Derivatives of indolinone-3 with antihypertensive activity and method of production thereof

 

(57) Abstract:

Usage: as substances having antihypertensive activity. The inventive product is a derivative of indolinone - 3 total f - crystals 1 specified in the text of the description, where R=R1=CH3; R+R1=(CH2)5. Yield 71% , so pl. 220C (decomp. of DMF and 75% , so pl. C (decomp. from DMF), respectively. Reagent 1: 2-dialkylaminomethyl-3 total f - crystals II specified in the text of the description, where R and R1- have the specified values. Reagent 2: malononitrile. Reaction conditions: inert solvent boiling. 1 C. p. F. - ly, 1 table.

The invention relates to new derivatives of 2-(21-cyano-31-dialkylamino-21- enylidene)indolinone-3 of the General formula I

(I) where R= R1= CH3(Ia),

R + R1= (CH2)5(IB) with antihypertensive activity.

The closest structural and pharmacological analogue of the compounds I is the drug delcarmen (1,2-dimethyl-3-etoxycarbonyl-5-oxyindole) formula

(II) are known in medical practice as an antihypertensive drug (I). Delcarmen low toxicity (LD50>mg/kg)/ however, the reduction Arte is - search in the number of derivatives of indolinone-3 substances/ with increased antihypertensive activity/ and the way they are received.

This goal is achieved derivatives indolinone-3 of the General formula I which are produced by interaction of 2-dialkylaminomethyl-indolinones-3 of the General formula II where R and R1have the specified values/ malononitrile in an inert solvent (preferably benzene)/ boiling.

The diagram of a method, However, in the literature there are no practical methods for direct nucleophilic connection amines to NITRILES with education amidino. The method according to the invention, is new and allows you to get first connection of a number of indolinone-3, which contain the grouping, where one carbon atom has two amine functions, and show antihypertensive activity.

The invention is illustrated by the following examples.

Abbreviations: DMF - dimethylformamide. DMSO - dimethyl sulfoxide. SD3OD - deuterated methanol.

P R I m e R 1. Obtaining 2-(21-cyano-31-amino-31- dimethylaminopropan-21-enylidene)- indolinone-3 (Ia).

The mixture 3,76 g (20 mmol) 2-dimethylaminoethylmethacrylate, washed with methanol and ether.

Obtain 3.6 g (71% ) of 2-(21-cyano-31-amino-31- dimethylaminopropan-21-enylidene) indolinone-3, so pl. 220aboutC (decomp. from DMF).

IR spectrum , cm-1: 3440, 3360-3300, 3200-3100, 2180, 1670, 1640.

Found, % : C 66,38; N VS. 5.47; N 22,18; M+254.

WITH14H14N4ABOUT

Calculated, % : C 66,13; N. Of 5.55; N 22,03; M 254.

P R I m m e R 2. Obtaining 2-(21-cyano-31-amino-31-piperidinedione -21-enylidene) indolinone-3 (IB).

The mixture 4,56 g (20 mmol) 2-piperidinemethanol-3, 200 ml of benzene and 1.60 g (24 mmol) of malononitrile is boiled under stirring for 1.5 hours Cooled, the precipitate filtered off, washed with methanol and ether.

Obtain 4.4 g (75% ) of 2-(21-cyano-31-amino-31- piperidino-21- enylidene)indolinone-3, so pl. 225aboutC (decomp. , DMF).

IR spectrum , cm-1: 3460, 3300, 2180, 1695, 1645.

Found, % : C 69,25; N 6,18; N OF 19.03; M+294.

WITH17H18N4ABOUT

Calculated, % : C 69,37; N 6,16; N 19,04; M 294.

Biological tests.

Antihypertensive activity of the compounds was studied in spontaneously hypertensive rats of both sexes lines Okamoto Aoki in the introduction the main (SG) rats weighing 250-280 g blood pressure (BP) was detected by the direct method in the common carotid artery pressure sensor Trantec (USA) recording on the recorder Gemini 7070 firm Ugo Basile, Italy). Compounds Ia and IB were injected through a catheter in the jugular vein in doses of 0.1, 1.0, 2.0 and 5.0 mg/kg

As a result of experiments shows that the compound Ia in a dose of 0.1 mg/kg has no effect on blood pressure; increasing the dose to 1.0 mg/kg was observed the reduction of blood pressure by 15 mm RT. Art. , duration 10 minutes At doses of 2.0 and 5.0 mg/kg reduced the HELL was 20 and 30 mm RT. Art. , respectively, the duration of antihypertensive action - 40-45 min, after which the AD was returned to the original level.

Compound IB in these experiments was more active. The reduction of blood pressure was observed at a dose of 0.1 mg/kg and was 15 mm RT. Art. , the duration of effect is 10 minutes When the dose is increased BP was decreased dose-dependent: at 1.0 mg/kg reduced the HELL was 20 mm RT. century , with doses of 2.0 and 5.0 mg/kg there was a decrease HELL, 25 and 35 mm RT. Art. , respectively. Duration of antihypertensive action is also increased. The reduction of blood pressure in a dose of 1.0 mg/kg was continued for 30 min, the dose of 2.0 mg/kg 40 min and at a dose of 5.0 mg/kg 45 min of observation.

On generalizirovanny SG rats studied the effect of compounds Ia and IB to HELL with the inside. The BP measurement carried out a bloodless method of registration in the tail artery of the LM is/kg. Recorded the initial level of HELL (before the introduction of compounds) and after 1, 2, 3 and 4 h after injection.

As the comparison drug in these experiments was used delcarmen (at a dose of 50 mg/kg).

The results of the experiments presented in the table.

As follows from the data presented in the table, compound I is called a dose-dependent decrease pressure in SG-rats with the inside and on the activity and duration of antihypertensive action of 2-3 times higher than the comparator drug-delcarmen.

Acute toxicity of the compounds Ia and IB were determined in mice-males weighing 18-20 g with the inside. Found that LD50these compounds exceeds 1000 mg/kg, which can be attributed to their low toxic substances. (56) 1. Mashkovsky M. D. Medicines. M. : Medicine, 1986, T. 1, S. 447.

1. Derivatives of indolinone-3 of the General formula I

< / BR>
where R = R1= CH3(1A)

R + R1= (CH2)5(1B),

having antihypertensive activity.

2. The method of obtaining derivatives of indolinone-3 of the General formula I on p. 1, characterized in that 2-dialkylaminomethyl-3 of the General formula II

< / BR>
where R and R1have to benzene, when boiling.

 

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5 cl, 1 tbl, 1 ex

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44 cl, 1 tbl, 44 ex

FIELD: chemistry.

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17 cl, 1 tbl, 6 ex

FIELD: chemistry.

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8 cl, 11 ex

FIELD: chemistry.

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EFFECT: obtaining of compounds with antiviral activity.

26 cl, 1 tbl, 18 ex

FIELD: chemistry.

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EFFECT: obtaining novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids which have antiviral activity, especially against the influenza virus and hepatitis C virus (HCV).

19 cl, 3 tbl, 20 ex

FIELD: medicine, pharmaceutics.

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8 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of at least one compound of formula (I): (I), which is capable of being in form of salts of physiologically acceptable acids such as hydrochlorides, where: the values of R, R1, R2, R3, R4, R5, R6, R7 and B are given in claim 1, for producing a medicinal agent possessing either antibacterial activity or efflux pump inhibiting activity. Methods of producing certain compounds are described.

EFFECT: high activity of derivatives.

24 cl

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