • PROTAC Proteinolysis Targeting Chimera
  • PROTAC Proteinolysis Targeting Chimera
  • E3 ubiquitin ligases Such compounds can induce the intracellular proteasome system to recognize the target protein, thereby causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • L is selected from single bond, *-Cy 1 -Ak 1 -Cy 2 -Ak 2 -Cy 3 -Ak 3 -(Cy 4 -Ak 4 ) n -, *-Cy 1 -(OCH 2 CH 2 ) m -NH - and *-Cy 1 -(OCH 2 CH 2 ) m -O-, where * indicates connection with PTM;
  • Cy 1 is selected from phenyl and 5-6 membered heteroaryl
  • Ak 1 is selected from single bonds and -O-;
  • Cy 2 , Cy 3 and Cy 4 are independently selected from 3-6 membered heterocycloalkyl groups, and the 3-6 membered heterocycloalkyl groups are optionally substituted by 1, 2 or 3 R a ;
  • Ak 2 , Ak 3 and Ak 4 are independently selected from single bond, C 1-3 alkyl and -C 1-3 alkyl NH-, said C 1-3 alkyl and -C 1-3 alkyl NH - optionally substituted by 1, 2 or 3 R b ;
  • n 0 or 1
  • n 2, 3 or 4;
  • ULM is selected from the structures shown in formula (I-1), formula (I-2) and formula (I-3):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H;
  • R a and R b are independently selected from F, Cl, Br, I, oxo, C 1-3 alkyl and C 1-3 alkoxy;
  • L is selected from single bond and *-Cy 1 -Ak 1 -Cy 2 -Ak 2 -Cy 3 -Ak 3 -(Cy 4 -Ak 4 ) n -;
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • L is selected from single bond, *-Cy 1 -Ak 1 -Cy 2 -Ak 2 -Cy 3 -Ak 3 -(Cy 4 -Ak 4 ) n -, *-Cy 1 -(OCH 2 CH 2 ) m -NH - and *-Cy 1 -(OCH 2 CH 2 ) m -O-, where * indicates connection with PTM;
  • Cy 1 is selected from phenyl, piperidinyl and 5-6 membered heteroaryl
  • Ak 1 is selected from single bonds and -O-;
  • Cy 2 , Cy 3 and Cy 4 are independently selected from 3-6 membered heterocycloalkyl groups, and the 3-6 membered heterocycloalkyl groups are optionally substituted by 1, 2 or 3 R a ;
  • Ak 2 , Ak 3 and Ak 4 are independently selected from single bond, C 1-3 alkyl and -C 1-3 alkyl NH-, said C 1-3 alkyl and -C 1-3 alkyl NH - optionally substituted by 1, 2 or 3 R b ;
  • n 0 or 1
  • n 2, 3 or 4;
  • ULM is selected from the structures shown in formula (I-1), formula (I-2) and formula (I-3):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H;
  • R a and R b are independently selected from F, Cl, Br, oxo, C 1-3 alkyl and C 1-3 alkoxy;
  • hetero of the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl is a heteroatom independently selected from O, S and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • L is selected from single bond, *-Cy 1 -Ak 1 -Cy 2 -Ak 2 -Cy 3 -Ak 3 -(Cy 4 -Ak 4 ) n -, *-Cy 1 -(OCH 2 CH 2 ) m -NH - and *-Cy 1 -(OCH 2 CH 2 ) m -O-, where * indicates connection with PTM;
  • Cy 1 is selected from phenyl, piperidinyl and 5-6 membered heteroaryl
  • Ak 1 is selected from single bonds and -O-;
  • Cy 2 , Cy 3 and Cy 4 are independently selected from 3-6 membered heterocycloalkyl groups, and the 3-6 membered heterocycloalkyl groups are optionally substituted by 1, 2 or 3 R a ;
  • Ak 2 , Ak 3 and Ak 4 are independently selected from single bond, C 1-3 alkyl and -C 1-3 alkyl NH-, said C 1-3 alkyl and -C 1-3 alkyl NH - optionally substituted by 1, 2 or 3 R b ;
  • n 0 or 1
  • n 2, 3 or 4;
  • ULM is selected from the structures shown in formula (I-1), formula (I-2) and formula (I-3):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H;
  • R a and R b are independently selected from F, Cl, Br, oxo, C 1-3 alkyl and C 1-3 alkoxy;
  • hetero of the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl is a heteroatom independently selected from O, S and N.
  • Cy 1 is selected from phenyl and pyridyl, and other variables are as defined in the present invention.
  • Cy 2 , Cy 3 and Cy 4 are independently selected from said Optionally substituted by 1, 2 or 3 R a , other variables are as defined herein.
  • the above-mentioned Ak 2 , Ak 3 and Ak 4 are independently selected from single bonds, -CH 2 - and -CH 2 CH 2 NH-, and the -CH 2 - and -CH 2 CH 2 NH - optionally substituted by 1, 2 or 3 R b , other variables are as defined in the present invention.
  • the above-mentioned Ak 2 , Ak 3 and Ak 4 are independently selected from single bonds, -CH 2 - and -CH 2 CH 2 NH-, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from:
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the compound of the present invention has significant cell proliferation inhibitory activity on MDA-MB-231 cell line, and has weak or substantially inactive activity on GSPT1; the compound of the present invention can degrade BRD4 protein concentration-dependently in MDA-MB-231 cell line, And it has no obvious degradation activity on GSPT1; the compound of the present invention has excellent pharmacokinetic properties.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • acid addition salts of certain specific compounds of the present invention can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Compounds contain basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-6-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolid
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention is commercially available.
  • Fig. 1 is the test result of the degradation activity of the compound of the present invention on BRD4 and GSPT1 in MDA-MB-231 cell line.
  • Compound 04-4 (0.05g, 94.23 ⁇ mol, 1eq) was dissolved in DMF (5mL), 01-10 (37.78mg, 94.23 ⁇ mol, 1eq), DIEA (24.36mg, 188.46 ⁇ mol, 32.83 ⁇ L, 2eq) were added, HATU (35.83mg, 94.23 ⁇ mol, 1eq) was added at 0°C, and the mixture was gradually heated to 25°C and stirred for 1 hour.
  • Step 8 Synthesis of Compound 05-11
  • Step 11 Synthesis of Compounds 05 and 06
  • DIEA 47.24mg, 365.48 ⁇ mol, 63.66 ⁇ L, 3eq
  • HATU 92.64mg, 243.65 ⁇ mol, 2eq
  • test compound The effect of the test compound on the anti-proliferation activity of the cells was determined in the MDA-MB-231 cell line by means of CTG.
  • Cell culture medium complete cell culture medium (RPMI 1640+10% serum+1% L-glutamine+1% double antibody)
  • test compound The effect of the test compound on the degradation activity of GSPT1 was determined in HEK293 cell line by HiBiT method.
  • Cell culture medium DMEM+10% serum+2mM L-glutamine+1mM sodium pyruvate+double antibody
  • the compound of the present invention has significant cell proliferation inhibitory activity on MDA-MB-231 cell line, and has weak or almost no activity on GSPT1.
  • the effect of the test compound on the degradation activity of BRD4 was determined in the MDA-MB-231 cell line by Western Blot method.
  • MDA-MB-231 cells were recovered and cultured to a suitable state
  • MDA-MB-231 cells were seeded in a 12-well plate at 2 ⁇ 10 5 cells per well, and treated with a certain concentration of the test compound after adhering overnight;
  • the compound of the present invention can degrade BRD4 protein in a concentration-dependent manner in MDA-MB-231 cell line, and has no obvious degradation activity on GSPT1.
  • mice Female Balb/c nude mice were used as test animals to measure the blood drug concentration of the compound and evaluate the pharmacokinetic behavior after a single administration.
  • Experimental operation Select 4 healthy adult female Balb/c nude mice, 2 for the intravenous injection group and 2 for the oral administration group.
  • the compound to be tested was mixed with an appropriate amount of solvent (10% DMSO, 40% PEG300, 5% Tween-80plus 45% saline), vortexed and sonicated to prepare a 1.0 mg/mL clear solution, which was filtered through a microporous membrane for use.
  • the compound of the present invention has excellent pharmacokinetic properties.

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Abstract

L'invention concerne un nouveau composé chimère ciblant la protéolyse, ainsi qu'une application correspondante dans la préparation d'un médicament pour le traitement de maladies associées. Un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci sont plus particulièrement divulgués. PTM-L-ULM (I)
PCT/CN2022/103762 2021-07-02 2022-07-04 Composé chimère ciblant la protéolyse WO2023274418A1 (fr)

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Citations (8)

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CN104136435A (zh) * 2011-12-30 2014-11-05 艾伯维公司 溴结构域抑制剂
CN105189461A (zh) * 2013-03-14 2015-12-23 葛兰素史克知识产权第二有限公司 2,3-二取代的1-酰基-4-氨基-1,2,3,4-四氢喹啉衍生物和它们作为溴结构域抑制剂的用途
WO2016016316A1 (fr) * 2014-08-01 2016-02-04 Nuevolution A/S Composés actifs envers des bromodomaines
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