WO2020228478A1 - Inhibiteur de protéine d'apoptose diazobicyclique anti-tumoral - Google Patents

Inhibiteur de protéine d'apoptose diazobicyclique anti-tumoral Download PDF

Info

Publication number
WO2020228478A1
WO2020228478A1 PCT/CN2020/085124 CN2020085124W WO2020228478A1 WO 2020228478 A1 WO2020228478 A1 WO 2020228478A1 CN 2020085124 W CN2020085124 W CN 2020085124W WO 2020228478 A1 WO2020228478 A1 WO 2020228478A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
isomer
amino
reaction
Prior art date
Application number
PCT/CN2020/085124
Other languages
English (en)
Chinese (zh)
Inventor
宋志春
张崇光
何东伟
包金远
张孝清
Original Assignee
南京华威医药科技集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京华威医药科技集团有限公司 filed Critical 南京华威医药科技集团有限公司
Publication of WO2020228478A1 publication Critical patent/WO2020228478A1/fr

Links

Classifications

    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the field belongs to the field of medicinal chemistry, and specifically relates to an inhibitor of apoptosis protein and a preparation method and application thereof.
  • Apoptosis or programmed cell death is a genetically and biochemically regulated mechanism, which plays an important role in the development and homeostasis of invertebrates and vertebrates.
  • Abnormal apoptosis that leads to premature cell death has been linked to a variety of developmental disorders.
  • Defects in apoptosis that result in a lack of cell death have been linked to cancer and chronic viral infections.
  • IAP protein effectively inhibits the apoptosis of cancer cells induced by many kinds of apoptosis stimuli (including chemotherapeutics, radiation and immunotherapy), and is a new target of the apoptosis pathway.
  • Patent applications for inventions involving IAP inhibitors include WO2011018474A1, WO2008016893A1, WO2014047024A1, CN101484151A, etc.
  • IAP inhibitors currently under development include LCL161, Birinapant, BV6, GDC-0152, AZD5582, AT406, etc.
  • AT-406 is an effective, oral Smac mimic, an antagonist of IAPs, which can inhibit XIAP.
  • the structural formulas of cIAP1 and cIAP2 proteins are as follows:
  • IAP inhibitors have a synergistic immune checkpoint inhibitor treatment
  • the role of cancer has very good application prospects, but there are still many major challenges in the development of this species.
  • the purpose of the present invention is to provide a new inhibitor of apoptosis protein or a pharmaceutically acceptable salt or isomer thereof, characterized in that the compound has the following general formula:
  • X represents a C or N atom, when X is a C atom, Y is a CONHR 3 and Z represents a H atom; when X is a N atom, Z is a CONHR 3 and Y does not exist;
  • the R 1 and R 2 are each independently selected from C 1-20 alkylamino groups, C 5-8 cycloalkylamino groups, C 1 ⁇ 20 alkyl group, Or ⁇ -amino acid residues,
  • the ⁇ -amino acid residue is a substituent formed by the deletion of the carboxyl group on the ⁇ -carbon in the ⁇ -amino acid;
  • the Ar group represents an aryl or heteroaryl group with 5-8 atoms,
  • the m and n are each independently selected from any integer of 1 to 3;
  • R 3 is selected from substituted or unsubstituted benzyl, and the substituent is optionally selected from phenyl, halogen, C 1-4 alkyl or p-fluorophenyl;
  • a compound or a pharmaceutically acceptable salt or isomer thereof the compound has the following general formula:
  • R 1 is selected from C 1-20 alkylamino groups, C 1 ⁇ 20 alkyl group, Or any of the ⁇ -amino acid residues,
  • R 2 is selected from C 1-20 alkylamino group, C 5-8 cycloalkylamino group, C 1-20 alkyl group, Or any of the ⁇ -amino acid residues,
  • the ⁇ -amino acid residue is a substituted residue formed by the deletion of the carboxyl group on the ⁇ -carbon in the ⁇ -amino acid
  • the Ar group represents an aryl group and a heteroaryl group with 5-8 atoms.
  • the m and n are each independently selected from any integer of 1 to 3,
  • R 3 is selected from substituted or unsubstituted benzyl, and the substituent is optionally selected from phenyl, halogen, C 1-4 alkyl or p-fluorophenyl;
  • the alkylamino group described in formula I or II is And its isomers
  • the ⁇ -amino acid residue is or
  • R 2 in formula I or II is selected from C 1-13 alkyl
  • the aryl group described in formula I or II is phenyl
  • heteroaryl group described in formula I or II is imidazolyl
  • the halogen is F.
  • the present invention also provides methods for preparing compounds of formula I and formula II and their salts or isomers, but are not limited to the methods described below. All raw materials are prepared according to the group characteristics of the target molecule in accordance with the general formula, and are prepared through the schemes in these routes and methods well known to those of ordinary skill in the organic chemistry field or directly purchased.
  • the compounds of the present invention can be synthesized by combining the following methods with synthetic methods known in the field of synthetic organic chemistry or related modification methods recognized by those skilled in the art.
  • the preparation route of the compound of the present invention is as follows:
  • Option 1 includes the following steps:
  • N-Boc pyrrolidine-2-carboxylic acid methyl ester as starting material, react with allyl bromide under the action of lithium bistrimethylsilylamide, etc. to produce compound 1.
  • the reaction temperature is selected from -80°C to -20°C
  • the reaction solvent is selected from inert aprotic solvents such as tetrahydrofuran and toluene;
  • the Boc protecting group of compound 1 is removed under acidic conditions to obtain compound 2.
  • the acid can be hydrochloric acid, p-toluenesulfonic acid, etc.
  • the reaction solvent can be methanol, ethanol, tetrahydrofuran, etc.;
  • P 1 and P 2 are protecting groups for amino groups, and you can choose tert-butoxycarbonyl (Boc), 9-fluorenylmethylenoxycarbonyl (Fmoc), Boxycarbonyl (Cbz), and allyloxycarbonyl (Alloc), triphenylmethyl (Trt) and any suitable protecting groups, P 1 is not equal to P 2 (in embodiments, P 1 and P 2 are orthogonal protecting groups).
  • the condensing agent can be selected from N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7- Nitrobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and other condensing agents;
  • the carbon-carbon double bond is oxidized to an aldehyde with one less carbon to obtain compound 4.
  • the reaction temperature is from -80°C to -20°C
  • the reaction solvent is tetrahydrofuran, dichloromethane, methanol
  • the reducing agent is selected Triphenylphosphine, sodium sulfite, triethylamine, etc.;
  • Compound 4 removes the protective group P 2 under acidic conditions (when P 2 is the Boc protecting group), palladium-carbon hydrogenation (when P 2 is the Cbz protecting group) or piperidine (when P 2 is the Fmoc protecting group), and further Reductive amination to obtain macrocyclic compound 5, the reaction solvent is tetrahydrofuran, dichloromethane, methanol, toluene, etc., and the reducing agent is sodium borohydride, sodium cyanoborohydride, etc.;
  • Compound 5 is in an inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, under the action of a condensing agent, and a carboxylic acid compound containing R 1 group undergoes condensation reaction to obtain compound 6, temperature Choose from 25°C to 120°C, choose N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, condensing agent 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluoro Phosphate etc.;
  • an inert organic solvent such as acetonitrile, toluene, chloro
  • Compound 6 is saponified under alkaline conditions, and then the pH value is controlled under acidic conditions to obtain compound 7.
  • the organic solvent is methanol, ethanol and other water-soluble solvents, and the alkali is inorganic alkalis such as lithium hydroxide and sodium hydroxide;
  • Compound 7 is in inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, under the action of a condensing agent, and an amino compound containing R 3 group is condensed to obtain compound 8, and the temperature is selected At 25°C to 120°C, the condensing agent is N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2 -(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate Salt etc.;
  • Compound 8 removes the protective group P 1 under acidic conditions (when P 1 is a Boc protecting group), palladium-carbon hydrogenation (when P 1 is a Cbz protecting group), or piperidine (when P 1 is a Fmoc protecting group), etc.
  • Amino compound 9 the reaction solvent is tetrahydrofuran, dichloromethane, methanol, toluene, etc.;
  • Compound 9 is in an inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, under the action of a condensing agent, and a carboxylic acid compound containing R 2 group undergoes a condensation reaction to obtain compound I.
  • an inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • N,N'-diisopropylcarbodiimide choose from 25°C to 120°C, choose N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, condensing agent 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluoro Phosphate etc.
  • Option 2 includes the following steps:
  • the ring is closed under the action of inorganic bases such as potassium carbonate and cesium carbonate to produce compound 11.
  • inorganic bases such as potassium carbonate and cesium carbonate
  • the reaction temperature is 25°C to 120°C
  • the reaction solvent is acetonitrile, tetrahydrofuran, and N,N-dimethylformaldehyde.
  • Inert aprotic solvents such as amides;
  • P 1 and P 2 are protecting groups for amino groups, and you can choose tert-butoxycarbonyl (Boc), 9-fluorenylmethylenoxycarbonyl (Fmoc), Boxycarbonyl (Cbz), and allyloxycarbonyl (Alloc), triphenylmethyl (Trt), etc., P 1 is not equal to P 2 (in embodiments, P 1 and P 2 are orthogonal protecting groups).
  • Condensing agent selected N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzene Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, etc.;
  • the carbon-carbon double bond of compound 12 is oxidized to an aldehyde with one less carbon to obtain compound 13.
  • the reaction temperature is selected from -80°C to -20°C
  • the reaction solvent is tetrahydrofuran, dichloromethane, methanol
  • the reducing agent is selected Triphenylphosphine, sodium sulfite, triethylamine, etc.;
  • Compound 13 removes the protective group P 2 under acidic conditions (when P 2 is the Boc protecting group), palladium-carbon hydrogenation (when P 2 is the Cbz protecting group), or piperidine (when P 2 is the Fmoc protecting group), and further Reductive amination to obtain macrocyclic compound 14, the reaction solvent is tetrahydrofuran, dichloromethane, methanol, toluene, etc., and the reducing agent is sodium borohydride, sodium cyanoborohydride, etc.;
  • Compound 14 is in inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, under the action of a condensing agent, and a carboxylic acid compound containing R 1 group undergoes condensation reaction to obtain compound 15.
  • inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • N,N'-diisopropylcarbodiimide choose from 25°C to 120°C, choose N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, condensing agent 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluoro Phosphate etc.;
  • Compound 15 is saponified under alkaline conditions, and then the pH value is controlled under acidic conditions to obtain compound 16.
  • the organic solvent is methanol, ethanol and other water-soluble solvents, and the alkali is inorganic alkalis such as lithium hydroxide and sodium hydroxide;
  • Compound 16 is in inert organic solvents such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, under the action of a condensing agent, and an amino compound containing R 3 group undergoes condensation reaction to obtain compound 17, and the temperature is selected
  • the condensing agent is N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2 -(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate Salt etc.;
  • Compound 17 removes the protective group P 1 under acidic conditions (when P 1 is a Boc protecting group), palladium-carbon hydrogenation (when P 1 is a Cbz protecting group), or piperidine (when P 1 is a Fmoc protecting group), etc.
  • Amino compound 18, the reaction solvent is tetrahydrofuran, dichloromethane, methanol, toluene, etc.;
  • Compound 18 is in an inert organic solvent such as acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, under the action of a condensing agent, and a carboxylic acid compound containing R 2 group undergoes condensation reaction to obtain compound II, temperature Choose from 25°C to 120°C, choose N,N'-diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, condensing agent 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluoro Phosphate etc.
  • an inert organic solvent such as acetonitrile, toluene, chloro
  • the P 1 and P 2 groups are the protecting groups of the amino group, and the R 1 , R 2 and R 3 groups are defined as described above in the specification.
  • the method for preparing compounds involves protecting and deprotecting various chemical groups, and those skilled in the art can easily select a suitable protecting group according to the needs of protection and deprotection.
  • the above-mentioned group features mentioned in the present invention or the features mentioned in the examples can be combined arbitrarily on the basis of compliance with the laws of pharmacy.
  • Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. .
  • the disclosed features are only general examples of the same or similar features.
  • Another aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of any compound selected from the compound of formula I'or formula I or formula II or a pharmaceutically acceptable salt or isomer thereof as an active ingredient , And one or more pharmaceutically acceptable carriers, diluents and/or excipients.
  • the pharmaceutical composition preferably contains a compound of formula I'or formula I or formula II or a pharmaceutically acceptable salt or isomer thereof in a weight ratio of 1% to 90% as an active ingredient, more preferably a weight ratio of 10 %-80% active ingredients.
  • C 1 ⁇ 20 alkyl group means a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, including straight-chain and branched-chain groups (the numerical ranges mentioned in this application, for example, “1-20”, refers to The group, in this case an alkyl group, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms).
  • the alkyl group in the present invention includes "alkylene".
  • An alkyl group containing 1 to 6 carbon atoms is called a lower alkyl group. When a lower alkyl group has no substituent, it is called an unsubstituted lower alkyl group.
  • the alkyl group is a medium-sized alkyl group having 1-10 carbon atoms, such as methyl, ethyl, ethylene, propyl, propylene, 2-propyl, n-butyl, isopropyl Butyl, butylene, tert-butyl, pentyl, etc.
  • the alkyl group is a lower alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, butylene, isobutyl or tert-butyl.
  • Alkyl groups can be substituted or unsubstituted.
  • C 1-20 alkylamino group means an R-amino compound, and the definition of R is as described for the C 1-20 alkyl group.
  • C 5-8 cycloalkaneamino group means an amine compound formed by substituting one carbon on a C 5-8 cycloalkane with an amino group, for example Wait.
  • ⁇ -amino acid residue means a substitution residue formed after the carboxyl group on the ⁇ -carbon of an amino acid is deleted.
  • benzyl means "benzyl", with a simple structure of C 6 H 5 CH 2 -, or Bn (abbreviation for Benzyl).
  • aryl refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms with a fully conjugated ⁇ -electron system.
  • Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • Aryl groups can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, and even more preferably one or two, independently selected from lower alkyl, trihaloalkyl, halogen, and hydroxyl , Lower alkoxy, mercapto, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thioamino Formyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido.
  • the aryl group is a 5-membered monocyclic aryl group or a 6-membered monocyclic aryl group.
  • heteroaryl means a monocyclic or condensed ring group of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, and the remaining ring atoms are C, in addition has a fully conjugated ⁇ electron system.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one, two or three, and still more preferably one or two.
  • Non-limiting examples of unsubstituted heteroaromatic bases are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine and carbazole; preferably, Heteroaryl groups are nitrogen-containing 5-membered monocyclic heteroaryl groups and nitrogen-containing 6-membered monocyclic heteroaryl groups.
  • isomer can be understood to cover the conventional compound “stereoisomerism” in the art, including enantiomers and diastereomers, where diastereomers include cis and trans isomers, for example, From its cis isomer, trans isomer or a mixture of cis and trans isomers.
  • halogen means fluorine, chlorine, bromine or iodine.
  • salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by the reaction of the free base of the parent compound with an inorganic acid or organic acid, such as (but not limited to) hydrochloric acid, hydrobromic acid, etc., and organic acid such as (but not limited to) acetic acid, Malic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, tartaric acid, citric acid, lactic acid, succinic acid or malonic acid, etc.
  • organic acid such as (but not limited to) acetic acid, Malic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, tartaric acid, citric acid, lactic acid, succinic acid or malonic acid, etc.
  • Such salts have safety, effectiveness and due biological activity when used in mammals.
  • “Pharmaceutical composition” refers to one or more of the compounds described herein or their pharmaceutically acceptable salts, isomers and prodrugs and other chemical components, such as pharmaceutically acceptable carriers and Mixture of excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • “Pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to organisms and does not interfere with the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of a compound.
  • excipients include (not limited to) lactose, sucrose, microcrystalline cellulose, sorbitol, polyvinylpyrrolidone, cellulose, water, methylcellulose, and the like.
  • the pharmaceutical composition may also contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate, etc.; sweeteners and flavoring agents.
  • lubricants such as talc, magnesium stearate and mineral oil
  • wetting agents such as talc, magnesium stearate and mineral oil
  • emulsifiers and suspending agents such as methyl benzoate, etc.
  • preservatives such as methyl benzoate, etc.
  • sweeteners and flavoring agents such as talc, magnesium stearate and mineral oil.
  • composition of the present invention is formulated, dosed and administered in a manner consistent with good medical practice.
  • the factors to be considered in this situation include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the location where the agent is delivered, the method of administration, the dosing regimen, and what is known to the medical practitioner Other factors.
  • the present invention also provides the use of the compound of formula I'or formula I or formula II or a pharmaceutically acceptable salt or isomer thereof:
  • IAP protein for example, c-IAP1, c-IAP2, X-IAP or ML-IAP.
  • the compounds of the present invention can be used to treat all types of cancer drugs that fail to undergo apoptosis.
  • cancer types include neuroblastoma, bowel cancer such as rectal cancer, colon cancer, familial adenomatous polyp cancer and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, Tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer , Prostate cancer, testicular cancer, breast cancer, urinary system cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Ho
  • the positive control compound AT-406 of the compound of the present invention is an inhibitor of cIAP1 and cIAP2, and its inhibitory effect on XIAP is weaker than that of cIAP1 and cIAP2, while the compound of the present invention has stronger inhibitory activity on the three proteins of XIAP, cIAP1 and cIAP2. Therefore, the compound of the present invention has a stronger inhibitory effect on apoptosis proteins as a whole;
  • the compound of the present invention has a strong inhibitory effect on MDA-MB-231 breast cancer and PC-3 pancreatic cancer cells, while the positive control compound AT-406 only has a better effect on MDA-MB-231 breast cancer. Strong, the inhibitory effect on PC-3 pancreatic cancer cells is relatively weak;
  • the compound of the present invention has good IAP inhibitory activity, and can be developed into a cancer treatment drug used alone in the later stage, or can be combined with other targeted drugs to treat cancer;
  • the compound of the present invention has good binding affinity with XIAP, cIAP1, and cIAP2 proteins, and has a good inhibitory effect on cell growth in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines. Its medicinal value and broad market prospects.
  • the dichloromethane solution prepared in the first step was added dropwise to the yellow clear solution, and stirred at room temperature for 6 hours to obtain a reddish brown solution. TLC detected that the reaction was complete.
  • the solvent was evaporated under reduced pressure, the residue was dissolved in 400 mL ethyl acetate, washed with 1M HCl solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, the organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Diazaoctane-10a-carboxylic acid 1.8g (3.3mmol), 2.6g PyBop (5.0mmol) in a 100mL single-mouth reaction flask, add 50mL DMF, take another 0.85g DIEA (6.6mmol) , Stir at room temperature for 30 minutes. Another 1.2 g (6.6 mmol) of benzhydrylamine was added to the system, heated to 90° C. and stirred for 12 hours.
  • Example 46 Preparation of 1-acetaldehyde-2-((3-benzyloxycarbonyl-amino-2-tert-butoxycarbonyl-amino)propionyl)-pyrazole-3-carboxylic acid ethyl ester
  • Triazaoctane-8-carboxylic acid 0.95g (2.3mmol), 1.8g PyBop (3.6mmol) in a 100mL single-necked reaction flask, add 50mL DMF, another 0.60g DIEA (4.6mmol), and stir at room temperature for 30 minutes. Another 0.84 g (4.6 mmol) of benzhydrylamine was added to the system, heated to 90° C. and stirred for 12 hours. TLC detected that the reaction was complete.
  • Example 65 Test of the binding affinity of the compound to XIAP, cIAP1, and cIAP2
  • a fluorescence polarization (FP)-based competitive assay method was used for the assay.
  • fluorescently labeled Smac mimics Smac-2F
  • the K d values of Smac-2F, cIAP1-BIR3, and cIAP2-BIR3 are determined by monitoring the total fluorescence polarization of a mixture composed of a solid concentration fluorescent probe and an increasing concentration of protein up to complete saturation.
  • the K i value of the compound is determined by a dose-dependent competitive binding experiment, in which a serial dilution of the compound competes with a fixed concentration of fluorescent probe to bind to a fixed concentration of protein (usually the Kd value measured above is 2-3 times) .
  • 5ul test compound in DMSO and 120ul pre-incubated protein/tracer in assay buffer solution (100mM potassium phosphate, pH 7.5; 100ug/ml bovine gamma globulin; 0.02% sodium azide, Invitrogen)
  • the final concentrations of protein and probe were 3nm and 1nm, 5nm and 1nm for cIAP1-BIR3 and cIAP2-BIR3, respectively.
  • a negative control containing only protein/probe complexes (equivalent to 0% inhibition) and a positive control containing only free probes (equivalent to 100% inhibition) were included in each assay plate.
  • the IC50 value was determined by nonlinear regression fitting of the competition curve.
  • the Ki value of the competitive inhibitor is calculated using the previously described derivation equation based on the measured IC50 value, the Kd value of the probe and different proteins, and the concentration of the protein and probe in the refining assay.
  • the FP-based assay for the XIAP-BIR2-BIR3 protein was performed using the same procedure.
  • a bivalent fluorescent-tagged peptide Smac mimic (Smac-1F) was used as a fluorescent probe, and the Kd value of XIAP-BIR2-BIR3 was measured similarly to the saturation experiment.
  • 0.01% Triton X-100 was added to the assay buffer to achieve the stable fluorescence and polarization values of the dimer fluorescent probe.
  • the final protein and probe concentrations used in the competition assay were 2nm and 1nm, respectively.
  • the test results of the compounds of the present invention are shown in the following table.
  • Example 67 Cell growth inhibition test in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines
  • the effects of the compounds of the invention on the growth of different cancer cell lines were tested.
  • the cells were seeded on a 96-well flat-bottom cell culture plate together with the test compound at a density of 3000 cells/well and the cells were cultured at 37°C in an atmosphere of 95% air and 5% CO 2 for 4 days.
  • Use WST-8 kit and 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H- Tetrazolium monosodium salt was used to determine the cell growth inhibition rate after treatment with different concentrations of the compound.
  • WST-8 was added to each well at a final concentration of 10%, and then the plate was incubated at 37°C for 2-3 hours.
  • the absorbance of the sample was measured at 450 nm using a ULTRATecan reader (Molecular Device). By comparing the absorbance of untreated cells and the treated cells with the test compound, the test compound is calculated inhibitory concentration (IC 50) 50% of cell growth. The test results are shown in the table below.
  • the compound of the present invention has a good inhibitory effect on cell growth in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouvel inhibiteur de protéine d'apoptose ou un sel pharmaceutiquement acceptable de celui-ci, un isomère de celui-ci, un procédé de préparation associé et une composition pharmaceutique, la définition de chaque groupe étant telle que présentée dans la description. La présente invention concerne également l'utilisation du composé, du sel pharmaceutiquement acceptable de celui-ci et de son isomère dans la préparation d'un médicament pour des maladies associées à des protéines IAP. Le composé selon la présente invention a une meilleure affinité de liaison vis-à-vis des protéines de XIAP, cIAP1 et cIAP2, a un meilleur effet inhibiteur sur la croissance cellulaire du cancer du sein MDA-MB-231 et des lignées cellulaires du cancer du pancréas PC-3, présente une excellente valeur pharmaceutique et une large perspective de marché.
PCT/CN2020/085124 2019-05-16 2020-04-16 Inhibiteur de protéine d'apoptose diazobicyclique anti-tumoral WO2020228478A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910408971.2A CN110028508B (zh) 2019-05-16 2019-05-16 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂
CN201910408971.2 2019-05-16

Publications (1)

Publication Number Publication Date
WO2020228478A1 true WO2020228478A1 (fr) 2020-11-19

Family

ID=67242449

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/085124 WO2020228478A1 (fr) 2019-05-16 2020-04-16 Inhibiteur de protéine d'apoptose diazobicyclique anti-tumoral

Country Status (2)

Country Link
CN (1) CN110028508B (fr)
WO (1) WO2020228478A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210309668A1 (en) * 2018-08-01 2021-10-07 Agency For Science, Technology And Research Bicyclic compounds as kinase modulators, methods and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110028508B (zh) * 2019-05-16 2021-05-28 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101686981A (zh) * 2007-04-13 2010-03-31 密执安州立大学董事会 重氮双环类smac模拟物及其用途
CN102066361A (zh) * 2008-04-11 2011-05-18 密歇根大学董事会 杂芳基取代的双环的smac模拟物及其用途
WO2014085489A1 (fr) * 2012-11-30 2014-06-05 Sanford-Burnham Medical Research Institute Antagonistes des protéines inhibitrices de l'apoptose (iaps)
CN108484640A (zh) * 2018-05-22 2018-09-04 南京华威医药科技集团有限公司 一种抗肿瘤的细胞凋亡蛋白抑制剂
CN110028508A (zh) * 2019-05-16 2019-07-19 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2553874A1 (fr) * 2004-01-16 2005-08-04 The Regents Of The University Of Michigan Mimetiques de smac contraints de maniere conformationnelle et utilisations associees
CA2920045A1 (fr) * 2013-07-30 2015-02-05 Health Research Inc. Procede de traitement
WO2015187998A2 (fr) * 2014-06-04 2015-12-10 Sanford-Burnham Medical Research Institute Utilisation d'un inhibiteur des antagonistes de la protéine d'apoptose (iap) dans une thérapie contre le vih

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101686981A (zh) * 2007-04-13 2010-03-31 密执安州立大学董事会 重氮双环类smac模拟物及其用途
CN102066361A (zh) * 2008-04-11 2011-05-18 密歇根大学董事会 杂芳基取代的双环的smac模拟物及其用途
WO2014085489A1 (fr) * 2012-11-30 2014-06-05 Sanford-Burnham Medical Research Institute Antagonistes des protéines inhibitrices de l'apoptose (iaps)
CN108484640A (zh) * 2018-05-22 2018-09-04 南京华威医药科技集团有限公司 一种抗肿瘤的细胞凋亡蛋白抑制剂
CN110028508A (zh) * 2019-05-16 2019-07-19 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210309668A1 (en) * 2018-08-01 2021-10-07 Agency For Science, Technology And Research Bicyclic compounds as kinase modulators, methods and uses thereof
US11702425B2 (en) * 2018-08-01 2023-07-18 Agency For Science, Technology And Research Bicyclic compounds as kinase modulators, methods and uses thereof

Also Published As

Publication number Publication date
CN110028508A (zh) 2019-07-19
CN110028508B (zh) 2021-05-28

Similar Documents

Publication Publication Date Title
AU2014235816B2 (en) IDO inhibitors
CA3149963A1 (fr) Inhibiteurs heterocycliques de la kinase rip1
US11267825B2 (en) Highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis B virus (HBV)
KR20170134981A (ko) 암의 치료를 위한 인돌아민-2,3-디옥시게나제의 억제제
CA2917964A1 (fr) Inhibiteurs de l'ido
ES2657905T3 (es) Inhibidores de BACE
EP1519729A1 (fr) Composes de pyrrolotriazinone et leur utilisation dans le traitement de maladies
CN113474346A (zh) 用于抑制泛素特异性蛋白酶1的组合物
US20140309192A1 (en) Modulators of the g protein-coupled mas receptor and the treatment of disorders related thereto
CN106536491B (zh) 作为盐皮质激素受体调节剂的苯并噁嗪酮酰胺
WO2015077193A1 (fr) Inhibiteurs de lysine méthyle transférase
BR112015026410B1 (pt) Derivados de dolastatina 10 e auristatinas, seu uso, sua composição farmacêutica e seus métodos para preparação
TW202321251A (zh) 新穎螺環吡咯啶衍生的抗病毒劑
AU2004279553B2 (en) Certain substituted spirocyclic lactams and use thereof as pharmaceuticals
IL296994A (en) compounds and their uses
JP2022506337A (ja) Ｂ型肝炎ウイルス（ｈｂｖ）に対して活性を有する６，７－ジヒドロ－４ｈ－ピラゾロ［１，５－ａ］ピラジンインドール－２－カルボキサミド
BR112015017963A2 (pt) composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto
KR20180021820A (ko) Ido 억제제
WO2020228478A1 (fr) Inhibiteur de protéine d'apoptose diazobicyclique anti-tumoral
BR112020025013A2 (pt) novos compostos de piridina e pirazina como inibidores do receptor 2 de canabinoide
WO2022255888A1 (fr) Dégradation de protéine ciblée à l'aide de composés bifonctionnels qui se lient à l'ubiquitine ligase et à la protéine mcl-1 cible
CN108440507B (zh) 作为细胞凋亡蛋白抑制剂的化合物及其应用
TW202334167A (zh) 作為ｅｒｂｂ２抑制劑之稠合四環喹唑啉衍生物
WO2019074824A1 (fr) Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation
CA3165339A1 (fr) Modulateurs de cd206, leur utilisation et leurs procedes de preparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20806488

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20806488

Country of ref document: EP

Kind code of ref document: A1