SU1470186A3 - Method of producing heterocuylic 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

7J-N

L hs s sh

Target compound: 2-hydroxy-4-3- - (5-mercapto-1,3,4-thiadiazol-2-mil) thio propoxy-3-propyl acetophenone

ABOUT

 D

but

nSzNt

Physicochemical properties. M.p. 127-129 ° C.

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

C ,, S,

Found,%: C 50.00; H 5.33; N 7.19; S 24.82.

Target compound: 4- {4- (2-amino-1,3,4-thiadiazol-5-yl) thio-butoxy -2-hydroxy-3-propyl acetophenone

ABOUT

II

IT-K

but T OlCH2) 4 - S S H2 NSzNt

Physicochemical properties. M.p. 107-108 S.

Calculated,%: C 53.52; H 6.08, N 11.01; S 16.81.

C, H2, N ,.

Found,%: C 53.24; .H 5, N 10.97; S 16.74.

Example 9. The original connection

 SH S

Target compound: (2-benzothiazolylthio) propoxn 2- hydroxy 3- -propylacetophenone

B

Olchab-s

NSNT

; Physicochemical properties. Mas I is a lobar product ,.

Calculated,%: C 62.81 ,; H 5.77; N 3.49. I C ,, H ,, NO, S

Found,%: C 62.98 H H 5.98;

: N 3.36.

 PRI me R 10. The original connection for reference example 2.

The target compound: ethyl 4- (5- - 3- (4-acetyl-3-hydroxy-2-propyl-fe; noxy) propyl thio -1,3,4-thiadiazol--2-yl) thio butyrate

about

Mn

, for

 S Sl JHzbCOOCjHs NHSN,

Physicochemical properties. Oily product.

Calculated,%: C 52.99 (H 6.06, N 5.62; S 19.29,

11 5 3

Found,%: C, 52.99; H, 6.11;

N 5.53; S 19,18.

25 Calculated,%: C 65.60; H 6.28. . N 7.29.

C, Hj NjOjS

Found,%; C 65.46; H 6.34; N 7.25.

Example 13

thirty

35

 IT

but A o1 "YagS1, L-" S SCBjCOOCiHi BC} YATESZNt

example:

11. The original connection of the -SH

A mixture of 21.87 g of 4- (3-chloropropoxy) -2 -2-hydroxy-3-propylac8Tophenone, 18.18 g of ethyl- (5-mercapto-1,3,4-thiadiazole-2-Sh1) thio acetate, 12 7 g of anhydrous potassium carbonate 40 and 80 ml of methyl ethyl ketone are heated under reflux for 2.5 hours with vigorous stirring. After cooling, insoluble compounds are filtered off and

Target compound: (b-ami-filtrate is concentrated under reduced nobenzothiazol-2-yl) thio-propoxy -2 - pressure. 200 ml of ethyl acetate was added to the obtained α-hydroxy-3-propyl acetophenone residue.

 ml of toluene, the mixture is washed with a dilute aqueous solution of sodium hydroxide Q and water, dried over anhydrous magnesium sulfate and concentrated - 1NH2; P reduced pressure. Half-; The residue was applied to a silica gel chromatography column.

Physicochemical properties. The oil-j was eluted with a mixture of toluene and ethyl acetate (10: 1) and 33 g of ethyl p5- -i Cz- (4-acetyl-3-hydroxy-2-propyl-noxy) propyl thio, 4-thiadiazol-2- -yl) thio acetate. M.p. 71-72.5 ° C.

oa

No

OlCHzjg-S- S HCiHt

shaped product.

Nuclear Magnetic Resonance Spectrum (CDCl, TIS, ppm): 1.95 (singlet, 3N) -, L, 2-2.0 (2H); 2.53 (singlet, SN); 2.0-2.9 (4H),

4, A8 (triplet, ЗН), 3.4-4.0 (2H, -NH); 4.17 (triplet, 3N), 6.2–7.8 (5H), 12.7 (1H).

Example 12. The original connection:

ten

VSH

15

Target compound: (2-benzimidazolylthio) propoxy -2-hydroxy-3-propyl acetophenone

20

HO T OlCHzb-S

НСзН7 Н

Physicochemical properties. M.p. 143-146 ° C.

25 Calculated,%: C 65.60; H 6.28. . N 7.29.

C, Hj NjOjS

Found,%; C 65.46; H 6.34; N 7.25.

Example 13

thirty

 IT

but A o1 "YagS1, L-" S SCBjCOOCiHi BC} YATESZNt

A mixture of 21.87 g of 4- (3-chloropropoxy) -2 -2-hydroxy-3-propylac8Tophenone, 18.18 g of ethyl- (5-mercapto-1,3,4-thiadiazole-2-Sh1) thio acetate, 12 7 g of anhydrous potassium carbonate and 80 ml of methyl ethyl ketone are heated under reflux for 2.5 hours with vigorous stirring. After cooling, insoluble compounds are filtered off and

13

Calculated,%: C 51.04; H 5.57; N 5.95; S 20.44.

,

Found,%: C 51.07; H 5.49; N 5.69i S 20.17.

According to the procedure of Example 13, the following compounds are obtained.

PRI me R 14. The original connection

ABOUT

II

(СН2) ЗВГ НСзН7

and the compound according to reference example 4.

Target compound: ethyl-5- (5- - 3- (4-acetyl-3-hydroxy- + 2-propyl-phenoxy) propyl) thio -1,3,4-thiadiazol--2-yl) thio valerate ABOUT

wn

VolCHib-8 8 (CHiUCOOC | H KvjHT

Physicochemical properties. Oily product.

Nuclear Magnetic Resonance Spectrum (CDC1 ,, TMS, ppm): 0.92 (triplet, 3N), 1.24 (triplet, 3N), 1.5-2.0 (multiplet, 6H), 2.34 (2H ), 2.54 (singlet, 3N), 3.28 (triplet, 2H), 3.46 (triplet, 2H), 3.8-4.4 (4H), 6.42 (doublet, 1H), 7 , 58 (doublet, 1H), 12.68 (singlet, 1H).

Example 15, the Original connection for reference example 5 and

but

0 (CH2) 3BJ NSzNt

47018614

NMR spectrum (CDCl, ppm): 0.92 (triplet, 3N), 1.24 (triplet, 3N), 1.2-2.0 (8H), 2.1-2.5 (4H) .2.54 J (singlet, 3N), 3.28 (triplet, 2H), 3.48 (triplet, 2H), 4.0-4.3 (4H), 6.43 (doublet, 1H) , 7.60 (doublet, 1H), 12.7 (singlet, 1H),

Example 16. Initial connection: 10

ABOUT

II

15

BUT-B OlCHjbBi NS 3117

and reference reference connection

Target compound: ethyl-2- (5- ЕЗ- (4-acetyl-3-hydroxy-2-prop 1-phenoxy) propyl} thio -1,3,4-thiadiazole-2-yl) thio propionate

ABOUT

I "w

 Vi jCl

(sn,)

NSNT

Physicochemical properties. Oily product.

Calculated,%: N 5.78; S 19.85. 71 3

Found,%: N-5.85-, S 20.05. Example 17. The original connection:

iT

 SCBCOOCiHs

BUT T 01SN2) zvg NSzN7

45 and the connection according to reference example 6,

Target compound: ethyl-6- (5- - 113- (4-acetyl-3-hydroxy-2-propylpheno- ... si) propyl thio -1,3,4-thiadiazol-2-yl) thiohexanoate O

Target compound: (4-acetyl-3-hydroxy-2; si) propyl thio) -1,3,4-thia thio-valerate

HO Y

oh, b, l. (a..b-co.c, 5 ". (". b-ilj

HCjH,

Physicochemical properties. Oily product.

Target compound: eth-4- (5- (4-acet-1-3-hydroxy-2-propylpheno-; si) propyl thio) -1,3,4-thiadiazl-2-yl) thio-valerate

. (". L-ILJ

HCjH,

cHieHjCcoctBi

Physicochemical properties. Oily product.

5H-H J 1

 "SraaCOOfisHs

T

i A mixture of 596 mg of 4 (3 bromopropoxy) H2-hydroxy-3-propyl acetophenone, 372.4 ml of dityl- (5-mercapto -1 e344-ti, adiazol-2-- - | yl) yew acetate e 326 ng of anhydrous 4-carbonate potassium and 3 K 1 1 - dimethyl - 4-ammamide is stirred for 2 hours at room temperature. The resulting reaction is 1; the ionic mixture is concentrated under reduced pressure, chloroform is added; the mixture is washed with water and dried

hell is anhydrous magnesium sulphate and is concentrated under heavy pressure. The residue obtained is applied to a chromium-chromatographic 1-column with silica gel and eluted with a mixture of toluene and ethyl acetate (10; 1) j to give 663 .. 3 mg ethyl- (5-- 3- (4-acetyl-3-hydroxy) 2 -; aropoxy phenoxy) propyl 3 thio 1 er 3, α-thiadiazole) thio acetate. The properties obtained are VYG of a compound similar to :: property of the compound of example 13. Example 19.

 oh oh

3-2f

, D 1

-S S yShgSoov.

BUT t Oi H2) zVGNO

nsznt

, 44cHj |

NSEE,

2

A mixture of Sv1 g 4- (3-bronp} ro, G1SKSI) - -oxy-3-prosh-etofenok, 2, 4 g | (5-mer-ap 4-thiadia zol - 2-yl) thio1 acetic, Acids5 3 g potassium carbonate and 30 ml S,) W – d 1et {(The mixture was stirred for 3 hours at constant temperature. After 150 ml of water, the resulting reaction mixture was extracted with etryacetate, the aqueous layer was acidified 10% hydrochloric acid and extracted with ethyl acetate, washed with extra water, 5 sugs; 5 mg of magnesium sulfate without water, disintegrated when distilled: 1 weight of dBlenium, and a solid compound is produced Roe perekrkstsgl, G1IzovyE,;, k-L n from ethanol to give 2.5 g of ((4-atsetyu1

not

0 (CBij) 4SPHQ

aCjHT

B-lf

ojcH

HCjH

five

A mixture of 1.3 g of 4- (4-bombombutoxy) -2-oxy-3 propyl acetophenone obtained in Reference Example 12 (1.0 g of (5-mercapto-1.3 4-thiadiazol-2-yl) thio3 acetic acid acids 1.0 g of anhydrous potassium carbonate and 5 ml of M, K-dimethylformamide is stirred for 3 hours at 50 ° C. The resulting reaction mixture is mixed with 30 ml of water, washed with toluene j and acidified with dilute hydrochloric acid and extracted ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized 1.15 g of C (- (4-acetyl-3-hydroxy-2-propylphenoxy) butyl thio 1 -1, 3, diazol-2-un} thio acetic acid, T.Sh1, are obtained from ethyl acetate n 123-124.5 pp.

Calculated 6.14; S

% C 49.98; H 5.30V

21.07,

M

19 H.Mi i -,. Found,%. C 49.76 H 5.29;

6.07; S 21.13,

Similarly, 20 are obtained after blowing compounds,

Example 21 “Initial connection by reference pr tcher u t and syngenie according to reference example 11,

The target compound s ((4 acetyl-3-hydroxy-2-propipfenoke K) eH tyl | thio -15 3,4-thiadiazol-2-yl) tkoZ

acetic acid.

Physical properties, 107-108 С,

M.p.

Calculated,%: C 51.04; H 5.57. N 5.96V S 20.44.

,

Found,%: C 50.81; H 5.64; N 5.98; S 20.40.

Example 22. The original connection for reference example 1 and the connection for reference npimepy 9.

Target compound: f ((4-acetyl-3-hydroxy-2-propnylphenoxy) ethyl 3 thio) -1,3,4-thiadiazol-2-yl) thio acetic acid

five

and-to

S SCHiCOOK

 .

Physicochemical properties. M.p. 135-137 S.

NMR spectrum (DMSO-dg, TMS, ppm): 0.98 (triplet, 3N), 1.44 (multiplet, 2H), 2.60 (singlet, 3N), 3.72 (trit lash, 2H), / 4.16 (doublet, 2H), 4.40 (triplet, 2H), 6.66 (doublet, 1H), 2.78 (doublet, 1H), 12.81 (singlet, 1H).

Example 23. The original connection:

0 (СН2) ЗВГ НСзНт

and the compound of Reference Example 1.

Target compound: 3- (5-W- (4-α-acetyl-3-hydroxy-2-proxyphenoxy) propyl, 3,4-thiadiazol-2-yl) thio propionic acid

TH-V

,) 3COOH

Physicochemical properties. M.p. 102-107 S.

Calculated,%: N 6.14; S 21.06.

,

Found,%: N 6.28; S 21.03.

Example 24. Starting compounds:

soon he

+ v 0 (CH2) 381 HS 5

: Target compound: (4-aceticl-3-hydroxy-2-propylphenoxy) propyl thio) -3-hydroxy-4-isothiazolecarboxylic acid

soon he

V olCHjlj-s-p

RR

:,

20

25

50

five

Physicochemical properties. M.p. 182-184 sec.

Calculated,%: C 52.54, H 5.14 N 3.40i S, 15.58. C aHiiNOfiSj

Found,%: C 52.23- H 4, -96; N 3.20, - S 15.48.

The proposed compounds are strong antagonists in relation to the action of SRS-A, therefore, are suitable for the prevention and treatment of -specific personal 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.

In addition, new compounds include, along with compounds that have antagonistic activity against the action.; SRS-A, also compounds that have activity that inhibit the production and exposure of SRS-A and the bronchodilatory effect along with the indicated activity. These compounds are also used as anti-ulcer agents.

Inhibition of contractions of ileum and trachea, vyzgeemyh SRS-A and LTD in guinea pigs.

Methodology: Male Guinea Pigs Hartley weighing 500-700 g are slaughtered with a heart beat. The strips of ileum and trachea, obtained by the method of Constantine (1985), were placed under a live load of 1.0 g per bath, for isolated organs containing 10 ml of Tyrodo solution balanced with respect to a mixture of 95%

35

40

45

14

nineteen

Oxygen and 5% carbon dioxide at, Fabric brought to equilibrium within 60 minutes; during this period, the tyrode solution was dusted every 15 min and the tensile load was adjusted to 1.0 g. force i, 1) induced by the tissues, measured isothermally using a linear transducer, and recorded n device., lecticorde ,. The contractile response of ileum to the submaximal concentration of SRS-A (obtained from the lungs of the guinea pig) and the contractile response of the trachea to a concentration of LTD, .. equal to 10 m are measured without and then in the presence of various concentrations of the tested compounds. Compounds are incubated for | 20 min.

I Results obtained: the data are given in Table 1. I. According to: Ep 19, the reduction of the tracheal response of the marine snag to the administration of LTD, ICU (M) (concentration S inhibitory response by 50%) is 1.3.

Inhibition of anaphylactic Iastma Processed with the participation of SRS ™ A in sensitized: guinea pigs

The method of male guinea pig Hartley weighing 370–410 g nassly: is sensitized by intravenous injection of 1 Wi / kg of rabbit serum containing antibodies against bovine serum albumin in Lake. (RNA-txtr: 20480). 24 hours after sensitization, prior to the introduction of the antigen through the iodoccus vein, injections are administered indometam (2 m: g / kg) mepiranamine (2 mg / kg) and propranolol

20.5

(0.3 mg / kg), respectively, 4 minutes before the introduction of the antigen. After that, the animals are placed with a 1 ml glass chamber with a capacity of 1 ml, connected with a glass pulverizer e'er-eMe and injected into the chamber in the flow:;: 30 with a 1% solution of bovine syrup. Full-time albumin. The animals were allowed to stand under the antigen aerosol for 2 minutes and washes were taken 15 minutes after the introduction of the antigen. The time from the beginning of inhalation to the onset of coughing and mortality is recorded. Test compounds are injected ornately 30 mic before the antigen is introduced

Thus, the compound of example 19 at a dose of 3 mg / kg5 administered orally, reveals a tendency to inject

20

Anaphylactic asthma that occurs in sensitized guinea pigs, however, has a slight effect on this effect (Table 2). When administered orally the compound of Example 19 and at a dose of 10 kg / kg or more, it significantly inhibits anaphylactic asthma that occurs with the participation of SRS-A. (Mepiramine (2 mg / kg, intravenously), propanolol (0.3 mg / kg, intravenously) and indomethacin (2 mg / kg, intravenously), respectively, 5, 5 and 20 minutes before the antigen administration, and the test compound was administered orally 30 minutes before the antigen administration). Tokskgchnost. The minimum lethal dose, determined in the case of oral administration of the compound according to Example 19, to the rats and in each case was more than equal. 1000 mg / kg. The proposed compounds are classified as low-toxic compounds with

Claims (1)

Invention Formula The method of obtaining heterocyclic compounds of the general formula R Nz T CR € $ L 4 five 0 Where R,  2 BUT 5 0 5 a lower acyl group; a lower alkyl group; lower alkylene group Y is sulfur or oxygen; Hat is a thiadiazole residue, triazole, oxopyranyl or isothiazole, R ,, R and Rj are the same or different, each hydrogen, hydroxy, mercapto group, for our j u-iKi-m- thio group, hydroxymethyl formula group -S-Aj-Rg " where AJ, a lower alkylene group, Rg is a carboxy group or a lower alkoxycarbonyl group, an amino group or a carboxy group, g different teme that halogen-containing compound formulas 21 0-a-x where B, R and A have the indicated value of hydrogen or alkaline HHHJ metal; X - halogen, Het, Y, R ,, K have indicated subjected to interaction with the compound - JQ value, mnem general formula T a b l i P 0.05. , 01 (significantly different from the value of the control group) .. U70186 22 M-Y