Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings

A technology of peptide deformylase and inhibitor, which can be applied in the field of spiro five-membered ring peptide deformylase inhibitor and new spiro three-membered ring, which can solve the problems of toxicity, clinical manifestation and inactivity.

Active Publication Date: 2017-11-21
广东和博制药有限公司
View PDF4 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although many PDF inhibitors have been developed for preclinical research, and even some compounds have entered the clinic (such as formula (b) ~ (d)), but due to the nature of the compound itself, the activity is not good, or it shows Clinical toxicity, ultimately failed to market
For example: actinomycin Actinonin is the first PDF inhibitor discovered, which shows good activity against Gram-positive bacteria and negative bacteria, but due to the instability of metabolism in the body, it eventually has no activity in vivo
LBM415, which has entered the Phase I clinical trial of antibacterial activity, has broad-spectrum activity, but it was found that high doses can cause methemoglobinemia (Clin.Pharmacol.Ther.2011, 90, 256); GSK1322322, also terminated by the FDA antibacterial activity Phase I clinical study of the same reason, the occurrence of metabolically active compounds, causing toxicity to the body (see the project number NCT01818011 in ClinicalTrials.gov for reasons for termination of clinical trials)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings
  • Peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings
  • Peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] (S)-5-((R)-2-((N-hydroxycarboxamido)methyl)caproylamido)-N-(1H-pyrazol-3-yl)-5-azaspiro[2.4 ]Synthesis of heptane-6-amide

[0123]

[0124] Step 1: Add 3-aminopyrazole (1.50g, 18.0mmol), trimethylamine (4.5g, 20.6mmol), 4-(dimethylamino)pyridine (0.15g, 1.2mmol) in 60mL dioxane, Add Boc after stirring to dissolve 2 O, heated to reflux for 8h, after the reaction was completed, the solvent was spinned out, then diluted with EA and extracted, washed successively with 10% citric acid and saturated brine, and the organic phase was concentrated to obtain an oil, which was passed through the column (PE / DCM=2 / 1) The product was obtained as a white solid (1.6 g, yield 48%).

[0125]Step 2: the operation is as in step 1 in the synthetic general formula (X1). After adding 20mL of DMF to the acid (2.05g, 8.5mmol) to dissolve, add N-methylimidazole (1.54g, 18.7mmol) under ice cooling, then slowly add MsCl (1.07g, 9.4mmol), stir for 15min and then add Boc Protected amine (1.5...

Embodiment 2

[0136] 5-Fluoro-2-((S)-5-((R)-2-((N-hydroxycarboxamido)methyl)hexylcarbonyl)-5-azaspiro[2.4]heptane-6-amide base) synthesis of pyridine N-oxygen compounds

[0137]

[0138] Step 1: The operation is as in Step 1 in the synthesis of general formula (X1).

[0139] Step 2: The operation is as in step 2 in the synthesis of general formula (X1) (2.1 g, white solid, two-step yield 68%).

[0140] Step 3: The operation is as in step 3 in the synthesis of general formula (X2).

[0141] Step 4: The obtained oil (242mg, 0.46mmol) was dissolved in ethyl acetate (3mL), hydrogen peroxide urea complex (133mg, 1.40mmol) and phthalic anhydride (207mg, 1.40mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium thiosulfate and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product.

[0142] Step 5: The operation is as in step 4 in the synthesis of gen...

Embodiment 3

[0148] (S)-N-(5-(tert-butyl)isoxazol-3-yl)-5-((R)-2-((N-hydroxycarboxamido)methyl)hexylcarbonyl)-5- Synthesis of Azaspiro[2.4]heptane-6-amide

[0149]

[0150] Step 1: The operation is as in Step 1 in the synthesis of general formula (X1).

[0151] Step 2: The operation is as in step 2 in the synthesis of general formula (X1) (1.4 g, white solid, two-step yield 47%).

[0152] 1 H NMR (400MHz,D 2 O)δ6.14(s,1H),4.44-4.41(m,1H),3.12-2.93(m,2H),2.19(dd,J=13.4,8.9Hz,1H),1.86(dd,J=13.4 ,6.1Hz,1H),0.52-0.29(m,4H).

[0153] 13 C NMR (101MHz,D 2 O) δ183.22, 167.90, 157.06, 93.24, 60.23, 52.67, 37.13, 32.51, 27.67, 20.09, 9.86, 8.49.

[0154] Step 3: The operation is as in step 3 in the synthesis of general formula (X2).

[0155] Step 4: The operation is as in step 4 in the synthesis of general formula (X2), column chromatography (DCM:MeOH=10:1) gives a white solid, and the two-step yield is 28%.

[0156] LC-MS(ESI):[M+1] + =435.24,t R =2.25min.

[0157] 1 H NMR (400MHz,...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses novel peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings, and the inhibitors have antimicrobial activity and antineoplastic activity. The peptide deformylase inhibitors containing spiro rings such as the spiro three-membered rings or the spiro five-membered rings provided in the invention can be taken as a class of novel antibacterial agents, by inhibiting activity of peptide deformylase required in synthesis of bacterial proteins, the inhibitors have effects on gram-positive bacterium strains which have drug resistance to a plurality of antibiotics, and have no influences on synthetic processes of human proteins, thus the bacteria are selectively killed; and the peptide deformylase inhibitors containing the spiro rings such as the spiro three-membered rings or the spiro five-membered rings provided in the invention can also be taken as a class of novel anti-cancer drugs, by inhibiting peptide deformylase in mitochondria of cancer cells, the inhibitors can have influences on energy balance of the cells, thus mitochondrial membranes are depolarized, ATP is depleted and apoptosis is promoted, and the inhibitors have relatively-good inhibition activity on a plurality of cancer cell bacterial strains such as colorectal cancer cell bacterial strains, lung cancer cell bacterial strains, stomach cancer cell bacterial strains and liver cancer cell bacterial strains under relatively-low concentrations.

Description

technical field [0001] The invention belongs to the technical research field of antibacterial and anticancer drugs, and relates to a class of peptide deformylase inhibitors, in particular to novel spiro three-membered ring and spiro five-membered ring-like peptide deformylase inhibitors. Background technique [0002] Antibiotics refer to a series of chemical substances that can inhibit and kill pathogens at a certain concentration, including metabolites produced by microorganisms, animals and plants, as well as chemically synthesized or semi-synthesized compounds. Antibiotics not only refer to antibacterial substances, but also antitumor, antiviral, antiparasitic and other substances also belong to the category of antibiotics. Antibiotics are an important pillar enabling us to live longer, healthier lives and benefit from modern medicine. [0003] With the emergence and widespread use of antibiotics, the problem of antibiotic resistance has become increasingly prominent, an...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D403/12C07D401/12C07D413/12C07D401/14C07D417/12C07D403/04C07D413/14C07D471/04C07D209/96C07D409/12A61P31/04A61P35/00
CPCC07D209/96C07D401/12C07D401/14C07D403/04C07D403/12C07D409/12C07D413/12C07D413/14C07D417/12C07D471/04
Inventor 胡文浩吕峰平汤洋陈晨韦建海
Owner 广东和博制药有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products