SU1491337A3 - Method of producing heterocyclic compounds - Google Patents

Abstract

The invention relates to the preparation of heterocyclic compounds of formula @, where R _{1 is a} lower acyl

R ₂ lower alkyl

A ₁ -lower alkylene, HET-residue of thiadiazole

A ₂ lower alkylene

R _{3 is} lower alkyl

R ₄ -hydroxy group, which can be used in medicine for the treatment of various allergic diseases. The preparation of the target compounds is carried out from the corresponding carboxylic acid and amine of the formula HN (R ₃ ) (R ₄ ), where R ₃ , R ₄ have the indicated values, at a molar ratio (1.2-1) :( 1-1, 2) in an inert organic solvent. 2 tab.

Description

where R is lower acyl; R lower alkyl; A is lower alkylene; Het - os-, tiadiazol tatok; Aj is lower alkylene; RJ is lower alkyl; R / j is a hydroxy group that can be used in medicine for the treatment of various allergic diseases.

The invention relates to a method for the production of new chemical biologically active compounds, in particular - $ - Ag-juice.

R

The preparation of the target compounds is carried out from the corresponding carboxylic acid and amine of the formula HN (R,) (R), where Rj, have the indicated values, with a molar ratio of (1, 2-1): (1-1.2) in inert organic solvent. 2 tab.

§

(L

Nbsti new heterocyclic compounds of the formula

. (B f

CO OQ

BUT

O-At-S-fHeO- -Az-COl

where R is lower acyl; R, is lower alkyl; A is lower alkylene; Het-thiadiazole residue; AI is lower alkylene;

az

O- -Az-COl

(I) R is lower alkyl;

R is a hydroxy group, antagonists of the slow-reacting anaphylactic compound SRS - A, which is

 CM

314913

a mixture of leukotrienes - lipoxygenated products of polyunine-acetic acids, which takes part as a chemical mediator in fast hyper-sensitive reactions in the body, as well as in changing mucus production, reducing contractions of the heart, etc. This property suggests the possibility of using compounds of Formula-I (I) in medicine for the prevention and treatment of various allergic diseases (for example, bronchial asthma, allergic rhinitis

I-n

L 1 HS SH

After stirring the mixture with 60 g of 2,5-dimercapto-1,3, A-thiadiazole, 25 g of potassium hydroxide and 750 ml of ethanol for 1 hour at 70 ° C, 68 g of ethyl o-bromoacetate are added to the mixture and the resulting mixture is boiled t under reflux for 2 hours. After cooling the reaction mixture, the insoluble compounds are filtered off and the filtrate is concentrated under reduced pressure. To the residue thus obtained is pri

pgr

A mixture of 2 g of 4- (3-bromopropoxy) -2-oxy-3-propyl acetophenone, 1.6 g of 2 g of mino-5-mercapto-1,3,4-thiadiaole, 1.6 g of potassium carbonate and 20 ml The N, N-dimethylformamide is stirred for 1 hour at 20-30 seconds and after adding 100 cl of water to the resulting reaction mixture, the product is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sulphate.

yut. The residue obtained is applied to a silica gel chromatography column and eluted with toluene to give

(SNG) s PRG

374

etc.) and ischemic heart and brain diseases caused by SRS-A.

The purpose of the invention is to obtain new heterocyclic compounds, providing a new type of biological activity, antagonists of the anaphylactic compound SRS-A in a series of thiadiazole derivatives.

Examples of the preparation of the starting compounds, pgr means p-propyl group).

Example.

to-and

D ik

HS S SCHjCOOH

five

0

600 ml of 10% sodium hydroxide solution are added. The mixture is stirred for 1 h at. After cooling, the reaction mixture was acidified by adding concentrated hydrochloric acid (pH below 1), the resulting crystals were collected by filtration, washed with water, recrystallized from acetone, and 60 g (5-mercapto-1,3,4-thiadiazole-2 -yl) thio acetic acid, so pl. 170 C.

Example 2

one

0 (SNg) s; S S

2.3 g of 4-j 3 - ((5-amino-1, 3,4-thiadiazol-2-yl) thio propoxy -2-hydroxy-3-propyl acetophenone, mp 144-145 C.

Calculated,%: C, 52.29; H 5.76; N 11, 43; S 17.45.

CfbHi / NjO S,

Found,%: C 52.09; H 5.71; N 11, 58; S 17.61.

According to the described procedure, the desired compound 2-hydroxy-4- | 3-C (5-mercapto-1,3,4-thiadiazol-2-yl) thio1 nponoKCHf-3-propyl acetophenone is obtained, m.p. 127-129 ° C.

Nn

0 (СН2) ЗВг НО

pgr

A mixture of 3.1 g of 4- (3-bromopropoxy) -2-oxy-3-propyl acetophenone, 2.4 g of (5-mercapto-1,3,4-thiadiazol-2-yl) thio acetic acid, 3 g potassium carbonate and 30 ml of K, 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 aqueous layer was acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is rinsed with water, dried over anhydrous magnesium sulphate, the solvent is distilled o1c2) s13

"PRR

about

(CH2) s PRG

According to the procedure described in Example 3, using 100 mg of 2-hydroxy-4-ft- (5-mercapto-1,3,4-thiadiazol-2-yl) thio 7 propoxy I-3-propyl acetophenone, obtained as starting compounds in example 2, and 40 mg of bromoacetic acid get 70 mg

YES

(CNG) s-5 S cnsoon PRG

pgr

V-v

l 1

0 (CH 2) 3-5 iS SCH2-COOH

put under reduced pressure to obtain a solid compound. The latter was recrystallized from ethanol to obtain 2.5 g of t (5- 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl thio | -1,3,4-thiadiazol-2-yl) thio7 acetic acid, t .pl. 129-130 C.

Calculated,%: C 48.85; H 5.01; N 6.33; S 21.74.

CfiHcaN OsSj. Found,%: C 48.78; H 5.13; N 6.29; S 21.49. Example4.

. -N $ SCHgCOOH

f (5-jf3- (4-acetyl-3-hydroxy- -profylphenoxy) propyl-7TiO-1,3,4-thiadiazbl-2-yl) thio} acetic acid. The compound obtained has the same properties as the compound obtained in Example 3. Example5.

Nn

YES

 S

HO) 3

nPp

to a mixture of 0.5 g of (5- (4-acetyl-3-hydroxy-2-propylphenoxy)) prolyl} thio - 1,3,4-thiadiazol-2-yl) thio acetic acid, 0.23 g of dicyclohexylcarbodi imide, 0.14 g of 1-hydroxybenzotriazole and 50 ml of tetrahydrofuran are added to a mixture of 0.27 g of N-methyloxyamine hydrochloride salt, 0.3 g of triethyl-amine and 5 ml of N, N-dimethylformamide and the resulting mixture is stirred overnight at room temperature. . After this, the insoluble compounds are filtered off and the filtrate is condensed under reduced pressure. 100 ml of ethyl acetate was added to the resulting residue, and the mixture was washed successively with water, dilute aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble compounds were triturated, and the filtrate was concentrated. The residue obtained is recrystallized from a mixture of toluene and n-hexane, and I obtain 0.18 g of 2- (5- (GZ- (4-acetyl-3-hydroxy-2-prop1-phenoxy) propyl) thio | -1,3,4-thiadiazole -2-yl) thio1 -N-hydroxy-N-methyl acetamta, yes, mp 97-99 ° C. Calculated,%: N 8.91.

Found,%: N 9.06. The compounds of the invention of the general formula (I) are strong antagonists to the action of SRS-A and, therefore, are suitable for the prevention and treatment of various allergic diseases (for example, 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.

Furthermore, the compounds according to the invention include, in addition to the compounds N-N

s scHjCONc;

SNS

OH

The compounds that have antagonistic activity against the action of SRS-A are also compounds that have an activity that inhibits the production and excretion of SRS-A, and a bronchodilator effect along with the indicated activity. The proposed compounds are also suitable as anti-ulcer agents.

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

The technique. Male guinea pigs

Hartles weighing 500-700 g are slaughtered with a heart beat. The strips of ileum and trachea, obtained by the method of Sopantine (1965), are 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 fabrics 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 record it on a Recticorder. The contractile response of ileum to a submaximal concentration of SRS-A (obtained from the lungs

mumps) and the tracheal contractile response to a LTD concentration of 10 M are measured in the absence and then in the presence of various concentrations of the tested compounds. Compounds are incubated for 20 minutes.

When the compound of Example 5 is tested for Inhibition of Ileum Cuts, a decrease in the guinea pig ileum response to the introduction of SRS-A IC to TO 1.6 X 10 M is observed.

When the compound of Example 5 is tested for inhibition of tracheal contractions, a decrease in the guinea-pig tracheal response to administration is observed.

  (concentration, inhibit-V-7

LTD, IR;

conductive response at 50%) to A, 2 10

Toxicity. The minimum lethal dose, determined in the case of oral administration of the proposed compound to mice and rats in each case, is more than 1000 mg / kg.

In order to limit the dynamic role of SRS-A and to modulate its actions in carious pathological conditions, it is desirable to have specific

r fTl

lo-Vo-Y o-Vo cooNo (A)

The new compounds of formula I in comparison with the analogue of formula A have a higher absorption capacity when administered orally, as a result of which they have a prolonged R, lower acyl;

lower alkyl;

lower alkylene;

thiadiazole residue;

lower alkylene;

lower alkyl;

hydroxy group

and y u and with the fact that rbonovoy acid formula

CHA HetAjR R

t l ich

O-AI-S- {"O-S-AI-un

chesky and active in vivo receptor antagonist. In addition, from a clinical point of view, it is desirable to obtain an orally active compound. Compound FPL 55712 (compound of formula A) exhibits potential anti-CC5-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.

Claims (1)

action in comparison with the analogue. Invention Formula The method of obtaining heterocyclic compounds of the formula -.S-AI-COV R3 RA where R ,, R, A, A and Het have the indicated meanings, are reacted with an amine of the formula HN Dz where R and R have the indicated meanings, at their molar ratios (1.2-1):: (1-1.2) in an inert organic solvent.