Novel Oxopyrido[1,2-a]pyrimidine Compounds for Treating Bacterial Infection

Important Compound Classes

Title

Oxopyrido[1,2-a]pyrimidine Compounds for the Treatment and Prophylaxis of Bacterial Infection

Patent Publication Number

WO 2020/127624 A1

Publication Date

June 25, 2020

Priority Application

CN PCT/CN2018/122365

Priority Date

December 20, 2018

Inventors

Dey, F.; Ding, X.; Hu, Y.; Liu, Y.; Shen, H.; Shi, H.; Tan, X.; Zhou, C.; Zhou, M.

Assignee Company

F. Hoffmann-La Roche AG, Switzerland and Hoffmann-La Roche Inc., USA

Disease Area

Bacterial infection

Biological Target

DNA gyrase and topoisomerase IV

Summary

Bacterial infections pose a continuing medical problem because antibacterial drugs eventually engender resistance in the bacteria on which they are used. Bacterial resistance against virtually all current antibiotic drugs is increasing. Many forms of antibiotic resistance can even cross international boundaries and spread with remarkable speed.

One target for the development of antibacterial drugs has been DNA gyrase and topoisomerase IV (bacterial type IIA topoisomerases), which are essential to cell life, that solve DNA topological problems resulting from the replication, transcription, and recombination of DNA. DNA gyrase controls DNA supercoiling and relieves topological stress that occurs when the DNA strands are untwisted such as during replication. Topoisomerase IV primarily resolves linked chromosome dimers at the conclusion of DNA replication. Both enzymes can introduce double stranded DNA breaks, pass a second DNA strand through the break and rejoining the broken strands. The activity of both enzymes is driven by the binding and hydrolysis of ATP.

Inhibition of DNA gyrase and topoisomerase IV has potential for the development of broad-spectrum antibiotics. The enzymes are highly conserved across a broad range of Gram-positive and Gram-negative pathogens. Recently, strong inhibition of DNA gyrase and topoisomerase IV has been recognized to be important for low resistance development in bacterial strains treated by inhibitors of the enzymes.

The present application describes a series of novel oxopyrido[1,2-a]pyrimidine compounds as inhibitors of DNA gyrase and topoisomerase IV and that are useful for treatment and/or prophylaxis of bacterial infection. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = H, (C_1–6alkyl)₂aminoC_1–6alkyl, C_1–6alkoxy, C_1–6alkoxyC_1–6alkyl(C_1–6alkyl)aminoC_1–6alkyl, C_1–6alkyl, C_1–6alkyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolylC_1–6alkyl, morpholinyl, morpholinylC_1–6alkyl or pyrrolidinylC_1–6alkyl;

R₂ = ((C_1–6alkyl)₂amino)C_1–6alkylhalopyrrolidinyl, ((C_1–6alkyl)₂amino)C_1–6alkylpyrrolidinyl, (C_1–6alkyl)₂amino, (C_1–6alkyl)₂aminopyrrolidinyl, C_1–6alkoxyC_1–6alkyl(C_1–6alkyl)amino, C_1–6alkoxyC_1–6alkyl(C_1–6alkyl)aminoC_1–6alkylpyrrolidinyl, C_1–6alkyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl, C_3–7cycloalkyl, C_3–7cycloalkyl(C_1–6alkyl)aminoC_1–6alkylpyrrolidinyl, cyano, haloC_1–6alkyl(C_1–6alkyl)₂amino, haloC_1–6alkyl(C_1–6alkyl)₂aminoC_1–6alkylpyrrolidinyl, haloC_1–6alkylpyrazolyl, halopyrrolidinyl, hexahydropyrazino[2,1-c]oxazin-8(1H)-yl, morpholinyl, phenylpyrrolidinyl or pyrrolidinyl;

R₃ = H, or halogen;

R₄ = H, or halogen;

R₅ = H or halogen;

R₆ = C_1–6alkyl; and

R₇ = carboxy.

Key Structures

Biological Assay

The bacterial growth inhibition assay was performed. The compounds described in this application were tested in vitro for antibacterial activity against Escherichia coli (BW25113) and Klebsiella pneumoniae (ATCC10031). The data of IC₅₀ (μM) over E. coli (BW25113) and K. pneumoniae (ATCC10031) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for bacterial growth inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 18

Compound claims: 11

Pharmaceutical composition claims: 1

Use of compound claims: 4

Method for preparing compound claims: 1

Method of treatment claims: 1

Recent Review Articles

• 1.Baglini E.; Salerno S.; Barresi E.; Robello M.; Da Settimo F.; Taliani S.; Marini A. M.. Eur. J. Pharm. Sci. 2021, 156, 105594.
• 2.Jaswal S.; Nehra B.; Kumar S.; Monga V.. Bioorg. Chem. 2020, 104, 104266.
• 3.Dighe S. N.; Collet T. A.. Eur. J. Med. Chem. 2020, 199, 112326.
• 4.Kolaric A.; Anderluh M.; Minovski N.. J. Med. Chem. 2020, 63, 5664.

The author declares no competing financial interest.