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Pteridines useful as HCV inhibitors and methods for the preparation thereof

a technology of pteridine and hcv, which is applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems of persistent infection, high rate of chronic infection, and existing infections that continue to present serious medical and economic burden, and achieve the effect of reducing the viral load of patients

Inactive Publication Date: 2009-06-18
JANSSEN R&D IRELAND UC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]Thus, there is a high medical need for low molecular weight compounds that lead to an inhibition of HCV replication.
[0019]In addition, the compounds of the invention are valuable in that they may diminish the HCV viral load of a patient to undetected levels.

Problems solved by technology

HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection.
In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection.
However, given the slow progression to the end-stage liver disease, the existing infections will continue to present a serious medical and economic burden for decades (Kim, W.R. Hepatology, 36, 5 Suppl.
The treatment of this chronic disease is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects.
Beside the limited efficacy on HCV type 1, combination therapy has significant side effects and is poorly tolerated in many patients.
For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients.
Major side effects of combination therapy include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms.
If and when the disease progresses, the inflammation and liver cell death may lead to fibrosis.
Chronic infection by HCV is associated with an increased risk of liver cancer.
Fibrosis is both a sign of liver damage and a potential contributor to liver failure via progressive cirrhosis of the liver.

Method used

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  • Pteridines useful as HCV inhibitors and methods for the preparation thereof
  • Pteridines useful as HCV inhibitors and methods for the preparation thereof
  • Pteridines useful as HCV inhibitors and methods for the preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(4-pyridylamino)pteridine, Compound No. 1

[0163]

3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxylic Acid Methyl Ester 102

[0164]Pyridine (7.75 g, 98.0 mmol) was added at 0° C. under N2 to a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester 101 (1.5 g, 9.80 mmol) and 5-bromo-2-fluorobenzoylchloride (9.45 g, 49.0 mmol) in CH2Cl2. The reaction mixture was warmed at 40° C. for 4 h, then cooled down at room temperature. The reaction mixture was quenched with 20 mL of ethanol, evaporated, partitioned between CH2Cl2 and 1N NaHCO3, dried (Na2SO4) and evaporated. The crude material was triturated in EtOH, filtered, washed with EtOH and ether to give 2.6 g of 3-(5-bromo-2-fluorobenzoyl-amino)pyrazine-2-carboxylic acid methyl ester 102 as a white powder (LCMS analysis).

3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxamide 103

[0165]A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxylic acid methyl ester 102 (2.6 g, 7.34 mmol) and ...

example 2

Synthesis of 4-[[2-(5-Bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic Acid, Compound No. 16, and 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]nicotinamide, Compound No. 21

[0168]

2-(5-Bromo-2-fluorophenyl)-4-Chloropteridine 106

[0169]Thionyl chloride (371 mg, 3.11 mmol) was added to the stirred suspension of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 (200 mg, 0.623 mmol) in chloroform (5 mL) and dry DMF (100 μL). The reaction mixture was refluxed under nitrogen for 1 h (starting material gone by HPLC). The solvent was removed in vacuo. Then the residue was triturated in Et2O and filtered off to give 210 mg of the title product 106 as a yellow solid (LCMS analysis).

4-[[2-(5-Bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic Acid Methyl Ester 107

[0170]To a solution of 2-(5-bromo-2-fluorophenyl)-4-chloropteridine 106 (200 mg, 0.589 mmol), 4-aminonicotinic acid methyl ester (224 mg, 1.47 mmol) in dichloroethane (5 mL), was added dropwise triethy...

example 3

Synthesis of 2-(5-Bromo-2-pyrrolidin-1-ylphenyl)-4-(3-methyl-4-pyridylamino)pteridine, Compound No. 6

[0173]

2-(5-Bromo-2-pyrrolidin-1-ylphenyl)pteridin-4-one 110

[0174]A solution of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 in pyrrolidine was heated in a microwave cavity (Power=270 W, Temp=110° C.) for 12 min. The pyrrolidine was evaporated, then residue partitioned between NaHCO3 0.5 N and CH2Cl2, dried (Na2SO4) and evaporated. Trituration in Et2O afforded the title product 110 as a yellow powder (LCMS analysis).

2-(5-Bromo-2-pyrrolidin-1-ylphenyl)-4-(3-methyl-4-pyridylamino)pteridine 6

[0175]The title product was synthesized by reaction of the 2-(5-bromo-2-pyrrolidin-1-yl-phenyl)pteridin-4-one 110 and 4-amino-3-methylpyridine following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).

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Abstract

The present invention relates to the use of pteridines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to compounds per se and their use as medicines. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.

Description

[0001]The present invention relates to the use of pteridines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to compounds per se and their use as medicines. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.[0002]Following its discovery in 1989 as the agent implicated in the majority of viral non-A, non-B hepatitis (Choo et al., Science 244, 359-362, 1989), hepatitis C virus (HCV) has become a focus of considerable medical research (Lauer, G. M and Walker, B. D., New Eng. J. Med. 345, 41-52, 2001). HCV is a member of the Flaviviridae family of viruses in the hepacivirus genus, and is closely related to the flavivirus genus, which includes a number of viruses implicated in human disease, such as dengue virus and yellow fever ...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61K31/4985C07D475/00C07D413/14A61P31/12
CPCA61K31/519C07D487/04C07D475/10A61K31/5377A61P1/16A61P31/12A61P31/14A61P43/00Y02A50/30A61K2300/00A61K45/06
Inventor RABOISSON, PIERRE JEAN-MARIE BERNARDSURLERAUX, DOMINIQUE LOUIS NESTOR GHISLAINLIN, TSE-ILENZ, OLIVERSIMMEN, KENNETH ALAN
Owner JANSSEN R&D IRELAND UC
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