前苏联专利SU1342410A3 Method of producing diazine-containing derivatives of oxamic acid or salts thereof with primary or s

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专利摘要:
Compounds of the formula <CHEM> wherein R1 is hydrogen or alkyl of 1 to 4 carbon atoms; R2 is hydrogen, methyl, hydroxyl, alkoxy of 1 to 4 carbon atoms, di(alkyl of 1 to 2 carbon atoms)amino-(alkoxy of 1 to 4 carbon atoms) or -HN-CO-CO-OR1; A is <CHEM> R3 is hydrogen, methyl, alkoxy of 1 to 4 carbon atoms, hydroxyl, amino, alkanoyloxy of 1 to 2 carbon atoms, di(alkyl of 1 to 2 carbon atoms)amino-(alkoxy of 1 to 4 carbon atoms) or acetamido; and R4 is hydrogen, amino, alkoxy of 1 to 4 carbon atoms, halogen or -HN-CO-CO-OR1; and, when R1 is hydrogen, non-toxic, pharmacologically acceptable salts thereof. The compounds as well as their salts are useful for the treatment of immunological, inflammatory and allergic disorders such as allergic asthma, rhinitis, conjunctivitis, hay fever, urticaria, food allergies and the like.
公开号:SU1342410A3
申请号:SU843784980
申请日:1984-08-29
公开日:1987-09-30
发明作者:Грозингер Карл；Оливер Джеймс
申请人:Берингер Ингальгейм Лтд (Фирма)；
IPC主号:

专利说明:

eleven
This invention relates to a process for the preparation of new diazine containing compounds, their oxamic acid derivatives or their salts with primary or secondary ones. amines, or alkali metals, or acid additive salts with mineral acids - biologically active compounds that can be used in medicine.
The purpose of the invention is new diazine-containing oxamic acid derivatives with low toxicity and higher antiallergic activity.
Example 1. 2- (4-pyrimidinyl) ethenylfvnil-2-oxamic acid ethyl ester.
1-2 g of ethyl oxalic acid chloride are added dropwise to a suspension of 1.3 g of (p-aminophenyl) ethenyl pyrimidine B 30 ml of methylene chloride containing 1.6 ml of pyridine. The mixture is stirred overnight at room temperature and washed first with an aqueous solution of sodium bicarbonate, then with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and finally evaporated to dryness. The residue is recrystallized from chloroform and petroleum ether. The yield of 1.3 g (66.3% of theoretical) of the above compound, having so pl. 171-173 S.
The original compound was prepared as follows.
24.2 g of p-nitrobenzaldehyde, 15.5 g of 4-methyl-pyrimidine and 16.7 g of acetic anhydride are mixed at room temperature and the mixture is heated to 120 ° C for 5 hours. After cooling, the mixture is poured into 500 ml of water and the mixture is now extracted with chloroform. The combined chloroform extracts are then dried over magnesium sulfate and concentrated to form crystals. After the addition of ether, 28 g (77% of theory) of (p nitrophenyl) ethenyl pyrimidine are obtained; 213-215 ° C.
100 ml 4 n. hydrochloric acid was added dropwise to a mixture of 28 g of (p-nitrophenyl) ethenyl pyrimidine, 250 ml of ethanol and 28 g of iron filings. The reaction temperature was increased to 65 ° C and at this temperature
After the reaction mixture is stirred for 2 hours. Water is added and then 200 ml of a 30% aqueous solution of potassium hydroxide and 1 l of chloroform are added. The mixture is filtered, the chloroform layer is separated, dried over sodium sulfate and then concentrated. After the addition of ether, 10.3 g (42.4% of theoretical) of 4-2- (p-aminophenyl) ethenyl pyrimidine with mp. 227-230 ° C, which can be used as a starting compound without further purification.
EXAMPLE 2. 2- (4-Pyrimidinyl) ethenylphenyl-4-oxamic acid and its ethanolamine salt.
13.5 ml of solution 1N. Sodium hydroxide was added dropwise To a suspension of 4 g of ethyl 4- (4-pyrimidinyl) ethenyl-phenyloxy-aminic acid ester (see Example 1) in 50 ml of water and 50 ml of ethanol, stirring vigorously until a clear solution was formed. The resulting solution is acidified with 2N. hydrochloric acid, the precipitate formed is filtered off. The filter cake is dried and 2 g of 2- (4-pyrimidinyl) ethenylphenyl-4-oxamic acid are obtained with a mp. 214-216 ° C.
The acid is suspended in a mixture of 50 ml of S, K-dimethylformamide and 1 g of this nolamine. The precipitate formed is filtered off and washed with ether. Get 1., 3 g (29% of theoretical) ethanolamine salt of the specified acid with so pl. 202-205 ° C.
EXAMPLE 3 2- (2-ethoxyoxalylaminopyrim din-4-yl) ethyl ethenylphenyl-4-oxamic acid ethyl ester.
19 ml of ethyl oxalic acid chloride was added dropwise to a solution of 13.5 g of (p-aminophenyl) etheyl-2-aminopyridine in 75 ml of dry pyridine. The reaction mixture is stirred for 12 hours at room temperature. The reaction is periodically monitored by thin layer chromatography. At the end of the reaction, the reaction mixture is poured into ice water. The crude product is extracted with chloroform, dried and purified on a column of silica gel. After recrystallization from chloroform and ether, 9.0 g (34% of theoretical) of ethyl ester (ethoxyoxalylaminopyrimidin-4-yl) are obtained. 313
ethenyl phenyl-4 oxamic acid with so pl. 191 - 193 ° C.
The original compound was prepared as follows.
A solution of 2-amino-4-methylpyrimidine and 30.2 g of p-nitrobenzaldehyde in 45 ml of formic acid is heated under reflux for 24 hours. After cooling, the reaction mixture is poured into 1 liter of water and the aqueous mixture is neutralized with 5N sodium hydroxide solution. The crude product is extracted with chloroform and the extract is dried over sodium sulfate and concentrated to dryness. The crude product is purified on a column of silica gel, and 27.8 g (57% of the theoretical) (p-nitrophenyl) -ethenyl -2-aminopyrimidine with t, mp, 214-216 C, which can be fed to the next stage without purification, are obtained. ,
100 ml of 4N hydrochloric acid are added dropwise to a stirred mixture of 21.8 g of (p-nitrophenyl) -tetyl -2-aminopyrimidine, 250 ml of ethanol and 22 g of iron filings. During the addition of the acid, the reaction temperature rises to 65 ° C and stirring is continued at this temperature for 2 hours. Water is added and then 200 ml of an aqueous solution of sodium hydroxide and 1 l of chloroform. The chloroform layer is separated and dried over sodium sulfate. After evaporation and addition of ether, 13.5 g are obtained ( 71.7% of theoretical) 4- L2- (p-aminophenyl) -ethenyl) -2-aminopyry Idina which can be used without further purification as the starting compound.
Example 4, Ethyl ester of 2- (2-acetamidopyrimidine-4-Sh1) ethenylphenyl-3-oxamic acid,
To a solution of 1 g (0.0034 mol) of 2-acetamido-4- (3-aminostyryl) pyrimidine hydrochloride in 50 ml of pyridine was added 1 g (0.007 mol) of ethyl chloric acid chloride. The reaction mixture was stirred at room temperature. for 18 hours. The crude product is extracted with methylene chloride and purified on a column containing silica gel. Obtain 0.5 g (41% of theoretical) of ethyl 2- (2-acetamidopyrimidin-4-yl) ethyl ethenylphenyl-3-oxamic acid ethyl ester with mp, 234-236 C,

5 o 0
five
Q g
five
0
PRI me R 5, 2- (2-ethoxyoxalylaminopyrimidin-4-yl) -ethenylphenyl-3-oxamic acid ethyl ester,
To a solution of 3 g (0.009 mol) of 2-amino-4- (3-aminostyryl) pyrimidine hydrochloride in 75 ml of pyridine was added 4.1 g (0.03 mol) of ethyl oxalic acid chlorohydride at 10 ° C. The reaction mixture stirred at room temperature overnight, concentrated to a volume of 30 ml and poured into 250 ml of water. The crude product is extracted with methylene chloride and purified by chromatography using silica gel. The fractions containing the desired product are combined and recrystallized from a mixture of methylene chloride and ether. 2 g (54.5% of the theoretical yield) of 2- (2-ethoxyoxalylaminopyrimidin-4-yl) ethenylphenyl-3-oxamic acid ethyl ester are obtained with m, pl, 199-20l c,
Apply the appropriate starting materials, similarly to the examples. 1-5, the compounds shown in the table are obtained.
one
Biological tests have been carried out on compounds of formula I to evaluate antiallergic activity. The proposed compounds and the di-sodium salt of cromoglycic acid were studied in rats by passive subcutaneous anaphylacis. In this case, the serum of rats is diluted so that skin reactions are induced in areas with a diameter of 10-15 mm on non-sensitized rats. The test was carried out twice by injecting 0.1 ml of diluted serum on both sides of shaved rats of the rats. After 24 hours, 0.02 mg of egg protein is injected intravenously into rats in 0.5 ml of a 1% Evans Blyu solution, namely 30 minutes after oral administration of the test compounds. After 30 minutes from giving albumin, the rats are killed by asphyxiation. COj, and the skin is discarded. The diameter of the blue areas (in mm) is measured and the average diameter is determined. The middle section (c) of the control group is taken as 100%, and the activity of the test compounds is expressed as the percentage change in the control data. 51342410
There is a dose that reduces by 50% (ED) the size of the blue areas.
The antiallergic activity of diazine-containing oxamic acid derivatives is as follows:
Oh oh
NH-C-C-OFli
The proposed compounds have better antiallergic activity than the known ones.
The toxicity of the compounds of the formula I is of the same order as the toxicity of the known reference compound (1000 mg / kg; orally, mippi),

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining diazin-containing oxamic acid derivatives of general formula
where R is hydrogen or ethyl;
R is hydrogen, hydroxyl or groups,
—NHCOCOOC Hj, OCH-g (CHj); A is a radical of the formula
NPLL
lm
cY
Tss
or
ABOUT,
hg N
where R is hydrogen, methyl, ethoxy
-L1N-C-S-OR 1 -shsoskh D II 00
where R, has the indicated meanings; R is hydrogen, ethoxy, amino, or a group: -HN-CO-CO-OR where Rg has the indicated values for R ,; Ry is hydrogen, ethyl, chlorine, or their salts with primary or secondary amines, or alkali metals, or acid addition salts with mineral acids, which is derived from the general formula
6
Rj have the indicated values r
NH,
A-CH-CH
where a and
neither, or their acid addition salt is reacted with ethyl oxalic acid halide and, if necessary, the resulting product, where R, is ethyl, is subjected to hydrolysis and the desired product is given in free form or as a salt.
3-OCHJCEiN (CH,). 4-NHCOCOOC H5 156-15942.5
k A
N
Tx
4-OCH, CHiN (CHj), j 3-NHCOCOOCjHy
sesquihydrochloride
13
f Z-NHCOCOOC Hy 4-NHCOCOOCjH5
N
n CiHsO-V
H
176-17840
135-13746
4-NHCOCOOCjH 156-15942
Hjcj
Table continuation
di-tromethane salt
n
Tromethane - 2-amino-2-hydroxymethyl-1,3-propandiol.
Editor N.Kishtulinets
Compiled by V.Volkov Tehred I.Popovich
Order 4447/58 Circulation 371 Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
| Production and printing company, Uzhgorod, Projecto st., 4
1342410
12 Continuation of the table
Proofreader I. Muska

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引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

GB1259685A|1969-04-03|1972-01-12|Soc D Etudes Prod Chimique|Amino-pyrimidine derivatives|

US3993679A|1972-12-20|1976-11-23|The Upjohn Company|Cyano phenylene dioxamic molecules|

US4054666A|1973-03-23|1977-10-18|American Home Products Corporation|Compositions and methods of treating immediate hypersensitivity reactions with thiazolyl oxamic acid derivatives|

US3953468A|1974-03-15|1976-04-27|The Upjohn Company|3-Cyano thiophen-2-yl oxamic acid and derivatives|

CA1066714A|1974-06-10|1979-11-20|John B. Wright|Pharmaceutical n-phenyloxamic acid derivatives|

DE2828091C2|1978-06-27|1988-05-26|C.H. Boehringer Sohn, 6507 Ingelheim, De|

WO1992000963A1|1990-07-12|1992-01-23|Yoshitomi Pharmaceutical Industries, Ltd.|Styryl compounds and use thereof as medicine|

JP2832923B2|1990-07-13|1998-12-09|吉富製薬株式会社|Styryl compounds and their pharmaceutical uses|

WO1999035140A1|1998-01-12|1999-07-15|Novartis Ag|PYRIDINYLPYRIMIDINE AMINES AS IMMUNOGLOBULINE ESYNTHESIS INHIBITORS|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

US52852283A| true| 1983-09-01|1983-09-01|

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