CS235168B1 - Substituted 4,9-dihydro-3-methyl-4-oxo-2H-pyrazolo (3,4-b) quinoline and process for their preparation - Google Patents

Abstract

The invention relates to substituted 4,9-dihydro-3-methyl-4-oxo-2H-pyrazolo[3,4-b]quinolines of the general formula I where R is hydrogen or methyl. These new, previously undescribed substances exhibit antiviral activity against influenza A2-Hong Kong virus and against mouse encephalomyocarditis virus.

Description

(54) Substituted 4,9-dihydro-3-methyl-4-oxo-2H-pyrazolo (3,4-b) quinolines and a process for their preparation

2

The present invention relates to substituted 4,9-dihydro-3-methyl-4-oxo-2H-pyrazolo [3,4-b] quioliolines of formula I

wherein R is hydrogen atoin or methyl.

These novel substances have not yet been reported to have antiviral activity against influenza virus

A2-Hong Kong and against encephalomyocarditis virus in mice.

The present invention relates to substituted 4,9-dihydro-3-: methyl-4-oxo-2H-ipyrazolo [3,4-b] quinoilines of formula I

wherein R is hydrogen or methyl.

These novel substances, which have not been described yet, exhibit anti-inflammatory activity against the A2-Hong Kong influenza virus and the encephalomyocarditis virus (EMC) in mice.

The compound of formula (I) wherein R is hydrogen may be prepared according to the invention by cyclization of 3-unilino-1,5-dimethylpyrazole-4-carboxylic acid (cf. No. 235 166) with polyphosphoric acid at 80 ° C to 150 ° ^C. C, preferably at ¹ 90 <€.

The compound of formula (I) wherein R is methyl may be prepared according to the invention by alkylation of 4,9-dihydro-3,9-dimethyl-4-oxo-1H-pyrazolo [3,4-bquinoline (cf. No. 235,183) in dimethylformamide with methyl iodide at 0 ° C to 30 ° C, preferably at 20 ° C.

A compound of formula I wherein R is methyl may also be prepared by alkylating the sodium salt of a compound of formula I wherein R is hydrogen in dimethylformamide with methyl iodide at a temperature of from 0 ° C to 30 ° C, preferably at 20 ^° C. .

Said compounds according to the invention belong to the group of substances with antiviral effects. For these compounds, these effects were detected and evaluated against the A2-Hong Kong influenza virus and the encephalomyocarditis virus (EMC) in mice.

Evaluation of efficacy against A2-Homgfcong influenza virus in mice

Female white SPF mice (Velaz) weighing 10-11 g were used. The virus was administered iintranasally to mice under light ether anesthesia. The amount of LD 50 of the virus was determined in a separate experiment and was calculated according to REED and MUENCH [Reed L. J., Muench H .: Amer. J. Hyg. 27, 493 (1938)]. 7 mice were used for each virus concentration. Untreated mice died of pneumonia according to the virus concentration used 3 to 10 days after infection. Test substances were suspended with oleic acid monoester with tripolyethylene glycol anhydride sorbitol (Tween 80). Animals were administered per os by gavage, or were administered subcutaneously into the skin lash on the back in a volume of 0.2 ml each. Mice were treated orally or subcutaneously twice daily for 5 days (1 day before and 4 days after infection). The daily dose was 2 x 150 mg / kg. Efficacy was assessed by increasing the average survival time compared to the untreated control.

After oral administration, the active compound of formula I wherein R is hydrogen (increases the survival time of 5 LD 50 of the virus by 35%) and the compound of formula I where R is methyl (prolongs the survival time of 5 LD 50 of the virus by 13%, 50 LD50 virus by 16% and against 500 LD50 virus by 38%).

Evaluation against EMC virus in mice

Female white SPF mice (Velaz weighing 10 to 11 g) were used. The mice were injected subcutaneously in a volume of 0.2 ml into the fold of the back skin. Untreated mice died according to the virus concentration used 3 to 7 days after infection. doses of 100 mg / kg each 28, 22, 2 hours before and 2 hours after infection Oral treatment was performed 24 hours prior to infection with a single dose of 400 mg / kg. activity against the influenza virus A2-Hong Kong.

After oral administration, the active compound of formula (I) wherein R is hydrogen is active. The substance extends the survival time of mice against 5 LD 50 virus by 34.2% and against 50 LD 50 virus by 23%.

As can be seen from the above data, the compounds of formula I are active against influenza virus and against encephalomyocarditis virus (EMC). The preparation of these compounds is simple and was carried out according to the invention. Further details are given in the following examples. The examples illustrate the invention but do not limit it.

He did

4.9-Dihydro-2,3-dimethyl-4-oxo-2H-pyrazolo [3,4-b] quinoline

A mixture of 6.9 g of 3-anilino-1,5-dimethyl-4-pyrazolecarboxylic acid and 45 g of polyphosphoric acid having a content of 83% of oxide at a temperature of 90 ° C. After addition of 750 ml of water, the mixture was cooled to 5 ° C and the precipitate was filtered off with suction and washed with water. Recrystallization from ethanol yielded 5.55 g (86.8%), mp 324-328 ° C. Example 2

4.9-dihydro-2,3,9-trimethyl-4-oxo-2H-pyrazolo [3,4-b] quinoline,

To a stirred suspension of 1.07 g of 4,9-dihydro-2,3-dimethyl-4-oxo-2H-pyrazolo [3,4-b] quinoline (5 mmol in 25 ml of dimethyl235168 formamide) was added 0.18 g of 80 % sodium hydride (6 mmol) and the mixture was stirred at 20 ° C under nitrogen for 1 hour, then 0.85 g of methyl iodide (6 mmol) was added dropwise and the mixture was stirred for another 2 hours. The precipitate was filtered off with suction and washed with water and crystallized from ethanol to give 0.87 g (76.6%), m.p.

198.8 ° C.

SUBJECT

Substituted 4,9-dihydro-3-methyl-4-oxo-2H-pyrazolo [3,4-b] quinolines of the general formula I

wherein R is hydrogen or methyl.

2. A process for the preparation of a compound according to claim 1 of formula I, wherein R is hydrogen, as in Example 3

4,9-Dihydro-2,3,9-trimethyl-4-oxo-2H-pyrazolo [3,4-bquinoline]

Example 2 was prepared from 1.07 g of 4,9-dihydro-3,9-dimethyl-4-oxo-1H-pyrazolo [3,4-b] quinoline in

Claims (3)

yield 80.1%. The process of claim 3, wherein the 3-, anilino-1,5-dimethyl-4-pyrazolecarboxylic acid is heated with polyisulfuric acid at a temperature of 80 ° C to 150 ^° C, preferably at 90 ° C. 3. A process for the preparation of a compound according to claim 1, wherein R is methyl, by alkylating 4,9-dihydro-2,3-dimethyl-4-oxo-2H-pyrazolo [3,4-b] sodium salt. of quinoline with methyl iodide in dimethylformamide at a temperature of 0 ° C to 30 ° C, preferably at 20 ° C. 4. A process for the preparation of a compound according to claim 1, wherein R is methyl, wherein the sodium salt is 4,9-dihydro-3,9-dimethyl-4-oxo-1H-pyrazolo [3,4-b]. The quinoline is alkylated with methyl iodide in dimethylphonamide at a temperature of 0 ° C to 30 ° C, preferably at 20 ° C.