DE2327637A1 - N-OXYDE OF A BENZYLPYRIMIDINE - Google Patents

Description

The invention relates to the N-oxides of a benzylpyrimidine, namely the N-oxides of 2,4-diamino - 5- (3-niethoxy-4,5-methyiendioxybenzyl) pyrimidine, i.e. the 2,4-diamino ~ 5- ( 3-methoxy-4> 5-methylenedioxy "benzyl) -pyrimidine-IL-oxide, the 2,4-diainino-5- (5- ^m ethoxy-4,5-methylenedioxybenzyl) -pyrimidine-N" -oxide and the pharmaceutical The compounds of the present invention are useful as potentiators of the antibacterial activity of sulfonamides such as H - (3,4-dimethyl-5-isoxazolyl) sulfanilamide, etc.

The connections in question can, as further described below, from the 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine can be obtained.

3 0 9 8 8 3 / 140t

Ur / 5.5.73

The preferred compounds of the present invention are the 2,4-diamino-5 - (3-methoxy-4,5-methylene dioxybenzyl) -pyrimidine-N -, - oxide and the pharmaceutically acceptable acid addition salts thereof.

According to the invention, the new compounds can thereby be obtained by the 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine subjected to N-oxidation and the bases obtained, optionally in acid addition salts convicted. The N-oxidation can be known per se Methods using common N-oxidizing agents be carried out, for example by means of perbenzoic acid and especially with m-chloroperbenzoic acid.

The N-oxidation can, for example, in an inert solvent, such as chlorinated hydrocarbons, for example chloroform. Methylene chloride, or in alcohols such as methanol or ethanol, or in dimethylformamide, dimethyl sulfoxide, water or preferably in dioxane. The reaction temperature conveniently lies in a range between Saumtemperatur and the boiling point of the solvent, advantageously between about 20 ° and about 100 ⁰ C. Preferably, the range is from about 40 to about 60 ⁰ C.

The N-oxides according to the invention can be isolated from the reaction mixture in a customary manner. When using has m-chloroperbenzoic acid or perbenzoic acid as the N-oxidizing agent it has proven to be useful to mix the reaction solution with a mixture of ethanolic HCl / ethyl ether to shake out. The precipitate of the amine salt can be separated from the benzoic acid by filtration.

The N-oxidation of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine usually leads to mixtures of N -, - and Ν, -oxides; such isomer mixtures are also

309883 / U01

if subject of the present invention.

These isomeric reaction products are conveniently separated and purified by chromatography, e.g. Column chromatography and / or recrystallization, preferably from polar solvents such as alcohols, water Etc.

The 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine used as the starting material can e.g. be obtained according to the following reaction scheme:

3 0 3 8 8 3 / U 0 1

H ₃ CO

• GH

CHO

CH,

^ Ö

III

Alkali metal alkoxide

H ₅ CO

CT ₂

CET

CH =

* 0

Alkali metal alkoxide

R ₁ OH

309883/140

According to the reaction scheme, an aldehyde of the formula IH is first reacted with a (3-lower alkoxypropionitrile of the formula XV in the presence of a lower alkali metal alkoxide, such as sodium methoxide or potassium ethoxide, and a lower alkanol of the formula R ₁ OH, such as ¹ methanol, ethanol, propanol, etc.) The reaction temperature is not critical, but it is generally between r *> 60 and "« 170 ^° C. This gives a compound of the formula V which can easily be converted into a by treatment with an alcohol of the formula R ^ OH Compound of the formula II is converted, this in the presence of a lower alkali metal alkoxide under anhydrous conditions. Here, too, reaction temperatures of about 60 to about 140 ^{0 are} suitable. The compound of formula II is then reacted with guanidine, optionally in the presence of a solvent Compound of the formula I is obtained in almost quantitative yield.

The aldehyde of formula III can be prepared according to methods known per se, e.g.

after the Rosenmund reduction (Organic Synthesis, I.C, S. 1352), or according to the method W. Bonthrone and J.W. Cornforth, <J. Chem. Soc. (c) 1202 (1969).

The IL and ΪΓ, oxides of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine form acid addition salts and such salts are also an object of the present invention. The ΪΓ-oxides can e.g. pharmacologically compatible organic or inorganic acids such as acetic acid, succinic acid, formic acid, Methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, Phosphoric acid, sulfuric acid, lactic acid etc. into the corresponding salts are converted.

309883 / U01

The new M-oxides are useful as antibacterial agents in combination with one or more sulfonamides, for example N - (3,4-dimethyl-5-isoxazolyl) -sulfanilamide, i-methyl - ^ - sulfanilamido-isoxazole, N - (2, 6-dimethoxy-4-pyrimidinyl) sulfanilamide, ΪΡ-ethoxyacetyl-N - (5-methyl-3-isoxazolyl) sulfanilamide, Ή - (4,5-dimethyl-3-isoxazolyl) sulfanilamide, N - (5, 6-dimethoxy-4-pyrimidinyl) sulfanilamide, etc. as antibacterial agents. The addition of a compound of the formula I to one of the sulfonamides mentioned above results in a remarkable potentiation of the antibacterial activity of the sulfonamide. Thus the compounds of formula I are useful as sulfonamide potentiators. The combination of a compound of the formula I and a sulfonamide can simply be mixed together ^! obtained; as explained below, such _{(combinations} can be performed, for example, in oral dosage forms.

The ratio of therapeutically active U-oxide to Sulphonamide can vary over a wide range. The combination can be from about 1 to about 50, for example Parts, preferably about 1 to about 20 parts of sulfonamide or salt of a sulfonamide and 1 part of one Contains N-Oxyds or salts thereof. The inventive Compounds can be in the usual pharmaceutical dosage forms, for example for oral or parenteral administration, be transferred. The usual pharmaceutical carrier materials, for example organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, etc. be used. The pharmaceutical preparations can be in solid form (e.g. tablets, coated tablets, Capsules, suppositories) or liquid form (for example

3098 8 3/1401

Solutions, suspensions or emulsions). That pharmaceutical carrier material can contain auxiliaries such as preservation, Contain stabilizers, wetting agents or emulsifiers, etc., but also salts to change the osmotic Pressure or as a buffer can be used. Finally, the dosage forms can also be different contain therapeutically active materials. The combination of N-Oxide and Sulfonamide can be found in dosage forms containing approximately 500 mg of a sulfonamide (respectively Salt thereof) and about 10 to about 100 mg of N-oxide (or salt thereof) contain, are brought. But there are also amounts of about 250 mg to about 750 mg sulfonamide (or salt thereof) and approx

-ι -

5 to about 150 mg N-Oxide (or salt thereof) in question. ·

The frequency with which such doses are administered to warm-blooded animals naturally depends on the dose and the respective circumstances.

As mentioned above, sulfonamides form salts, for example with pharmacologically acceptable bases, such as alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide, etc.

In the following examples, the temperatures are given in degrees Celsius, the parts denote parts by weight. -

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■ - " Example 1

Preparation of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl ) -pyrimidine-N -, - oxide hydrochloride and 2 ^ 4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-N ^ -oxide hydrochloride:

To a solution of 6 g of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine 8.7 g of m-chloroperbenzoic acid ($ 85) are added in portions in 105 ml of dioxane. The temperature rises to 45 °. You leave that Stand the reaction mixture at room temperature for 5 hours with stirring and then filter off the precipitate formed. After washing with 20 ml of cold dioxane, 1 g (16 $ yield ) 2,4-Diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-IL-oxide from melting point 236-237 ° on. The mother liquor is left to stand overnight with stirring and is cooled and the resulting precipitate is filtered off. 1.9 g ($ 30) of 2,4-diamino-5- (3-niethoxy-4,5-methylenedioxybenzyl) pyrimidine-N_-oxide are formed. The N -, - oxide is recrystallized from methanol, whereby a product with the melting point 249-250 ° is obtained. The N -oxide is recrystallized from water, a product with a melting point of 237-238 ° being obtained. The hydrochlorides of 2,4-diamino-5- (3-methoxy-4,5-metlaylenedioxybenzylI-pyrimidine-N-j-oxide and 2,4-diamino-5- (3-methoxy-4 »5 ^ methylenedioxybenzyl) pyrimidine N, oxide after recrystallization from methanol a melting point of 232-234 ° or 192-193 °.

3 09883/1

Example 2

Preparation of 3-methoxy-4,5-methylehdioxy-a-methoxymethy ! -cinnamonitrile.

3.8 g of sodium are dissolved in 120 ml of methanol at reflux temperature solved. 56 g of methoxypropionitrile and SDg 3- ^ fethory-4,5-methylenedioxybenzaldehyde are added and the mixture is refluxed in methanol for 5 hours. Tray cooling crystallized 3-methoxy-4,5-methylenedioxy-a-methoxymethyl cinnamonitrile in needles with a melting point of 115 °, yield 68 g ($ 83). To Recrystallization from methanol melts the product at 115.5-116.6 °.

Example 3

Preparation of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine. ■

12.8 g of sodium are dissolved in 185 ml of methanol with stirring dissolved at reflux temperature. 68 g of 3-methoxy-4,5-methylenedioxy-a-methoxymethylcinnamonitrile are added and keeps the mixture at reflux temperature for 48 hours. The reactants gradually dissolve and the solution turns dark in color. The reaction mixture is added to 500 ml of water, neutralized with 20 ml of acetic acid and then extracted three times with benzene (600, 50, 50 ml). The benzene layer will dried over sodium sulfate and filtered through activated charcoal. The solvent is distilled off in vacuo and the Distilled residue: boiling point 184-198 °, 1.5 mm Hg

22 The product is a viscous colorless oil of n = 1.5320 41 g of this are refluxed with 290 ml of a 1 molar methanolic guanidine solution for 1.5 hours. That Methanol is then removed by distillation (oil bath) at 160 ml and the residue is kept at this temperature for as long

"309883 / U0-1

23276 3 '/

held until it is a crystalline mass. The time required for this is 10-15 minutes. The reaction product is then suspended in water and filtered. Man receives 37 g (92 ^) of crude product with a melting point of 215 ° (unsharp). For the purpose of cleaning, the raw material is slurried in 120 ml of acetic acid and the slurry is heated. After cooling, the acetate crystallizes as white needles off, these are pressed on a suction filter and then dissolved in 250 ml of hot water. You clean the solution by means of activated charcoal and the 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine is precipitated with an excess of ammonia as the product with a melting point of 236-237 °, the yield is 28.5 g

Example 4

Capsules with the following composition are produced in the usual way:

N - (3,4-Dimethyl-5-isoxazolyl) sulfanilamide

2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-F -, - oxide

Lactose;

Cornstarch

Talk

Total

per capsule

250 mg 25th mg 68 mg 27 mg 5 m «

375

309883/1 AO 1

ORIGINAL IHSPECTED Example 5

The following tablets are used in the usual way Composition made:

per tablet

N -, (3,4-dimethyl-5-isoxazolyl) -

sulfanilamide. ~ 225 mg

2,4-Diamino-5- (3-methoxy-4,5-methylendiQxy "benzyl) -pyrimidine-H _: , -oxide 60 mg

Lactose '233 mg

Corn starch 100 mg

Gelatin 12 mg

Talk. 15 mg

Magnesium stearate 5 mg

Example 6

Suspensions of the following composition are prepared in the usual way:

per liter

Methyl paraben λ 0.9 Propyl paraben 0.5 NaEDTA - 0.1 Lactic Acid $ 85 8.3 ml 2,4-Mamino-5- (3-methoxy-4,5-methylene-
dioxybenzyl) pyrimidine-üL-oxide 5.1 Veegurn. 26.4 Sodium benzoate 2.5. Sucrose 400.0 Sorbo 110.0 Tragacanth-Penick Super Initial 3.5 Methocel MC 100 cps 0.3 Span 20 ". _
N - (3,4-Dimethyl-5-isoxazolyl) sulfanilamide 0.035 Ultra Pine 118.29 G-lycerin 125.0

309883 / U0

232763?

FD and C Yellow Uo. 5 0.016

Banana flavor Firmenich F 59.256A 0.16

Banana flavor ßivaudan F 4929 0.4

distilled water q.s. 1 liter

Example 7

The surprisingly increasing antibacterial activity of sulfonamides, for example of N - (3,4-dimethyl-5-isoxazolyl) sulfanilamide, after combination with 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-N, - or N, -oxide can be used in the case of various infections such as can be demonstrated as follows:

Swiss albino mice weighing 18 to 20 g were intraperitoneally lethal with 100 to 1000 minimal amounts Doses of various organisms infected. The inoculum was grown overnight from an appropriately diluted one Culture established. For all infections listed below except D. pneumoniae, S. pyogenes and K. pneumoniae, the inoculum was finally in 5% pig mucin created.

For all purposes of infection, the test animals were given 1.0 ml of the desired concentration of the respective sulfonamide-pyrimidine combination administered in liquid carboxymethyl cellulose by means of a stomach tube. The treatment included 6 single doses. Two doses (5 hours apart) were given on the day of infection and on the following day administered, followed by treatments on the second and third day after infection. The first dose was 5-10 minutes administered after infection. In the case of combinations, different concentrations of sulfonamide were present an inactive concentration of a potentiator.

3 0 9883 / U01

The observation period was 14 days. In the lifeblood of mice received during this observation period, the eventual was by means of culture on a suitable medium Presence of the various organisms detected.

The results are shown in Table I.

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Table I.

Antibacterial effectiveness of TST ~ ( 3,4-dimethyl-5-isoxazolyl) -sulfanilamide in combination with 2,4-diamino-5- (3-methoxy-4,5-ynethylenedioxyben2iyl) -pyrimidine-li ₁ - or N, - oxyd in the case of infected mäaaen.

organism

D. pneumoniae No. 6301 S. aureus Smith K. pneumoniae A P. vulgaris 190 S. typhosa P. 58a

Dose: mg / kg

2,4-diamino-5- (3-methoxy-

4,5-methylenedioxybenzyl) -

Increased activity of ^ - (J ^ -Dimethyl-5-iso2: azolyl) -sulf anilamide

pyrimidine-N-, -oxide (x-fold exponentiation) 50 > 5.4 10. 5.8 10 1.9 10 3.9 10 > 2

Increased activity (x-fold)

Dosia sulfonamide alone

Dose of sulfonamide in combination

^ Inactive dose of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-li ₁ -oxide applied alone.

Table I (continued)

Dose :, mg / kg Increased activity

.2,4-Diamino-5- (3-methoxy- from Er- (3,4-dimethyl-4,5-methylenedioxybenzyl) -. 5-isoxazolyl) sulfanilamide

Organism pyrimidine-N ^ -oxide (x-faohe potentiation)

Q D. pneumoniae No. 63OI 50> 1.7

£ J S. aureus Smith 10 2.1

^ro E. coli 257 50. 11.0

- ~ - K. pneumoniae A 10 '1.9

^ P. vulgaris 190 '10 ■ 2.2'

Ξ. S. typhosa P. 58a 10 ■ * wl, 0 vn

^a Increased activity (x-fold) dose sulfonamide (alone)

Dose of sulfonamide in combination

Inactive dose of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-N_-oxide ^

.. (alone) ■, ■, ■■ '. ·, Μ

Claims (6)

Claims Process for the preparation of the F-oxides of 2,4-diamino-5- (3-methoxy-4 »5-methylenedioxybenzyl) pyrimidine and of their pharmacologically acceptable acid addition salts, characterized in that 2,4-diamino-5- (3-meth.oxy-4,5-methylenedioxybenzyl) pyrimidine of N-oxidation subject, if desired, to a basic reaction product Converted into a pharmacologically acceptable acid addition salt. 309883 / U. 01 232763? 2. Process for the production of compositions with antibacterial properties, characterized in that one part of a U-oxide of 2,4-diamino-5- (3-niethoxy-4t5-niethylenedio3cybenzyl) pyrimidine is used as an active ingredient or a pharmacologically acceptable acid addition salt thereof, with about 1 "to about 50 parts of a sulfonamide or a salt thereof and with non-toxic, inert, therapeutically acceptable solid or liquid Carriers mixed. 309883/1401 3. Antibacterially effective composition, characterized by a content of about 1 to about 50 parts of a Sulfonamides or a salt thereof and approximately part of an N-oxide of 2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) pyrimidine or a pharmacologically acceptable acid addition salt thereof and a carrier. 30 9883 / 2321637 4. N-Oxides of 2,4-diamino ^ 5- (3-methoxy-4 »5-methylenedioxybenzyl) pyrimidine and their pharmacologically acceptable acid addition salts. 5 «2,4-diamino-5- (3-methoxy-4,5-methylenedioxybenzyl) -pyrimidine-N ^ -oxide and its pharmacologically acceptable acid addition salts. 6.2,4-diamino-5- (3-methoxy-4,5-methylenedioxybehzyl) -pyrimidine-li-oxide and its pharmacologically acceptable acid addition salts. 3098 83 / 14ΰ1