WO2012000322A1 - Inhibiteurs de peptide déformylase contenant de la 4-méthylène pyrrolidine - Google Patents

Inhibiteurs de peptide déformylase contenant de la 4-méthylène pyrrolidine Download PDF

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Publication number
WO2012000322A1
WO2012000322A1 PCT/CN2011/071367 CN2011071367W WO2012000322A1 WO 2012000322 A1 WO2012000322 A1 WO 2012000322A1 CN 2011071367 W CN2011071367 W CN 2011071367W WO 2012000322 A1 WO2012000322 A1 WO 2012000322A1
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WIPO (PCT)
Prior art keywords
methyl
product
mmol
peptide deformylase
added
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PCT/CN2011/071367
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English (en)
Chinese (zh)
Inventor
胡文浩
石炜
马海坤
段月娇
杨琍苹
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华东师范大学
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Publication of WO2012000322A1 publication Critical patent/WO2012000322A1/fr

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Classifications

    • 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
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • a peptide deformylase inhibitor containing 4-methylene pyrrolidine relates to a peptide deformylase (PDF) inhibitor. It belongs to the field of antibiotic antibiotics technology. Background technique
  • Antibiotic refers to a microbial product (secondary metabolite) that kills or inhibits certain specific microorganisms such as bacteria, fungi, rickettsia, mycoplasma, chlamydia and viruses at high dilution.
  • secondary metabolite secondary metabolite
  • certain specific microorganisms such as bacteria, fungi, rickettsia, mycoplasma, chlamydia and viruses at high dilution.
  • Florey and Chain based on the discovery of Fleming, invented penicillin for human injection.
  • Waksman isolated streptomycin and it is exciting that this antibiotic is highly resistant to tuberculosis, making tuberculosis no longer a terminal illness.
  • the process of synthesizing proteins between human cells and pathogens is basically similar.
  • the starting materials of both are methionine, but there is one biggest difference between them: Relative to human cells, the synthetic protein of the bacteria needs to be acylated with methionine. Finally, the peptide is subjected to deformylation by peptide deformylase, and then the N-terminal methionine is removed to complete the process of synthesizing the protein, and the human cell has no formylation-deformylation process.
  • an inhibitor of the peptide deformylase (PDF) of a metalloproteinase containing Fe( ⁇ ) is chelated with Fe(II) to achieve peptide deformylase loss.
  • the action of the activity inhibits the deformylation of the peptide deformylase, so that the bacteria cannot remove the N-terminal methionine, thereby selectively inhibiting the protein synthesis of the pathogen without affecting the protein synthesis process of the human cells.
  • Peptide deformylase inhibitors are a class of antibacterial drugs developed in recent years. These drugs have different mechanisms of action than known antibiotics, thus killing bacteria that are resistant to existing antibiotics. It has opened up a new path for the development of antibacterial drugs and has a good development prospect.
  • the first peptide deformylase inhibitor discovered was a natural product, actinoin, Actinonin.
  • This substance was found to have excellent in vitro inhibitory peptide deformylase activity and antibacterial activity.
  • this natural product does not have antibacterial activity in vivo and thus cannot be used as an antibacterial drug.
  • Peptide deformylase is a formyl metalloproteinase that plays a key role in bacterial protein synthesis.
  • Peptide deformylase (PDF) inhibitors inhibit PDF in this process. The action of the deformyl group, thereby inhibiting the process of bacterial synthesis of proteins. Therefore, this new mechanism of action for PDF inhibitors offers a new potential for antibiotic treatment without affecting the metabolism of eukaryotic organisms. As far as current research is concerned, the chances of bacteria developing resistance to PDF inhibitors are small.
  • two PDF inhibitors, BB-83698 and LBM-415 have entered Phase II clinical trials. In October 2001, the peptide deformylase developed by British Biotech inhibited U BB83698 ( II ) into one, and now the product has entered Phase II clinical trials.
  • the present invention provides a peptide formylase inhibitor comprising a 4-methylene pyrrolidine structure, and the 4-methylene pyrrolidine-containing peptide deformylase inhibitor has the following structure.
  • R 2 is H or an alkyl group
  • R 3 is an alkyl group or an aromatic group or a heterocyclic ring.
  • the molecular weight of the 4-methylene pyrrolidine-containing peptide deformylase inhibitor of the present invention is from 300 to 500; soluble in dichloromethane, methanol, ethanol, hydrazine, hydrazine-dimethylformamide, two Methyl sulfoxide; slightly soluble in toluene, benzene, ether at room temperature, slightly soluble in water, insoluble in petroleum ether.
  • the 4-methylenepyrrolidine-containing peptide deformylase inhibitor of the present invention is determined by a DRX500 nuclear magnetic resonance spectrometer.
  • the HH sample is prepared by using deuterated chloroform as a solvent, and the repetition period is 2 seconds, and the number of scans is 32 times.
  • the structure of the product was shown to be a peptide deformylase inhibitor containing a formylhydroxylamine derivative of 4-methylene pyrrolidine.
  • the peptide deformylase (PDF) of the peptide deformylase inhibitor of the 4-methylene pyrrolidine-containing formyl hydroxylamine derivative of the present invention is a formyl metalloproteinase capable of inhibiting bacteria The process of synthesizing proteins. Therefore, it not only provides a new possibility of antibiotic treatment, but also does not affect the metabolism of eukaryotes. At the same time, studies have shown that bacteria have little chance of developing resistance to PDF inhibitors. 2.
  • the in vitro antibacterial activity of the peptide-formylase inhibitor of the 4-methylenepyrrolidine-containing formyl hydroxylamine derivative of the present invention shows that against Staphylococcus aureus, Staphylococcus epidermidis, a resistant strain such as methicillin-resistant gold
  • the minimum inhibitory concentration (MIC) of Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae was 0.0625 ⁇ 8 ⁇ ⁇ / ⁇ 1, showing good antibacterial properties against Gram-positive, negative and resistant bacteria, see Table 1.
  • Awre ⁇ is Staphylococcus aureus
  • MSSA is methicillin-sensitive Staphylococcus aureus
  • MRSA is methicillin-resistant Staphylococcus aureus
  • ⁇ ⁇ r ⁇ Hifo is Staphylococcus epidermidis
  • penicillin and linezolid are commercially available bulk drugs, purity >99%. Linezolid for control was approved for marketing in 2000, and was developed by Pfizer. detailed description
  • Example 3 Example 4:
  • Example 5 Example 6:
  • Step e PMBCl (p-methoxybenzyl chloride), Et 3 N, DMF ( ⁇ , ⁇ -dimethylformamide); Step f) N 2 H 4 .H 2 0, DMF/CH 3 OH; Step g ) 50 ° C, 24 h;
  • Step h) LiOH, H 2 O 2 , THF/H 2 0; Step i) HCOOH, Ac 2 0, THF;
  • Step m HOBT (1-hydroxybenzotriazole), EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), ⁇ ( ⁇ -methylmorpholine) , CH 2 Cl 2 , 18h; Step n) LiOH, dioxane/H 2 0; Step o) ClCOOCH 2 CH 3 , Et 3 N, THF; Step p) CO(NH 2 ) 2 'H 2 0 2 (urea hydrogen peroxide), phthalic anhydride;
  • a lOOmL single-necked flask equipped with a condensing tube is protected by nitrogen. (7.8 g, 27.1 mmol) of the product (5) obtained in the step d and (10 g, 64.6 mmol) of the product (8) of the step f, warmed to 50 °, and reacted for 24 hr.
  • step g (9) In a 100 mL single-necked flask, (4.3 g, 9.8 mmoi; > product of step g (9) was dissolved in 26 mL of tetrahydrofuran and 6 mL of water, cooled to 0 °, slowly added (6.9 mL, 22.6 mmol 0% hydrogen peroxide and 9.5 mL1) .2mol/l lithium hydroxide solution, stirring for 1 hr under ice bath. Add 35 mL of 1 mol/1 sodium sulfite solution to the system and raise to room temperature for 30 min. The organic solvent was spun dry, and the aqueous phase was extracted 6 times with 10 mL of ethyl acetate.
  • Step i Synthesis of (2R)-2-(((4-methoxybenzyloxy)formylamino)methyl)hexanoic acid (11): A 500 mL single-necked flask was charged with 250 mL of anhydrous tetrahydrofuran under nitrogen atmosphere, and then C10.4 mL, 108 mmol) of acetic anhydride and P (25 mL, 540 mmol) of formic acid were added, and the mixture was heated to 50 °C for 2 hr, and then cooled to 0 °C.
  • a solution of the product (10) of the step h and 25 mL of tetrahydrofuran was slowly added dropwise to the above system, and the dropping rate was controlled, and the mixture was dropped in 30 minutes, and the reaction was carried out for 30 minutes.
  • the solvent was added to dryness, and 50 mL of dichloromethane and 50 mL of water was added.
  • NMM N-methylmorpholine
  • the product (18) obtained in the step o was added to a 25 ml single-necked flask, dissolved in 15 ml of ethyl acetate, and then added (0.57 g, 6 mm oi; > urea hydrogen peroxide complex (CO (NH) 2 ;) H 2 0 2 ;), adding (0.89 g, 6 mmol) of phthalic anhydride in three portions, reacting at room temperature overnight, and quenching with a solution of (1.24 g, 10 mmol) of sodium sulfite in 10 ml, partition, organic The phase was washed once more with 10 ml of a saturated aqueous solution of sodium carbonate, and then dried over anhydrous sodium sulfate, filtered, and evaporated to give the compound (2.sup.. -l-((2R)-2-(((4-methoxybenzyloxy))carboxamido;)methyl)hexanoyl)-4-m
  • step o the starting material was replaced by 2-amino-5-fluoropyridine to 2-amino-5methylthiazole.
  • Other conditions were unchanged, and the product (2S)-N-(5-methyl-2-thiazole; )-l-((2R)-2-(((4-methoxybenzyloxy)formylamino)) Methyl)hexanoyl)-4-methylenepyrrolidine-2-amide.
  • step q directly proceed to step q to obtain the final product (2S)-N-(5-methyl-2-thiazole)-WPR ⁇ -((formylhydroxylamino)methyl)hexanoyl)-4-methylenepyrrolidine- 2-amide.
  • the rest is the same as in the first embodiment.
  • step o (2S)-N-(5-fluoro-2-pyridine;)-l 2R)-2-W4-methoxybenzyloxy;)formylamino;)methyl)hexanoyl)-
  • step q is directly carried out to obtain the final product (2S)-N-(5-fluoro-2-pyridine)-1-((2R) )-2-((Formylhydroxylamino)methyl)hexanoyl)-4-methylenepyrrolidin-2-amide.
  • the rest is the same as in the first embodiment.
  • step o the starting material was replaced by 2-amino-5-fluoropyridine to aniline. Other conditions were unchanged, and the product (2S)-N-phenyl-1-((2R)-2-(((4-methoxybenzyloxy))carboxamido;)methyl)hexanoyl)- 4-methylene pyrrolidine-2-amide. Then directly proceed to step q to obtain the final product (2S)-N-phenyl-l-((2R)-2-((formylhydroxylamino)methyl)hexanoyl)-4-methylenepyrrolidine-2- Amide. The rest is the same as in the first embodiment.
  • step o the starting material was replaced by 2-amino-5-fluoropyridine to 4-fluoro-aniline. Other conditions were unchanged, and the product (2S)-N-(4-fluoro-phenyl;)-l-((2R)-2-(((4-methoxybenzyloxy))carboxamido;) Methyl)hexanoyl)-4-methylenepyrrolidine-2-amide. Then directly proceed to step q to obtain the final product (2S)-N-(4-fluoro-phenyl;)-1-((2R)-2-((formylhydroxylamino))methyl)hexanoyl)-4- Methylene pyrrolidine-2-amide. The rest is the same as in the first embodiment.
  • step o the starting material was replaced by 2-amino-5-fluoropyridine to morpholine. Other conditions were unchanged, and the product (2S)-morpholine-1-((2R)-2-(((4-methoxybenzyloxy))carboxamido;)methyl)hexanoyl)-4- Methylene pyrrolidine-2-amide. Then, step q is directly carried out to obtain the final product (2S)-morpholine-1-((2R)-2-((formylhydroxylamino)methyl)hexanoyl)-4-methylenepyrrolidin-2-amide. The rest is the same as in the first embodiment.

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

Abstract

L'invention concerne des inhibiteurs de peptide déformylase contenant de la 4-méthylène pyrrolidine ayant la structure suivante, dans laquelle R1=alkyle, R2=H ou alkyle, R3=alkyle, aryle ou hétérocycle. Les inhibiteurs de peptide déformylase de la présente invention peuvent inhiber la synthèse des protéines bactériennes, présentent un faible risque de résistance aux médicaments, et peuvent tuer les souches résistantes aux antibiotiques présentes comme MRSA et PRSP.
PCT/CN2011/071367 2010-07-02 2011-02-28 Inhibiteurs de peptide déformylase contenant de la 4-méthylène pyrrolidine WO2012000322A1 (fr)

Applications Claiming Priority (2)

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CN201010217418XA CN101869563B (zh) 2010-07-02 2010-07-02 含4-亚甲基吡咯烷的肽脱甲酰基酶抑制剂
CN201010217418.X 2010-07-02

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Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101869563B (zh) * 2010-07-02 2011-11-16 华东师范大学 含4-亚甲基吡咯烷的肽脱甲酰基酶抑制剂
CN103159660B (zh) * 2011-12-08 2016-07-06 天津市国际生物医药联合研究院 (2r)-1-(2-甲基-3-(甲氧基(甲基)氨基)-丙酰基)吡咯烷-2-羧酸及其应用
CN107362162B (zh) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 螺三元环、螺五元环类肽脱甲酰基酶抑制剂的抗肿瘤应用
WO2017193924A1 (fr) 2016-05-11 2017-11-16 如东瑞恩医药科技有限公司 Noyau spiro à trois chaînons, inhibiteur de peptide déformylase à noyau spiro à cinq chaînons et son utilisation dans des agents anti-bactériens et anti-tumoraux
CN107365303B (zh) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 螺三元环、螺五元环类肽脱甲酰基酶抑制剂的抗菌应用
CN107365302B (zh) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 螺三元环、螺五元环类肽脱甲酰基酶抑制剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101395148A (zh) * 2006-03-03 2009-03-25 诺瓦提斯公司 N-甲酰基羟胺化合物
CN101869563A (zh) * 2010-07-02 2010-10-27 华东师范大学 含4-亚甲基吡咯烷的肽脱甲酰基酶抑制剂

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CN101584694B (zh) * 2009-06-15 2011-01-12 华东师范大学 含2,5-二氢吡咯的肽脱甲酰基酶抑制剂及合成方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101395148A (zh) * 2006-03-03 2009-03-25 诺瓦提斯公司 N-甲酰基羟胺化合物
CN101869563A (zh) * 2010-07-02 2010-10-27 华东师范大学 含4-亚甲基吡咯烷的肽脱甲酰基酶抑制剂

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