SU1452481A3 - Method of producing heterocyclic compounds - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is acyl; R<2> is alkyl; A is alkykl which may be replaced with OH; Y is O, S, CONH or NHCO; Het is 5-6-membered hetero ring which contains 1-3 hetero atoms consisting of O, S and N and may be condensed with benzene ring; R<3>-R<5> are H, alkyl, OH, SH, alkoxy, amino, carboxy, etc.,) or its salt. EXAMPLE:2-Hydroxy-4-[2-hydroxy-3-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio] pro poxy]-3-propylacetophenone. USE:An SRS-A antagonist useful for preventing and remedying allergic diseases, ischemic cardiac diseases resulting from SRS-A, brain diseases, inflammations, etc. PREPARATION:For example, a halogen compound shown by formula II (X is halogen) is reacted with a compound shown by formula III (M is H or alkali metal; Y<2> is O or S) to give a compound shown by formula I when Y=Y<2>.

Description

cm

one

This invention relates to a process for the preparation of new biologically active chemical compounds, namely new heterocyclic compounds of thiadiazole derivatives of the formula I

c,

 S - @ -and. . 2S-A2-R3

where R, is a lower acyl group; RJ is a lower alkyl group; BUT; - a lower alkylene group, free or substituted by hydroxy;

Het - thiadiazole; Ai is a lower alkylene group; Rj - carboxy group

antagonists with respect to the action of the slow-reacting anaphylactic compound SRS-A, which is a mixture of leukotrienes - the lipoxygenase products of polyunsaturated fatty acids) and participates as a chemical mediator during rapid hypersensitivity reactions in the body, as well as in: change in production mucus, contraction of the heart, etc. This property suggests the possibility of using compounds of formula I in medicine for the prophylactic and treatment of various allergic diseases (for example, bronchial asthma, allergic rhinitis, etc.) and ischemic heart and brain diseases caused by SRS-A.

The aim of the invention is to obtain new heterocyclic compounds, derivatives of thiadiazole, which have a longer effect when administered orally as an antagonist of an anaphylactic compound.

The following examples illustrate the invention.

In addition, examples of the preparation of the starting compounds used in the examples are provided below in the reference examples.

Reference example 1. To a mixture of 600 mg of 2,5-dimercapto-1,3,4-thiadiazole, 560 mg of anhydrous potassium carbonate and 10 ml of N, N-dimethylformamide was added 250 mg of 4- (2,3-epoxy) proxy-2- -oxy-3-propyl acetophenone and the resulting mixture is stirred overnight at room temperature

0

j

0

5 о з

d 5

g

re. Diluted hydrochloric acid was added to the resulting reaction mixture and the product was extracted with toluene. The extract obtained is washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (4: 1) to give 260 mg of 2-oxy-4- (2-hydroxy-3 -) (5-mercapto-.1D4-thiadiazol-2-yl (thio) prbepoxy) -3-propyl acetophenone as an oil.

NMR spectrum (CDCl1, TMS as an internal standard, ppm: 0.92 (triplet, ZN); 1.2-1.8 (multiplet, 2H); 2.56 (singlet, ZN); 2.63 ( triplet, 2H); 3.48 (double doublet, 2H); 4.0-4.2 (multiplet, 2H); 4.2-4.6 (multiplet, 1H); 6.42 (double doublet, 1H) ; 7.61 (doublet, IH); 12.7 (singlet, 1H).

Reference Example 2. According to the procedure described in Reference Example 1, the indicated compound is obtained.

TS-N

ll

HS S SH

Target compound: 2-hydroxy-4 - // 3 - / - 5mercapto-1,3,4-thiad, azol-2-yl / thio / propoxy / -3-propyl acetophenone. M.p. 127-129 ° C.

Calculated,%: C 49.97; H 5.24; N 7.28; S 25.02.

C Found,%: C 50.00; H 5.33;

N 7.19; S 24.82,

Example 1. A mixture of 100 mg of 2-ox-4 - // - / 5 mercapto, 3,4-thiadiazol-2-yl / thio / propoxy / -3-propyl acetophenone obtained in Reference Example 2, 40 mg of bromoacetic acid, 3 mg of potassium carbonate and 30 ml of N, N-dimethylformamide is stirred for 3 hours at room temperature. After adding 150 ml of water to the resulting reaction mixture, the product is extracted with ethyl acetate. The separated water layer was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulphate, the solvent is distilled off under reduced pressure to obtain a solid compound. The solid compound is recrystallized from ethanol and semi-N

N

70 mg // 5 - // - i- / iii-aueTHJi-J-hydroxy -2-propylphenoxy / 11rog1yl / thio / -1, 3,4-thiadiazol-2-yl / thio / acetic acid, m.p. . .

Calculated,%; C 48.85; And 5.01; 6.33; S 21.74,

CfgH, z ..

Found,%: C 48.78; H 5.13; 6.29; S 21.49.

PRI mme R 2. Analogously to example 1, using as starting compounds 2-hydroxy-4- / 2-hydroxy-3 - // 5-mercapto-1,3,4-thiadiaool-2-yl thio / propoxy / -3-propyl acetophenone, obtained in Reference Example 1, and bromoacetic acid, // 5 - // 3- / 4-acetyl-3-hydroxy-2-propylphenoxy / -2-hydroxypropyl / thio / -, 3 , 4-thiadiazol-2-yl / thio- / acetic acid. M.p. 72-75 ° C.

NMR spectrum (CDC1

standard h

g million:

TMS as 0.92 (triplet.

25

ZN); 1.3-1.8 (multiplet, 2H); 2.54 (singlet, SN); 2.60 (triplet, 2H); 3.60 (triplet, 2H); 4.04 (singlet, 2H); 4.0-4.2 (multiplet, 2H); 4.2 - 4.6 (multiplet, 1H); 6.42 (doublet, W); 7.60 (doublet, 1H), 12.7 (singlet, W) .30

The compounds of general formula (I) are strong antagonists in relation to the action of SRS-A and are therefore suitable for the prevention and treatment of various allergic diseases (e.g., bronchial asthma, allergic rhinitis, urticaria, etc.) caused by SRS-A, as well as ischemic heart diseases and ischemic brain diseases, inflammations, etc., caused by SRS-A.

(The proposed compounds include, in addition to compounds that have antagonistic activity against the action of SRS-A, also compounds that possess activity that plays a role in the production and excretion of SRS-A and the bronchodilatory effect along with the aforementioned activity. In addition, the the compounds are also useful as anti-ulcer agents.

Inhibition of contractions of ileum and trachea caused by SRS-A and LTDi in guinea pigs.

The technique. Male Guinea Pigs Hartley, weighing 500-700 g, are slaughtered with a heart beat. Strips of ileum and

ten

15

25

thirty

S2A8I4

The traces obtained according to the method of Sopantine (1965) were placed under a tensile load of 1.0 g per bath for isolated organs containing 10 ml of Tyrode solution, balanced against a mixture of 95% oxygen and 5% carbon dioxide at. The tissues are brought to equilibrium within 60 minutes, during this period the Tyrode solution is changed every 15 minutes and the tensile load is adjusted to 1.0 g. The force developed by the tissues is measured isometrically and using a linear transducer and Recorded on a Recti-corder instrument. The contractile response of ileum to a submaximal concentration of SRS-A. (derived from the lungs of a guinea pig) and a tracheal contractile response to a LTD: concentration of 10 M is measured in the absence and then in the presence of various concentrations of the tested compounds. Compounds are incubated for 20 minutes.

The results of tests of compounds of the formula I on the inhibition of ileum contractions are given in table 1.

For the compound of Example 1, the reduction in the guinea-pig trachea response to the administration of LTD4 HKjo (50% inhibitory concentration, reaction)

20

35

40

45

50

55

, 1.3-10 m.

Inhibition of anaphylactic asthma with SRS-A in sensitized guinea pigs.

The technique. Male Guinea pigs Hartley weighing 370–410 g are passively sensitized by intravenous administration at a dose of 1 mg / kg of rabbit contraction containing antibodies against bovine serum albumin (PHA-titer: 20480). 24 hours after sensitization, before injection of the antigen through the saphenous vein, indomethacin (2 mg / kg), mepiperamine (2 mg / kg), propropanol (0.3 mg / kg) were administered by injection 20.2 and 5 minutes, respectively, before the antigen was injected. After that, the animals are placed in a 1 L glass chamber connected to a glass spray bottle, and a 1% solution of bovine serum albumin is injected into the chamber for 30 seconds. The animals are kept under an antigen aerosol for 2 minutes and inspected 15 minutes after antigen administration. The time from the onset of inhalation to the onset of coughing and mortality are recorded. Test compounds are orally administered 30 minutes before antigen administration.

Result. The compound of Example 1, at a dose of 3 mg / kg, administered orally, tends to inhibit SRS-A, anaphylactic asthma, in sensitized guinea pigs, but this effect is not significant. When administered orally to a compound of Example I at a dose of 10 mg / kg or more, it substantially inhibits anaphylactic asthma that occurs with the participation of SRS-A.

Table 2 shows the results of the effect of the compound of Example 1 on the anaphylactic asthma of sensitized guinea pigs involving SRS-A.

The animals were previously administered mepyramine (2 mg / kg, intravenously), propanolol (0.3 mg / kg, intravenously) and indomethacin (2 mg / kg, intravenously), respectively, 5, 5, and 20 me before the introduction of the antigen. The test compound was orally administered 30 minutes prior to antigen administration.

Toxicity. The minimum flying dose determined in the case of oral administration of the proposed soybean and rat in each case is more than 1000 mg / kg.

To limit the dynamic role of SRS-A and to modulate its actions in carious pathological conditions, it is desirable to have a specific and active in vivo receptor antagonist. In addition, with clinically. It is desirable to obtain an orally active compound from the viewpoint

Connection FPL 55712

exhibits potential anti-SRS-A activity in isolated tissues and is analogous to compounds of formula I.

However, its biological semi-decomposition period is very short, and it is very poorly absorbed orally.

The new compounds of formula I are more advanced compared to the analog.

 10 15

IA524816

juice absorption ability when administered orally, as a result of which they have a prolonged effect in comparison with the analogue.

Claims (1)

Invention Formula The method of obtaining heterocyclic compounds of general formula I L G1  AG S - et) - 11 gz-AG Z e R rj BUT, lower acyl group; lower alkyl group; lower alkylene group substituted free or hydroxy; Het - thiadiazole; A2 is a lower alkylene group; Rj is a carboxy group, different from the fact that the compound of the general formula II O-ai-s where M is a hydrogen atom or an alkali metal atom; R (, R, Het and A have the indicated meanings subjected to interaction with halogen-containing compound of general formula III where Aj and R have the indicated meanings; X is chromium halogen, at their molar ry1X ratios of 1-1.2:; lj2-, in an organic solvent. Table 1 Table 2