Method of producing 2,4-diamino-5-(substituted)pyrimidines or their salts

专利摘要:
Compounds of the formula (1): or a salt, N-oxide or acyl derivative thereof, wherein is a six membered ring optionally containing a hetero atom double bonds, both the phenyl ring and the being optionally substituted except that when does not contain a hetero atom either or both the phenyl ring or must be substituted other than solely by a hydroxy group at the 4-position of the phenyl ring, and that there are no substituents attached to the atom of adjacent to the 6-position of the phenyl ring are useful in the treatment of bacterial infections. A process for preparing these compounds and novel chemical intermediates used in their preparation are disclosed as is the first medical use of the compounds of the formula (I) and pharmaceutical compositions containing them.
公开号:SU1424732A3
申请号:SU813358051
申请日:1981-11-10
公开日:1988-09-15
发明作者:Мэри Далюг Сюзан；Марсель Сконези Пол
申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
IPC主号:

专利说明:


sn
The invention of the process of obtaining new biologically active compounds, in particular 2,4-diamine-5- (substituted) pyrimidines or their salts, which can be used in medicine and biology.
The purpose of the invention is a method for obtaining pyrimidine derivatives that are low toxic and have a higher antimicrobial activity. Example 1
A. Methyl-3, A-dimethoxy-5- (2-propyloxy) benzoate.
Methyl 3,4-dimethoxy-5-hydroxybenzoate (0.54 g, 2.54 mmol), propargyl chloride (0.23 g, 3.04 mmol), sodium iodide (3 mg, 2.54 mmol ) and potassium carbonate (0.53 g, 2.81 mmol) are refluxed in acetone (10 bp) for 18 hours, cooled, filtered and concentrated. The resulting oil was dissolved in ethyl acetate (20 ml) and washed with water (3 x 10 ml). The organic layer was dried over sodium sulfate, concentrated and recrystallized from alcohol (2.5 ml), hexane (20 ml) to obtain methyl-3,4-dimethoxy-5- (2-prprinyloxy) benanoate (0.29 G | 49%), mp. 72-73.5 S.
Calculated: C 62.39; H 5.64.
C ,, H, 4 Oj
Found,%: C 62.28; H 5.68.
B. Methyl 7,8-dimethoxy-2H-1-ben-eopyran-5-carboxylate.
Methyl-3,4-dimethoxy-5- (2-propynyloxy) benzoate (390 g, 1.56 mmol) in N, H-dimethylaniline (0.4 l) is refluxed for 40 minutes. The solution is cooled and diluted with methylene chloride (2 L). The organic solution is extracted with 1 K hydrochloric acid (5x1 L), dried over magnesium sulfate, and concentrated to obtain the title compound (390 g, 100%).
, In a sample recrystallized from ether-hexane, m.p. 88,
Calculated, X: C 62.39; H 5.64.
WITH, ,
Found,%: C 62.35; H 5.68.
B. 7,8-Dimethoxy-5-formyl-2H-1-benzopyran.
Methyl 7,8-dimethoxy-2H-1-benzopyran-5-carboxylate (390 j, 1.56 mol) in toluene (1.6 l) is cooled to -15 ° C and a solution of sodium bis (2-methoxyethoxy) is added. ) aryuzhnyhydride (908 bp, 3.5 M) in toluene (3.18 mol) and morpholine (277 g, 3.18 mol) in toluene
with (900 ml) in 45 min. After stirring for an additional 30 minutes, 2N sodium hydroxide solution (2.85 L) was added. The organic layer is separated, washed with 0.8 N hydrochloric
10 with acid (3x1 L), 5% sodium bicarbonate (500 mp) and water (1 L), dried over magnesium sulfate and concentrated to obtain 7,8-dimethoxy-5-formyl-2H-1-benzopyran
15 (344 g, 86%).
The sample recrystallized from a mixture of ether - hexane, etc. 82 - 82.5 C.
Calculated,%: C 65.44; H 5.49. 20 C, iH, .j04
Found,%: C 65.42; H 5.51.
G. 2- (7,8-Dimethoxy-2H-1-benzopyran-5-ylmethyl) -3-morpholinoacrylonitrile.
5 I
0
five
0
five
0
five
7,8-Dimethoxy-5-formyl-2H-1-benzopyran (362 g, 1.64 mol) in a solution of alcohol - dimethyl sulfoxide (1.5 l) is added to a boiling refluxing morpholinopropionitrile (299 g, 2 , 13 mol) and sodium methylate (116 g, 2.13 mol) in a mixture of alcohol-dimethyl sulfoxide (800 mp) for more than 45 minutes. The entire reaction mixture was diluted with water (100 mp), concentrated in vacuo to one-fourth of the original volume, and again diluted with water. The resulting solution was extracted with dichloromethane (2x2 L) and the organic phase was washed with water (2 L). The organic layer was concentrated and dried with SD3A azeotropic. Papuchennoe oil is used directly in the next stage. The NMR spectrum corresponded to the intended structure. Thin layer chromatography showed a mixture of E and Z isomers,
D, 2,4-Diamino-5- (7,8-dimethoxy--2N-1-benzopyran-5-ylmethyl) pyrimidine
2- (7,8-Dimethoxy-2H-1-benzopyran-5-ypmethyl) -3-morpholinoacrylonitrile (562 g, 1.64 mol) and anilingine hydrochloride (234 g, 1.80 mol) are boiled with reflux in 2.4 L of SD1A (ethanol) for 1 hour. Cool the reaction mixture and add guanidine hydrochloride (313 g, 3.28 mol) and sodium methyl acetate (275 g, 5.08 mol). After refluxing, the product is recrystallized from the cooled reaction, After filter 1, and followed by washing with water (2 p), 2,4-diamino-5- (7,8-dimethoxy-2H-1-benzopyran-5) is obtained. - methyl) pyrimidine (220 g, 42.7%). After recrystallization from ethanol-water mixture, the compound obtained in m.p. 235-238 C.
Example 2
L. 3- (7,8-Dimethoxy-2H-1-benzopyran-5-yl) -2-methoxymethylpropenonitrile.
A mixture of sodium methoxide (7.02 g, 0.13 mol) 7, 8-dimethoxy-5-formyl-2H-1-benzopyran (57 g, O, 26 mol) and 3-ethoxypropanitrile (28.35 g, 0.286 mole) in methanol (150 ° C) is heated at reflux for 4 hours, then cooled and diluted with water (150 ml) and ethyl ether (5.0 ml). The layers are separated and the ether portion is washed with water (3x250 and 1x100 ml) and dried over magnesium sulfate. The ether solution is concentrated to obtain 55 g (73%) of amber oil, which is used further without further purification.
B. 2,4-Diamino-5- (7,8-dimethoxy-2H-1-benzopyri-5-ylmethyl) pyrimidine
Guanidine hydrochloride (11.46 g, 0.12 mol) in methanol (25 ml) is added to sodium methylate (6.55 g, 0.12 mol) in methanol (40 mp), the sodium chloride is filtered and washed methanol (bO ml), guanidine solution is added to 3- - (7,8-dimethoxy-2H-1-benzopyran-5-nl) -2-methoxymethylpropenitrile (11.5 g, 0, OA mol), the resulting mixture boil under reflux for 2 hours. After cooling the mixture to 3 ° C, 5.38 g of a yellow solid are obtained. High performance chromatography gave a yield of 28.6%. The melting point of the sample recrystallized from an alcohol-water mixture was 232-4 ° C.
PRI me R 3.
A. 3- (7,8-Dimethoxy-2H-1-benzo-iran-5-yl) -2-dimethoxymethyl propane-ytryl. .
A mixture of sodium methoxide (8.86 g, 0.164 mol) and 3- (7,8-dimethoxy-2H-1-benzopyran-5-yl) -2-methoxymethyl-propenitrile (Example 2A, 23.0 g.
0
five
five
0
0.080 mol) in methanol (60 bp) is refluxed for 24 hours; leave to cool and dilute with water (200 ml). Extract the mixture with toluene (1x200 and 2x100). The combined toluene fractions are extracted with water (3x100 ml) and dried over magnesium sulfate. The toluene solution is concentrated. The residue gives a brown oil, which is distilled off under reduced pressure to yield 15.9 g (62%) of a yellow oil, which is used without further purification.
B. 2,4-diamino-5- (7,8-dimethoxy-2N-1-benzopyran-5-ylmethyl) pyrimidine.
The guanidine hydrochloride (11.94 g, 0.125 mol) and sodium methoxide (6.81 g, 0.126 mol) are combined in methanol (100 ml) and the resulting sodium chloride is filtered off. The methanol guanidine solution was added to 3- (7,8-dimethoxy-2H-1-benzopyran-5-nl) -2-dimethoxymethyl propanate (15.9 g, 0.05 mol), and the resulting mixture was boiled t under reflux for another 2 hours. After cooling, 2.85 g (18%) of 2,4-diamino-5- (7,8-di-methoxy-2H-1-benzopyran-5-ylmethyl) are filtered and dried pyrimidine, so pl. 233-234 s. The filtrate is concentrated to 70 ° C. It is heated for an additional 2.5 hours, 75 ml of methanol are added and the resulting solid is filtered off, 10.4 g of a light colored solid are obtained. A complete analysis by high performance chromatography gave a yield of 60.3%. The sample is recrystallized - the alcohol - water mixture is called,. m.p. 236 ° C.
Example 4. 2,4-Diamino-5- (8-g dimethylamino-7-methyl-5-quinolylmethyl) -pyrimidine.
A. / L-Morpholinopropionate (0.85 g), dimethyl sulfoxide (1 ml) and dry sodium methoxide (40 g) are heated and stirred at 65 ° C under a stream of nitrogen. A solution of 8-dimethylamino-7-methylquinoline-5-carboxaldehyde / (1 g) in dimethylsulphoxyde (2 ml) is added and the mixture is heated to 75 ° C. J- After 2.5 min. Analysis by gas chromatography ( 3% 210 + 22 OV 101, 152 cm column, 200 ° C) showed that the whole aldehyde reacted. The product is poured into water and then extra5.
0
0
bathed in ethyl acetate. The organic layer is washed with water, dried over magnesium sulphate and then evaporated under vacuum to give 2- (8-dimethylamino-7-methylquinolin-5-ylmethyl) -3-morpholinoacrylonitrile (1.3 g) as a light a brown solid that is recrystallized from isopropanol.
6 OMN, N NMK (CDC1,): 2.5 S (3N,
S. -sn,); 3.1 (bn, s, s / d „d);
3.1-3.35 (4H, m. 3 48 - - CH2
/ CH2, 3.7 (4H, tO, c |) P, 9 (2H, bS,
); 6.71 (1H, S, alkene, proton); 7.16-7.44 (1H, n, H-4); 7.35 (1H, S, H-6); 8.03-8.23 (1H, t, H-3) 8.8-9.6 (1H, t, H-2).
IR (rt) ", cm-: 2185, 1660, 1240, 1120.
B. The product from Example 6A (0.3 g) guanidine carbonate (0.313 g) and dimethyl sulfoxide (0.6 ml) are heated together in an oil bath at 180 ° C. for 1 hour. The mixture is then cooled and divided between water and ethyl acetate. The organic layer is separated, dried over magnesium sulfate and concentrated on silica gel. Load the resulting powder on top of a silica gel column and elute with chloroform followed by elution with 5% methanol in chloroform to give the compounds as a yellow solid (181 mg, 68.5%).
6 OMN, H NMR (CDC1,): 2.48 (3N, S, CH,); 3.08 (6H, S, N / CH, /); 4.03 (2H, bS,); 5.74 (2H, bS, B) 6.23 (2H, BS, NHi); 7.07-7.6 (ЗН, t, Н-4); 6 (1H-6); 8.2 -8.5 (1Н ш,, Н-3); 8.74 -8.92 (1H. T. H-2) (The signal disappears after suppression of deuterium oxide).
Crystallization from 95% ethanol containing HC1 gives the compound dihydrochloride, m.p. 250 - 252 ° С (decomposition).
Included, X: C 52.92; H 5.88;
N 21.78; C1 18.38,
Sp HtNb- 2HС1 0,25 Found,%: C 52.77; H 5.90;
N 21.74; C1 18.22.
0
0
five
0 5 0
five
0
Example 5. 2,4-Diamino-5- -18-dimethylamino-7-methyl-5-quinoline-methyl pyrimidine.
To a stirred mixture of 5-formyl-7-methyl-8 (N, N-dimethylamino) quinoline (2.52 g), 3-methoxypropionitrile (1.1 g) and dimethyl sulfoxide (0.4 ml) are added 29% methanol solution of sodium methoxide (5.2 ml) for more than 6 minutes. After stirring at room temperature for 17 hours, methanol (6 ml) and guanidine hydrochloride (2.1 g) are added, the mixture is then heated under reflux for 5 hours. The solvent is evaporated with a steam bath at 140 ° C in for more than 30 minutes The oily solvent is added again to the residue and it is heated for an additional 30 minutes. The suspension is cooled to 20 ° C and the solid is filtered off, washed with methanol (2 mp) and water (3x50 ml), then dried under vacuum at 80 C. A yellow solid is obtained (1.58 g, 44%), 2.4 -Diamino-5- (8-di-methylamino-7-methyl-5-quinolinmethyl) pyrimidine, m.p. 221-225 s. Example 6
A. 8-Methoxyquinoline-5-carboxaldehyde.
To a solution of 0.76 g (4.39 mmol) of 8-hydroxyquinoline-5-carboxaldehyde in 5 ml of dimethyl sulfoxide, 0.24 g (4.4 mmol) of sodium methoxide was added, keeping the mixture under a nitrogen atmosphere. After stirring for 5 minutes, 0.56 g (4.4 mmol) of dimethyl sulfate is added. The reaction mixture is stirred for 1 hour and the solvent is removed under vacuum. The residue was partitioned between dichloromethane (100 ml) and 0.5 N. sodium hydroxide (50 ml); the organic layer is dried with water (100 ml), grown over anhydrous magnesium sulphate and concentrated to give 0.61 g (74%) of 8-methoxyquinoline-5-carboxaldehyde, mp. 121-122 C after recrystallization from ethanol-hexane (2:25).

Calculated: C 70,58; H 4.85; N 7.48.
With „HgNOi
Found,%: C 70.55; H 4.91; N 7.44.
B. 3-Anilino-2- (8-methoxy-5-quinolylmethyl) acrylonitrile.
The product of example 1A (0,) 1 g, 3.79 mmol) is dissolved in 2 ml of dimethyl sulfoxide together with 3-anilicopionitrile. 0.21 g (3.89 mmol) of sodium methylate are added to this solution, heated at 130 ° C for 15 minutes, then cooled and diluted with a mixture of water - ethanol 8: 1. The resulting solid product is mixed, extract This is boiled with ethyl acetate and recovered. 0.28 g (23%) of 3-anipino-2- (8-methoxy-5-quinolylmethyl) acrylonitrile is obtained. An additional 0.26 g (22%) is obtained from the filtrate by chromatography on silica gel.
B. 2,4-Diamino-5- (8-methoxy-5-quinolylmethyl) pyrimidine dihydrochloride.
To 10 ml of an ethanogenic solution of guanidine, obtained from 0.20 g (2.1 mmol) of guanidine hydrochloride and 0.12 g (2.2 mmol) of sodium methylate, was added 0.52 g (1.65 mmol) of 3-an- lino-2- (8-methoxy-5-quinolmethyl) acrylonitrile. The solution is heated under reflux for 0.5 h, and then 5 mp of 2-methoxy-ethiol is added. The temperature inside the reactor gradually rises to 120 ° C by distillation of ethanol, after which it is heated at this temperature for 1.5 hours. Then the hot mixture is filtered, and the resulting precipitate (0.19 g, 41% of the crude product) is recrystallized from 95Z- Horo ethanol in the presence of hydrochloric acid, resulting in the preparation of 2,4-diamino-5- (8-methoxy-5-quinolylmethyl) pyrimidine dihydrochloride (19 g), m.p. 252-255 С (decomposition).
B1 isleno,%: C 47.26; H 5.29;
18.37; C1 18.60. C ,, H, 5NsO -. 2CH1 1, 5 Found,%: C 47.19; H 5.33;
18.35; C1 18.58. N
N
Biological tests obtained under the conditions of the described method of pyrimidine derivatives were carried out.
These compounds have been found to be classified as low-toxic (LDjo, intraperitoneally to mice 500 610 mg / kg),
Table 1 shows the antibacterial activity of the tested compounds.
-Table 1

Medium effective dose in relation to S.aureus CN 491 bacteria in mice (mg / kg is equivalent to base)
6,510,7
4.7 ± 0.8
27.7 ± 2.1
Note. The compounds were administered to mice in aqueous solution as a forced feed after 1 and 6 hours after intraperitoneal infection with S. aureus P370 bacteria in an amount of 100 X, the average lethal dose.
The tests carried out showed that the compounds obtained by the proposed method have a lower effective dose in comparison with trimethoprim (4-6 times).
Comparison of trimethoprim (TMP) and 2,4-diamino-5- (7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl) pyrimidi- num (compound according to example 1) was carried out in experimental salmonellosis. tel
26 three-week bodies there orally administered doses of the culture of Salmonella dublin according to a method that causes symptoms close to the naturally occurring acute with almonellosis in the body, with a mortality rate of about 90%. Tel t was divided into four groups, each with 6–7 bodies. Two days after infection and up to 5 conservative days, the bodies there in groups 1-3 were administered daily injections of sulfadiosin (SDS) plus either Trimethoprim (TMP) or the compound of Example 1 in the doses indicated in Table 2, in which The results of mortality are also given.
SDS, even at doses of 40 mg / kg / day, does not affect mortality in this disease; therefore, mortality in groups 1–3 is low due to the simultaneous administration of benzylpyrimidine. In this regard, connectivity
Some of example 1 in doses of 1 mg / kg (group 2) npeBOcxoflHt NB in doses
1 mg / kg (group 1). Tel ta in a group
2 recovered much faster than the body in group 1. Even 0.5 mg / kg of the compound of example 1 (group 3) resulted in a decrease in mortality by

2
ten
compared with the group (TMP, 1 mg / kg), Therefore, the compound of Example 1 is approximately twice as effective as TMP for this disease syndrome in the body.
The results are shown in table 2.
The obtained results showed that the proposed compounds are of low toxicity, possess 4-6 times higher antibacterial activity than trimethoprim and, in addition, significantly reduce the mortality of the bodies when they are infected with salmonellosis.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining 2,4-diamino-5- - (substituted) pyrimidines of the general formula
N H2N4,
ABOUT
R, R.
C-Cc-Alksh1 or C, -C, -Alkoxy; 50
C, -C-alkoxy or di- (Su - 4-alkyl) amino group;
table 2
(X-Y) - -0-CHj- or, or their salts, characterized in that guanidine or its salt is reacted with a compound of the formula
AT,
Vg
where R ,, R, and (X-Y) have the indicated meanings
CN or CN
(I
-CH-CH (OR3), - C CH-R4
where R, - C, -CZ-alkyl;
R - C-C-alkoxy anilino or
morpholino,
and the chelating product is isolated in free form or as a salt.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8036135|1980-11-11|

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