DE1085884B - Process for the preparation of pyrimido [4,5-d] pyrimidines - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of new pyrimido [4,5-d] pyrimidines and their salts with acids. As free bases, these compounds have the formula

Method of manufacture
of pyrirnido [4,5-d] pyrimidines

.N,

NH ₂

in which R is hydrogen or an NH ₂ , acylamino, lower alkylamino, di-lower alkylamino or aralkylamino group, ζ. B. a benzylamino or halobenzylamino radical, also an anilino or lower alkyl mercapto group or an amino group which is part of a heterocyclic ring, and R _{1 is} hydrogen, an NH ₂ - or a lower alkyl group.

These compounds are prepared by adding a 4-amino-5-cyanopyrimidine of the formula

Applicant:

Parke, Davis & Company,
Detroit, me. (V. St. A.)

Representative: Dr.-Ing. F. Wuesthöff, Dipl.-Ing. G. Pulse

and Dipl.-Chem. Dr. rer. nat. E. Frhr, v. Bad luck man,

Patent Attorneys, Munich 9, Schweigerstr. 2

Claimed priority:
V. St. v. America April 10, 1957 and March 4, 1958

H ₂ N

NC

with a guanidine or an amidine or an amide of an aliphatic carboxylic acid and optionally obtained 2-lower alkylmercapto-pyrimido [4,5-d] pyrimidines in a manner known per se into the corresponding 2-lower alkylamino compounds and / or obtained pyrimido [4,5-d] pyrimidines converted into salt with acids. In general, the reaction can be carried out in the absence of a solvent or when carried out with a Guanidine or an amidine using a non-reactive organic solvent, e.g. B. Alcohol or 2-ethoxyethanol. The reaction temperature is not particularly critical. The process is preferably carried out at the reflux temperature of the reaction mixture. The preferred one The range for the reaction with formamide is from 130 to about 210 ° C., for the reaction with a guanidine or an amidine between 80 and 130 ° C. In general, the ratio of the reactants can be varied widely. Amides are preferably used in a substantial excess over the equimolar Amount applied as they serve as suitable solvents in most cases. When implementing with an approximately equivalent amount of a guanidine or amidine is used.

Robert F. Meyer, St. Clair Shores, Mich.,

and Milton L. Hoefle,

Big Pointe Woods, Me. (V. St. A.),

have been named as inventors

That the products according to the present invention have a much better diuretic effect than the known Have diuretic theophylline, can be seen from the following comparison tests. To determine the For diuretic effects, the compounds in question were administered to rats that were given a saline solution had gotten a drink. The rating of diuretic effectiveness is measured by the total volume urine excretion over the course of 24 hours. The results were measured at the end of 24 hours as

1 - \ - moderate effectiveness,

2 -f- medium effectiveness,

3 + good effectiveness,

4+ excellent effectiveness.

The results of this comparison are shown in the table below.

009 568/333

link dosage
mg / kg
body
weight degree of
activity
from 0 to
24 hours Theophylline 100 1 + Theophylline 200 six out of nine
Rats died
after 6 to 24
hours 2,5-diaminopyrimido
[4,5-d] pyrimidine 40 4 + 4-aminopyrimido [4,5-d] pyr-
imidine 100 3 + 5-amino-2-methylaminopyr-
imido [4,5-d] pyrimidine 50 3 + S-Animo-2-dimeth.ylamino-
pyrimido [4,5-d] pyrimidine 50 3 + 5-Amrao-2-benzylaminopyr-
imido [4,5-d] pyrimidine 50 4 + S-amino ^ -propylaminopyr-
imido [4,5-d] pyrimidine 50 3 +

The compounds obtainable according to the invention show a marked diuretic activity when administered orally. They are therefore important as diuretics. 2 ₎ 5-Diaminopyrimido [4 _J 5-d] pyrimidine, 5,7-diamino-2-ethylmercaptopyrimido [4,5-d] pyrimidine and 2-benzylamino-5,7-diaminopyrimido [4 , 5-d] pyrimidine. The compounds are also useful as intermediates for the preparation of other pyrimido [4,5-d] pyrimidine compounds. The compounds occur in some cases in a hydrated form. When used, the compounds obtainable according to the invention can be used as free bases or in the form of non-toxic salts which are formed by mixing the free base with a large number of inorganic and organic acids. These acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, acetic acid, benzoic acid, citric acid, maleic acid, malic acid, gluconic acid, ascorbic acid and related acids.

The invention is illustrated by the examples.

example 1

27 parts of 2,4-diamino-5-cyanopyrimidine are dissolved in 100 parts of formamide and the mixture is heated for 30 minutes to reflux temperature. The reaction mixture is cooled, 100 parts of ethanol are added and the mixture is filtered and washes the residue with 100 parts of ethanol to remove traces of formamide. The accruing 2,5-diaminopyrimido [4,5-d] pyrimidine monohydrate can be cleaned by dissolving it in 400 parts of 1N hydrochloric acid, decolorized by adding 1% charcoal, filtered and the filtrate neutralized with concentrated ammonia. The resulting solid mass is filtered off and washed successively with 200 parts of water and 100 parts of ethanol and dried in a vacuum oven at 60 ° C, F. above 300 ° C. The compound has the formula

- NH,

H ₉ O

NH ₂

Example 2

A solution of 10 parts of 4-amino-

2- (ethylthio) -5-cyanopyrimidine and 25 parts of 25 ° / ₀ strength aqueous methylamine in 40 parts of alcohol for 4 hours in an autoclave at 140 ° C., the mixture is cooled and nitrided from the resulting precipitate. This pale yellowish mass is 4-amino-2-methylamino-5-cyanopyrimidine, mp 230 to 232 ° C.

A mixture of 3 parts of 4-amino-2-methylamino-5-cyanopyrimidine and 8 parts of formamide is heated to 180 to 190 ° C. for 2 hours. The reaction mixture is decanted, poured into 30 parts of ethanol and filtered. The filter cake is washed with 60 parts of hot ethanol. The compound is then dissolved in 30 parts of 1η hydrochloric acid with heating. The acidic solution is treated with V ₂ % charcoal and filtered hot. The Fütrat is cooled and the precipitated product is filtered off and dried. The compound is S-amino ^ -methylaminopyrimido [4,5-d] pyrimidine monohydrochloride, m.p. above 300 ° C.

Example 3

A mixture of 10 parts of 4-amino-2- (ethylmercapto) -5-cyanopyrimidine is heated and 25 parts of Pi-

peridine in 40 parts of ethanol in an autoclave at 140 ° C. for 4 hours. After cooling, the 4-amino-2-piperidino-5-cyanopyrimidine is nitrated off and dry, m.p. 212 to 214 ° C.

A mixture of 23 parts of 4-amino-2-piperidino-5-cyanopyrimidine is heated and 50 parts of formamide at 180 to 185 ° C. for 5 hours. The reaction mixture is cooled and the 5-amino-2-piperidmopyrirnido [4,5-d] pyrimidine formed is filtered off and washes it with 200 parts of hot ethanol. The product can be purified by dissolving it in 100 parts of 2η-hydrochloric acid, Treated with charcoal, filtered and by adding concentrated ammonia until alkaline reaction the solution fails. The product is filtered off and dried, at a temperature above 300 ° C.

Example 4

A mixture of 5.5 parts of 4-amino-5-cyanopyrimidine

and 15 parts of formamide are heated to 190 ° C. for 30 minutes and then cooled. The 5-aminopyrimido- [4,5- d] pyrimidine is filtered off and washed with isopropanol, F. above 310 ° C.

Example 5

A solution of 18 parts of 4-amino-2- (ethylmercapto) -5-cyanopyrimidine is heated and 22 parts of benzylamine for 6 hours at 135 to 145 ° C. After cooling, the product 4-amino-2-benzylamino-5-cyanopyrimidine is crystallized from ethanol to, m.p. 176 to 178 ° C.

A solution of 5 parts of 4-amino-2-benzylaminocyanpyrimidine and 10 parts of formamide are heated to 180 ° C. for 4 hours. After cooling, the mixture is added Add 50 parts of ethanol and collect the product by filtration. The 5-amino-2-benzylaminopyrimido [4,5-d] -

pyrimidine can be purified by recrystallization from ethanol, mp 285 to 287 ° C.

Example 6

9.6 parts of guanidine hydrochloride are added to a solution of 5.4 parts of sodium methoxide in 200 parts absolute ethanol. 18 parts of 4-amino-2- (ethylmercapto) -5-cyanopyrimidine are then added and the reaction mixture is stirred for 18 hours at reflux temperature. After cooling, the product is filtered off and by dissolving in 200 parts of hot 2 η hydrochloric acid, treating with decolorizing charcoal and neutralizing with ammonia

niak cleaned. The product is filtered off, washed with 50 parts of water and dried in a vacuum oven at 60 ° C. The 5,7-diamino-2- (ethylmercapto) pyrimido [4,5-d] pyrimidine obtained can be further purified by recrystallization can be purified from 2-ethoxyethanol, F. above 300 ° C.

The above-mentioned guanidine hydrochloride can be replaced by 12.2 parts of methylguanidine sulfate or 13.6 parts of 1,1-dimethylguanidine sulfate be replaced. In both cases the same compound is 5,7-diamino-2- (ethylmercapto) -pyrimido [4,5-d] pyrimidine obtain.

The mixture is heated 5 parts of 5,7-diamino-2- (äthylmercapto) pyrimido [4,5-d] pyrimidine, 20 parts of 25 ° / ₀ strength aqueous methylamine and 50 parts of 2-ethoxyethanol in an autoclave for 4 hours at 140 ° C The reaction mixture is cooled and the 5,7-diamino-2-methylaminopyrimido [4,5-d] pyrimidine is filtered off. The compound can be purified by suspending it in 200 parts of boiling 2-ethoxyethanol and filtering the still hot suspension, mp above 300 ° C. ao

Example 7

9.6 parts of guanidine hydrochloride are added to a solution of 5.6 parts of sodium methoxide in 200 parts 2-ethoxyethanol. Then 13.5 parts of 2,4-diamino-as are added 5-cyanopyrimidine is added and the reaction mixture is heated to reflux temperature for 20 hours and filtered hot. The 2,5,7-triarriinopyrimido [4,5-d] pyrimidine can be purified by dissolving it in 600 parts of boiling water with 20 parts of concentrated hydrochloric acid, with Treated decolorization charcoal and filtered. The product separates out as monohydrochloride monohydrate on cooling from, F. above 300 ° C.

The following diaminopyrimidopyrimidines can be prepared in the same way by of guanidine hydrochloride, sodium methoxide, 2-ethoxyethanol and the aminocyanpyrimidines below goes out.

4-amino-2-anilino-5-cyanopyrimidine

4-amino-2-piperidino-5-cyanpyr-
imidine

4-amino-2-benzylamino-5-cyanopyr-
imidine

4-amino-2-dimethylamino-5-cyanpyr-
imidine

5,7-diamino-2-ani-pyrimido- [4,5- d] pyrimidine

5,7-diamino-2-piperidinopyrimido
[4,5-d] pyrimidine

5,7-diamino-2-benzylaminopyrimido
[4,5-d] pyrimidine

5,7-diamino-2-dimethylaminopyr-
imido [4,5-d] pyrimidine

anhydrous ethanol, adds 18 parts of 4-amino-2- (ethylmercapto) -5-cyanopyrimidine and the reaction mixture is stirred for 24 hours at reflux temperature and filtered while hot. The 5-amino-7-methyl-2- (ethylmercapto) pyrimido [4,5-d] pyrimidine obtained is purified by slurrying it in 300 parts of hot water and filtering to remove any inorganic salts to separate. The compound can be further purified by recrystallization from 2-ethoxyethanol, F. 279 to 280 ° C.

The preparation of the 4-amino-5-cyanopyrimidines used as starting materials should not be protected here be asked.

Claims (3)

Patent claims: 1. A process for the preparation of pyrimido [4,5-d] pyrimidines of the formula 35 above 4 <> 300 ⁰ C 45 above 300 ⁰ C 294 to 295 ° C . above 300 ⁰ C Example 8 9.5 parts of acetamidine hydrochloride are added to a solution of 5.4 parts of sodium methoxide in 200 parts NH ₂ wherein R is hydrogen or an NH ₂ -, acylamino, lower alkylamino, di-lower alkylamino, aralkylamino, anilino or lower alkyl mercapto group or an amino group which is part of a heterocyclic ring, and R _{1 is} hydrogen or an NH ₂ - or mean a lower alkyl group and the salts of these compounds with acids, characterized in that a 4-amino-5-cyanopyrimidine of the formula i-R H ₂ N NC with a guanidine or an amidine or amide of an aliphatic carboxylic acid and optionally obtained 2-lower alkylmercapto-pyrimido [4,5-d] pyrimidines in a manner known per se into the corresponding 2-lower alkylamino compounds and / or the resulting pyrimido [4,5-d] pyrimidines are converted into salts with acids. 2. The method according to claim 1, characterized in that the reaction is carried out with formamide at a temperature in the range from 130 to about 210 ° C. 3. The method according to claim 1, characterized in that the reaction with an approximately equivalent amount of guanidine, mono- or dimethylguanidine or an amidine at a temperature im Range from 80 to 130 ° C. Considered publications:
German patent specification No. 845 940. © 009 568/333 7.60