前苏联专利SU1554763A3 Method of producing derivatives of thiazole or their salts with alkali metals

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专利摘要:
Disclosed are a thiazole derivative represented by the following formula, a pharmaceutically acceptable salt thereof and leukotriene antagonist containing the same as the active ingredients: wherein R, and Rz each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group or cooperatively represent a tetramethylene group corresponding to a fused cyclohexane ring or a butadienylene group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to 3 carbon atoms corresponding to a fused benzene ring; R3, R4, R5 and R6 each independently represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3 carbon atoms or a halogen atom; A represents a linking group having 2 to 4 chain members; B represents a linking group having 2 to 5 chain members; and Q represents a carboxyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms or a 5-tetrazolyl group.
公开号:SU1554763A3
申请号:SU864028404
申请日:1986-10-15
公开日:1990-03-30
发明作者:Хаяси Есио；Огури Томеи；Синода Масаки；Цуцуи Микио；Такахаси Кацуо；Миида Хитоси
申请人:Мицубиси Касей Корпорейшн (Фирма)；
IPC主号:

专利说明:

This invention relates to methods for the preparation of new thiazole derivatives.
or their salts with alkali metals, which have antagonistic
leicotriene and can be used in medicine for the prevention and treatment of allergic diseases caused by leukotriene.
The aim of the invention is to obtain new compounds of the thiaeol series, which possess a new type of biological activity in this series of compounds.
Example 1. Getting 2- - TRANS-Z- (CIS-Z-carboxypropenamide) styryl benzothiazole (compound No. 1)
158 mg of 2- (trans-3-aminostyryl) -beneothiazol are added to 8 ml of toluene to 71 mg of maleic anhydride and the mixture is heated at 80 ° C for 1 hour. After cooling to room temperature, the crystals formed are collected by filtration and recrystallized from ethanol which gives 194 mg (yield 88%) of the title compound as a yellowish white substance. M.p. 190-191 ° C. t, 3,: 1700; 1625; 1550; 1490; 1405, 953.
Hereinafter, IR is removed using KBG tablets.
Example 2. Preparation of 2- - (trans-3-oxalylaminostrin) -4-phenylthiazole (Compound No. 2).
To a suspension of 1.0 g of 2- (trans-3-β-ethyl oxalyl aminosityl) -4-phenyl-thiazole, prepared as described in example 3, in 40 ml of dioxane is added with vigorous stirring, 1 ml of a 20% aqueous solution of potassium hydroxide and wire t hydrolysis at room temperature for 1 hour. To the reaction mixture is added 20% hydrochloric acid to bring the pH to 1-2. The yellow precipitates formed are collected by filtration, washed with ethanol and chloroform, then dried under reduced pressure to give 870 mg (yield 94%) of the title compound. M.p. 291-292 ° C. IR, 3, 1715; 1685; 1590; 1520; 1300; 1180; 740.
Example 3. Obtaining 2- - (TRANS-3-ethyloxalaminosyryl) -4-phenyl-thiazole (compound No. 3).
To 30 ml of toluene are added 0.7 g of pyridine, 2.0 g of 2- (trans-3-aminosteryl) -4-phenylthiazole and a solution of 1.1 g of ethyl oxalyl chloride in 5 ml of toluene,
,
1554763
dropwise at 0 ° C with stirring and heated at 50 ° C for 1.5 hours. The reaction mixture is poured into ice water, the formed crystals are collected by filtration and dried. Subsequent recrystallization from chloroform gives 2.5 g (yield 90%) of the indicated
in the title of the substance. M.p. 193-194 ° C. IR,},: 3325; 1715; 1700;
0
five
0
1300, 730.
Example 4. Preparation of 2- -jjrpanc-3 (cis-3-itoamyloxycarbonyl-5 propenamido styryl) benzothiazole (compound No. 4).
To 6 ml of hexamethylphosphorotriamide, 1.0 g of 2-trans-3- (cis-3-carboxypropenamido) sodium salt of styryl benzothiazole and 2.13 g of isoamyl iodide are added and the mixture is stirred at room temperature for 4 hours. The reaction mixture is extracted with toluene and usual thus, the extract is dried over anhydrous magnesium sulphate, the solvent is evaporated off under reduced pressure. Subsequent recrystallization of the residue from ethyl ether / toluene gave 616 mg (55% yield) of the title compound.
M.p. 82-83 ° C.
IR,), 3400; 1720; 1660; 1580; 1440; 1200; 755.
Example 5. Preparation of 2-5-trans-3- (cis-3-carboxypropeneamido) styryl benzothiazole sodium salt (Compound No. 5).
17.3 g of 2-trans-3- (cis-3-carboxypropenamide) styryl benzothiazole was added to 350 ml of methanol and then a solution of 9.1 g of sodium bicarbonate in 75 ml of water, then heated under reflux for 1 h. The solvent is evaporated under reduced pressure and the crude crystals of the residue washed with ethanol and ethyl ether. After drying under reduced pressure, 1.11 g (yield 97%) of the title compound is obtained.
M.p. 239-240 ° C.
IR,}, 1360; 1570; 1410; 940; 760.
Example 6. Preparation of 2- 5-trans-3- (cis-2-carboxy-cyclohexane-alomethylamino) aminosylLbenzothiazole N-methyl-B-glucamine salt (compound No. 6).
five
five.
96 ml of N-methyl-1) -glucamine and 200 mg of 2-trans-3- (cis-2 carboxycyclohexanoyl) aminostyryl bencothiazode and a mixture of persimi-AH1T at room temperature are added to the dissolving salt of 6 ml of methanol and 1 ml of the feed. temperature 30 min. By evaporation of the solvent under reduced pressure, crude krng.chlae are obtained, which are recrystallized from n-ethanol with ZTILLPR ether, h 215 mg (yield TU ,.) grgdingney indicated in the title.
M.p. 111-1 15 ° (., 4) -; 46 ° C.
IR, 3, cm 1: 16.4U, 1540; 1410; 1080; 750
Analogously to examples 1-6, derivatives of thiazole are obtained, the physicochemical characteristics of which are given. in tab. 1-4.
Example 7. Manufacturing TPP-years. 1000 g of the sodium salt of 2-Gtrans-3- (cis-3-carboxypropenamido) styryl benzothiazole (Compound No. 5) thoroughly ground to a powder, 1000 g of lactose, 2000 g of crystalline cellulose, 100 g of hydroxypropyl peptide part 1 C1 is a small degree of substitution and 100 g of magnesium magnesium is carefully sized and molded into flat tablets by the direct tabbing method. Each tablet contains 10 mg of the indicated compound and 100 mg by weight of the tablet. Sugar coating or film coating is applied to a flat tablet. In this way, a saccharified tablet and a film coated tablet are obtained.
Example 8. The manufacture of capsules. 1000 g of 2- -Trans-3- (syl-3-carboxypropenamide) styryl benzothiazole, carefully crushed to a powder, in the keel of sodium salt (compound V 5), 3000 g of corn starch, 6900 g of lactose, 1000 g of crystalline cellulose and 100 g of magnesium stearate is mixed and used to fill capsules, each containing 10 mg of the indicated compound in a 120 mg capsule.
Example 9: Preparation of a preparation for inhalation. 5 g of sodium salt of 2-trans-3- (cnc-3-clrboxypropenoamide-strinbenzacazole, finely ground into powder (. Product 547636
Disinfection 5), 10 g of a saturated fatty acid triglyceride having an average chain length and 0.2 g of sorbitan mono-oleate are well mixed and each 15.2 mg of the mixture is weighed into a 5 ml aluminum container for aerosol. Then each vessel is filled at a low temperature with a portion of 84.8 mg, p Freon 12/114 (smeg 1: 1), vessel
equipped with a dosing unit for quantitatively delivering the active preparation in the amount of 100 ml per spray. This makes it possible to obtain a device for inga-, l-cip, which provides a quantitative dose of opr..snanich, whose 5 ml vessel contains 5 mg of the above compound
Example; C. The establishment of an anti-irritant effect 20 relative to SRS of a slow-reacting substance in vi.li о. In the male Guinea pig Pyroda Hartlen weighing 200-450 g, the end part 2 of the iliac gland is removed, and the lumen of the duct is fixed in a 5 ml tissue treatment bath containing Tylord solution of the following composition, mM: NaCl 136; KC1 2.7; N.-UICO, 11.9; P8S12 1.05; Cac12 1.8; 0.4 and glucose 5.6. The temperature in the bath is maintained at 37 C. The lerapia is produced with a mixture of 95% Kioporod and 5% carbon dioxide. In order to avoid contraction of gistmin and acetylcholine under the action of a dose of 35 g / ml menylamine and 5-10 g / ml atropine, are added to this solution. An isotonic measurement of voltage change in grams is carried out by means of an isotonic transducer (trausducer) (Trade name TD-112 S, manufactured by Nippon Coden), conversion controller and recording device Recticoder (Trade name RTG-4124, manufactured by Nippon Coden). The ileum segment is subjected to a passive load with a tensile force of 0.5 g and the reaction is obtained in the form of a contraction of the intestine under the influence of SRS extracted from a guinea pig lung. For control, the degree of conserved contraction is used - 55 mon from the effect of 1 unit of SRS (corresponding to 5 ng of histamine). Tested drugs are added to the tissue bath.
40
50
in various concentrations. The results, expressed in units of the minimum effective concentration, which represents the concentration of the test drug, attenuating the reduction in the control experiment by 50% (IC50), are shown in Table 5.
Example 11. Antagonistic effect on 1TD with in vivo experience. In 4 male guinea pigs of the Hartley breed, weighing 350-500 g, the resistance to air flow was measured under urethane anesthesia using a Harvard-type respirator according to a modified Concept-Rasler method. The results of the calculation of the inhibition (%) achieved due to the intraduodenal administration for therapeutic purposes of the test drug against increasing the resistance of the pathway for air passage caused by the intravenous injection of TDD4 in an amount of 0.1-1.0 µg / kg are shown in Table. 6 „.
Example 12. Test for acute toxicity. From 4 to 5 male mice of ddy breed of 6 weeks of age as group 1, the compound is administered through the mouth according to the proposed method in the form of a suspension in a 1% solution of the traganant. The observation was carried out for 7 days. Examine the number of dead mice. The results are shown in Table 7.

权利要求:
Claims (1)
[1]
Thus, the thiazole derivatives produced by the inventive method exhibit antagonistic action against leukotriene and are very few toxic compounds. Invention Formula
The method of obtaining thiae la derivatives of the formula Q / R1
6 -CO-W COOR4
R, -C-Cg-alkyl, C, -C-alkoxycarbonyl, phenyl or phenyl, substituted by a halogen atom, C1-C-alkyl, C-C4-alkoxyradical or C -C-alkoxycarbonyl; RI is hydrogen or C-Cd-alkyl,
R, and K together form a tetra.
a methylene group corresponding to a fused cyclohexane ring, or a butadienylene group unsubstituted or substituted by a halogen atom, C, -C-alkyl,.-alkoxy radical, or C -C-alkoxycarbonyl, corresponding to the condensed benzene ring; R .. is hydrogen or halogen, hydroxy - or C (-C-alkoxygroupj R - hydrogen or C, -C5-alkyl, A - C -Cj-alkylene, in which
one methylene group can be replaced by an oxygen atom or a group NH, vinylene, a carbamido or vinylamido group, B is a simple chemical bond
or a bivalent hydrocarbon group containing 1 to 3 carbon atoms in the bonding chain, or in the case when R4 is hydrogen, or their salts with alkali metals, due to the fact that
And, k, (
0
five
N
$ and.
where R ,, Rit R and A have the indicated meanings, are reacted with a compound of the general formula
Z - B - COOR
four ;
0
0
where B and R4 have the indicated meanings, Z is a -COX group, where X is a halogen atom, or Z and R, together form the -CO- group; in the medium as a solvent of an aromatic hydrocarbon, an ether or a halogenated hydrocarbon, at a temperature of from 0 ° C to the boiling point of the reaction mixture in the case when Z and R together form the - CO - group, or in the presence of an organic or inorganic base at a temperature from 0 to 100 ° C, when Z is -COX group, where X has the indicated value, and the target product is isolated in free form or in the case when R4 is hydrogen, in the form of a salt with an alkali metal.
1554763
10 Table 1
Physico-chemical characteristics of thiazole derivatives of the formula
15
sixteen
II
Soszha
NaOOC (CH2) 955, 730
4-C1 225-228 1560, 1470, 1085, 945,
735
4-C1 228-191 1660, 1600, 1550, 1400,
1095, 955, 745
B-CONH
I
COOR4
32
Cun
СН3 (СНг) 5- 142-143
1530,
1525,
1630
1320,
1530,
80
1550,
1320,
75
1440,
75
1545, 55
1540, 1480,
55
1600, 1555
950, 755
1410, 970,
1580, 1440,
1605, 1340,
1555, 865
13
Me
46 me
soon
47
Me
soon
ie COOH
Me / COOH
Me
Me
x
50 Me (CH) lCH
51
Me me
COOH
(CH) 2CH-155-156
155-4763
14
i
Continuation of table 2
950, 775
1707, 1640, 1543, 1170, 960, 783
1705, 1655, 1540, 1170, 955, 780
1705, 1657, 1165, 955, 780
1680, 1540, 1405, 1190, 950, 785
175-176 1680, 1540, 950, 790
3300, 2950, 1680, 1540, 950, 780
1554763
four
five
6 7 8
9 0 1
62 63
64 65
66 67 68
69 70
71 72
NaOOCCCHj,) - NaOOC (CH2) 3COONd
NaOOC (Ci; 2) z - NaOOC (CH2) 3COONd
NaOOC (NaOOC (CH2) 3USC
CAOOS (SNg) g- NaOOC (CH,) 3COONO
NaOOC (CH2) 2- NaOOC (.CH2 ;,
CooNa
NaOOC (CH2) z- NaOOC (CH2), COONd
NaOOC (CH2) 2Cg 15-165-170
C2Hy-210-211
- (CI1Z) 118-120
- -183-185
- -195-197
- (,) 123-127
- -185-190
- -187-192
- "; H2) 135-138
- -170-176
- -225-226 - (C112) 5CH5 115-117
- (CH2) 5CH3 178-180
- -16 / - 170
(CH2) 6CH3 125-127
- () ysn, 150-155
- -199 - 200
-C (CH) 3154-156
- -174-177
sixteen
Continuation of table 2
1410, 950,
410, 950,
1440, 850,
1410,
0
1410, 950,
1545, 1400,
1410, 950,
1555, 1435,
1430, 948,
1410, 945,
1410, 940,
1440, 955,
1410, 950 1410, 955
1440, 950,
1410, 950,
1415, 955,
1440.1350,
1560, 1415,
17155476318
Continuation of table 2
955
74Ts-CH (CH), 140-145 1660, 1560, 1440, 1350,
SOOGA950, 780
75NaOOC (CH2) 2- - -207-2101660, 1550, 1410, 945,
780
76NaOOC (CHz) 3- -CH (CH3) 2 260-270 1650, 1555, 1408, 943,
.690
IU (
77 —CH (CH) 2 120-126 1660, 1550, 1410, 950,
780
..x.1,2
78 Me COONci 1650) 1540 1400 95 °
79 IU Apple Group “120125 166С 1550 126 and 960
COONQ785
80- to GPSM “55 6 ° 165 ° 155 ° 1А ° ° 95 °
MeCOONQ7 so
81 L - -130-1351650, 1540, 1400, 950,
Et sooca775
Me C
-120-1231650, 1540, 1400, 950,
Me Me COONa730
83G COONO-SSCHSN,) 2 90-951650, 1540, 1400, 950,
Me78 °
84Et jTr. - (CH2) 2CH, 159-1601670, 1520, 1190, 960,
d couNa760
Et
85Et - (CHa) zCH3 155-156 1670, 1540, 14U, 950,
Me COOH78 °
86I e N | XpCOOH 164-1651680, 1580, 1410, 1200,
Me me955
Me CHjEt C2HS
19155476320
Table 3 Physico-chemical characteristics of the derivatives of thiaeol formula
n

M € COONA
Me
Me COON / O
COONO
145-50
130-135
CH3 (CH4) Z- 153-157
-Et
NaOOCCCH - CH5 (CH4) t-, 164-166
-Et NaOOC (CHz) 3 - - - 100-109
CooNa
NaOOCCCHp., - (SI,), 240-250
250-260
830, 780
1660, 154b, 1410, 1360, 950, 780
1650, 1540, 1400, 950, 780
- 153-157
- 164-166
100-109
240-250
250-260
1660, 1560, 1440, 950, 850, 780
1660, 1550, 1405, 950,
775
1650, 1550, 1405, 950,
780
1660, 1550, 1430, 1310, 810
1665, 1585, 1520, 1400, 950, 810
Physico-chemical characteristics of conventional formulas
,
B - CONH CH, CH- - T I2 2 $ LK2
COOR4
Me j
117G
COOH i (C1c) 2nM-
118
Me
(CH) UNCT
Me jf
119T UNFIAH "-, Me
Me
120
Me cool
i2i me coo.Na SN (SNL Me
COONa
Mr. COONA Et, Me
124
Me
COONa
a b and c a 4
1,690.1660, 1545, 1440,
1210,790
1710.1660, 1605, 1440,
1175,780
1677.1540, 1430, 1190, 785
1705.1655, 1605, 1400,
1175,790
82-83
1650, 1540, 1400, 1105, 735
1650, 1540.1400, 1180, 735
2950, 1650.1540, 1435, 875, 780
2950, 1650,1545,
1435, 1300,780
25
Connection No.
5,409
1554763
Table 6
26
Table 7
Acute toxicity (LDgo mg / kg)
3000 E006

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP60228912A|JPH057386B2|1985-10-16|1985-10-16|

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