FI59403C - REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC ANALYSIS 2,4-DIAMINO-5-BENZYLPYRIMIDINE - Google Patents

Description

^ ---- Γλ1 ANNOUNCEMENT

^ (11) UTLÄGG NI NOSSKRI FT 5 9 4 Ο 3 fejftS C (45) Patent .'V * y V) "O:“ 31 ^ ^ ^ (51) Ky.ik.3 / iBt.a.3 OO? D 239A9 FINLAND — FINLAND pi) pmn «tihiiiM« -htMiwakiita | 2980/73 (22) HtkamlipUvi - Antttknlngadtf 25-09-73 (23) AlkupiWt — GlWjh «* d» g 0 ^ .03-70 (41) Has become public - Blivlt offantlig 25-09-73 P «tanttl · J. r.Mfrlh.llltu. (44) N» «lY« k, «p« on). K »» M «« «-» n nrtmt- och r * gl * t «r« tyr * lMn '' Ainokin utl «| d odi utl.ikrfftan pubikarad April 30 (32) (33) (31) Pyy4 *« Y muoMmi »—B« | lr4 priority 06-03- 69 06.03.69, 16.05.69, 13.06.69 England-England (GB) 11908/69, II909 / 69, 25171/69, 3021 + 7/69 (71) The Wellcome Foundation Limited, 183-193 Euston Road, London NW1,

England-England (GB) (72) Ronald Morton Cresswell, Scarsdale, New York, John William Mentha, Harts-Dale, New York, Russell Seaman, Chappaqua, New York, USA (US) (7 * 0 Oy Kolster Ah (5 * 0 Process for the preparation of therapeutically useful 2,1 + -diamino-5-benzylpyrimidines (Patent 53969) The present invention relates to a process for the preparation of therapeutically useful 2, U-diamino-5-benzylpyrimidines of the general formula R1 r2 NH2 = ¾ - <IX> 12-3 .....

wherein R, R and R are the same or different and each is a hydrogen or halogen atom or a methyl, methoxy or benzyloxy group, or R and R may together form a methylenedioxy group when R1 is a hydrogen atom.

2,1 + -Diamino-5-benzylpyrimidines have both antimalarial and bactericidal activity (J. Am. Chem. Soc. 73, (1951)) · The highest bactericidal activity has been observed in derivatives with electron 59403 donor substituents on the benzene ring and which are unsubstituted in the 6-position of the pyrimidine group. 2,7-diamino-5- (3 ', U', 5'-trimethoxybenzyl) pyrimidine, or trimethoprim (U.S. Patent 2,909,522), has a relatively broad antibacterial spectrum that includes several gram-positive species, but it is also active against strains of the species Proteus. Like other 2, Π-diaminopyrimidines, it is a competitor of folic and folinic acids in microorganisms in need of these nutrients and can be shown to inhibit dihydrofolate reduction in Streptococcus faecalis. A strong potent effect can be observed when this drug is co-administered with sulfonamides, as a result of the substantial inhibition of the biochemical event that causes F. de Novo synthesis of coenzymes. This potentiation can be demonstrated both in vitro and in experiments in mice using Staphylococcus and Proteus strains. 2, U-diamino-5-benzylpyrimidines including trimethoprim and 2, U-diamino-5- (3 ', N-dimethoxybenzyl) pyrimidine or diaveridine (U.S. Pat. No. 2,658,897) can be administered orally at 1- At doses of 30 mg / kg per day. These compounds are preferably administered in the form of a tablet to a mammal to be treated, in which case trimethoprim may be advantageously combined with sulpha-methoxazole, especially in the treatment of certain respiratory infections. Another example of this group is 2,1-diamino-5- (2, -methyl-U ', 5'-dimethoxybenzyl) -pyrimidine, or ormetoprim, which has been reported to have antibacterial activity and also has coccidiostatic properties when combined with sulfate. with dimethoxin.

A few years ago, a process for the preparation of 2, k-diamino-5-benzylpyrimidines was developed (see Stenbuck, Baltzly and Hood, J. Org. Chem. 28, (1963) 1983 and British Patent Publication No. 957,797). This process comprises the steps of: (i) condensing an aromatic aldehyde with a β-substituted propionitrile in the presence of both an alcohol as a solvent and a strong base to give a mixture of isomers of formulas (Ia) and (Ib), respectively;

CH

ArCHD + CH2 - CN -ArCH = C ^ (la)

0¾ - Ϊ ^ CH2Z

^ CN

+ ArCH2 - (Ib)

^ "CH

wherein Ar is an optionally substituted phenyl group, Y is an alkoxy, thioalkyl or dialkylamino group, and Z is a group Y or an alkoxy group derived from a solvent alcohol, and (ii) either a pure "benzal" isomer (Ia) or a "benzal Reacting a mixture of "- and" benzyl "isomers (Ia) and (ib) with guanidine to give a 5-benzylpyrimidine of formula

ArCK2- where Ar means the same as above.

Although it was known that the intermediate obtained in the first step is a mixture of isomers of formulas (Ia) and (ib), only the "benzal isomer (Ia) could be separated in crystalline form after a few purification steps. Both isomers are assumed to be in equilibrium when prepared under basic conditions and further reacting with guanidine as described above, but it is not clear which isomer mainly reacts in the second step.

Unfortunately, significant losses also occurred due to the formation of polymers and colored impurities, especially in cases where the phenyl ring of the isomers was unsubstituted in the para-position.

Further reaction of mixtures of derivatives and isomers according to British Patent Publication No. 957,797 provided the desired 2, U-diamino-5-benzylpyrimidines in only 25-1 + 5% yield, and given the importance of the final products and the difficulties caused by the by-products and impurities are the researchers also looked for other manufacturing methods. For example, British Patent Publication No. 1,132,082 comprises a process comprising the steps of: (a) reacting acetylthymine with N-bromosuccinimide to form acetylbromothymine, (b) condensing this product with substituted benzene, (c) reacting the resulting product with a halogen. and (d) amination of the halogen derivative. However, this method has the disadvantage that acetylbromothymine is expensive to prepare, condensation with the benzene compound does not provide the intermediate in high yield, and the last step requires treatment under pressure, and even then the yield is usually low.

Subsequent developments have shown that the polymer formation occurring using the process described in British Patent No. 957,797 could be prevented or significantly reduced in the case of the derivatives of compounds (Ia) and (Ib) / 3-alkoxy by temporarily satisfying ethylene double bond with alkoxide dissolved in alcohol 59403. This provides the corresponding acetal of formula (II), e.g. according to the following reaction scheme:

^ CN XCN

ArCH = C - ^ ArCH „- C

«^ - 2 ^ CH2OMe ^ CHOMe (I'a) (l'b)

MeOH + sup. NaOMe ____CN (II)

ArCH2 - CH

CH (0Me) 2

When the acetal (II) is then treated with an alcoholic solution of guanidine, alkaline conditions are thought to catalyze the re-formation of the double bond, initially to form (I'b), and the intermediate can thus react with guanidine to give the desired 5-benzylpyrimidine.

The acetals of formula (II) can also be prepared by condensing the corresponding aromatic aldehyde with 3,3-dialkoxypropionitrile and preferably catalytically reducing the 3,3-dialkoxy-2-benzalopropionitrile intermediate thus obtained.

The aforementioned British Patent Publication No. 957,797 also describes (Example IU) the reaction of veratrial aldehyde with N-dimethylaminopropionitrile in the presence of sodium in ethanol to give 3-dimethylaminoveratra-linitrile (lii) and β-ethoxyveral n catches.

Me0 x. mEQ

J ~ \ S *

MeO-V y — CH = C MeO ('-CH = C

\ - / ^ CH2NMe2 \ _ / ^ CHgOEt (III) (IV)

It is shown in the example that this mixture was then cyclized with guanidine to give 2, U-diamino -5- (31,1 * * -dimethoxybenzyl) -pyrimidine. It should be noted that both of the above compounds (III) and (IV) are "benzal derivatives.

It has been found that N-substituted β-amino-β-benzylacrylonitriles of formula VIII

5 59403 R1 R2 - y? \ ^ CN 5 (VIII) 12 3 5 wherein R, R and R are as defined above and R and G are as defined below, can be prepared quite easily under varying conditions, and that the products obtained are not only substantially free of the corresponding "benzal" isomer as an impurity, but also have unexpected stability and the ability to retain their spatial structure even under very different reaction conditions. The "benzyl" space structure of these compounds has little or no tendency to the "benzal" form prepared and disclosed in British Patent Publication No. 957,797. In addition, β-amino-benzylacrylonitriles are chemically reactive and can be advantageously modified by Formula IX. 2,4-diamino-5-benzylpyrimidines by reacting them with guanidine. Said processes for the preparation of starting materials of the formula VIII are described in Finnish Patent Publication Nos. 55,180, 55,495 and 55,496.

The process according to the invention for the preparation of the compounds of the formula IX is characterized in that the β-amino-° (-benzylacrylonitrile of the formula R1, R2- / TK, -0¾ -5¾-C7R-VIII). Wherein R, R and R are as defined above, and the group 6 59403 NR ^ R ^ is a secondary amino group in which one of R "* and R ^ is a hydrogen atom and the other is methyl, a benzyl, naphthyl or phenyl group optionally substituted by one or more halogen atoms or a methyl or methoxy group, or R 1 and R 2 together with an adjacent nitrogen atom form a morpholino, pyrrolidino, piperidino or N-methylpiperazino group, is reacted with guanidine or an acid addition salt thereof.

The present process starts from an N-substituted γ-amino-O- (benzylacrylonitrile compound of the formula VIII) which is substantially free of the impurity caused by the β-amino-θ (-benzylidenepropionitrile isomer), i.e. in general the benzal isomer cannot be detected. it is known that impurities adversely affect the yield and quality of the final benzylpyrimidine product, and the appearance of red and yellow discolouration may increase difficulties, especially separation in pure form, which is an absolute requirement then, in particular, by analytical methods detecting levels as low as 0,33% of the mixture. when the product is used clinically, and as a result, it is necessary to use several time-consuming and difficult and thus expensive cleaning steps.

N-amino-o (benzylacrylonitriles) and other similar N-amino-o-benzylacrylonitriles of the formula VIII are described as intermediates in Finnish Patent Publication No. 53,969. All these intermediates, and in particular the N-amino-o (-Benzylacrylonitriles can usually be readily prepared without any detectable "benzal" isomer by conventional analytical methods and can be further processed to give 2,4-diamino-5-benzylpyrimidines in very high yields with little or no polymer formation. it is very remarkable that the reaction with guanidine takes place easily under mild 7 59403 conditions and both the preparation and further processing of the amino-O (benzylacrylonitrile intermediates of formula (VIII) can be carried out within hours rather than weeks.

In the formula (VIII), the halogen atom may be a chlorine, bromine, fluorine or iodine atom.

κ is preferably a methoxy group (in the para position) and one or both of R and R are methoxy groups (in the meta position).

The N-amino group NR 1 R 2 in the formula (VIII) is preferably an unsubstituted anilino group. Other suitable groups include o- and p-toluidine, p-anisidine, p-chloroaniline, 2,5-dichloroaniline and 3,4-dichloroaniline.

The pyrimidine products of formula (IX) are obtained in satisfactorily good yield, as well as polymers and colored impurities without impurity. These factors are very important, as the current requirements for the purity of pharmaceutical products are very high, and these products must be manufactured in a very pure form and, of course, at a reasonable cost.

The β-amino-β-benzylacrylonitriles are preferably reacted with guanidine in a suitable lower alcoholic solvent, e.g. methanol, ethanol or isopropanol, at elevated temperatures. It is highly preferred that the reaction be carried out under reflux at the cooling temperature, but useful rates have also been found at lower temperatures up to room temperature. In particular, it has been found that the reaction takes place at reflux temperature very easily, lasting hours rather than weeks.

Although other β-amino-β-benzylacrylonitriles of formula (VIII) have a lower reactivity with guanidine than those with a β-anilino group, such as morpholino derivatives, especially in alkanols, it has been found that it can be The reaction is slow at temperatures below 140 ° C, but occurs rapidly at about 160 ° C and above. or in the vicinity thereof, and if the preceding reaction step has also been carried out in the same medium, it is not necessary to separate the N-amino-o-benzyl-acrylonitrile intermediate, although this separation is usually preferable because in this way purer benzylpyrimidine is obtained.

All the final products obtained as described above have either a bactericidal activity or a potentiating property, although the degree of such activity and the intensity of the potentiating effect may vary depending on the substitution and the purpose for which these compounds are used. In addition, these products themselves can be used as starting materials for the preparation of other derivatives and analogous compounds by reacting the functional groups therein. Thus, for example, benzyloxy-benzyl derivatives can be converted to the corresponding hydroxy-benzyl derivatives by hydrogenation or alkylated hydroxy-benzyl derivatives to give the desired alkoxy-benzyl-substituted compounds.

The process according to the present invention is very advantageous when the phenyl group is a 3,4-dimethoxy, 3,4,5-trimethoxy or 2-methyl-4,5-dimethoxy group, since then very valuable products are formed, namely diaveridine. , trimethoprim or ormethoprim.

The following examples illustrate the invention.

9 59403

Example 1 a) [3-Anilino-C1 {-3, * +, 5 ”trimethoxybenzylacrylonitrile (32 g) and a solution of guanidine hydrochloride (19 g) and sodium methoxide (13 g) in denatured ethanol (100 ml) were heated to reflux for 2 l / For 2 hours, the solvent (31 ml) was evaporated and the mixture was cooled to 5 ° C. The obtained 2, U-diamino-5- (3 ', 1' ', 5'-trimethoxybenzyl) pyrimidine crystals were collected and washed with denatured ethanol and acetone. Weight 27 g (9 * +%)> m.p. 198-200 ° C.

Using methanol instead of denatured ethanol gave 2,1-diamino-5- (3 ', 1 +', 5'-trimethoxybenzyl) pyrimidine in 86% yield after refluxing for 6 hours, and using isopropanol the reaction took more than 2 hours and the yield was 78%.

b) by the method according to a) β-2, U-dimethylanilino-o (-3,1 +, 5-trimethoxybenzylacrylonitrile was converted into 2,14-diamino-5- (3 ', U1,5-trimethoxybenzyl) to pyrimidine in U hours in a yield of $ 92, mp 200 ° C

c) by the method according to a) / 3-3,1 +, 5'-trimethoxyanilino - <* - 3,1 +> 5 "trimethoxybenzylacrylonitrile was converted into 2,1 + -diamino-5- (3 ', 1 +', 5'-trimethoxy) -benzyl) to pyrimidine within 3 hours in more than 90% yield. 200 ° C

d) by the method according to a) β-2,5-dichloroanilino-o (-3, J +, 5-trimethoxybenzylacrylonitrile was converted into 2,1-diamino-5 '(3', 1 + ', 5'-' trimethoxybenzyl) to pyrimidine in 1 1/2 hours in $ 95 yield, mp 200 ° C

e) by the method of a) β-1-naphthylamino-o (-3,1 +, 5-trimethoxy-benzylacrylonitrile was converted to 2,1 + -diamino-5- (3 ', U', 5'-trimethoxybenzyl) -pyrimidine within several hours in 72% yield, mp 200 ° C

f) by the method of a) β-anilino-β-3, U-dichlorobenzylacrylonitrile was converted to 2, β-diamino-5- (3 ', 1 +'-dichlorobenzyl) pyrimidine, m.p. 237-239 ° C. Yield 29%.

g) by the method according to a) β-anilino-Oi-2-iodide The acrylonitrile was converted to 2,1 + -diamino-5- (2, -iodobenzyl) pyrimidine, m.p. 265 ~ 267 °. Yield 28% by the method according to h) a) β-anilino-O-3-iodobenzylacrylonitrile was converted into 2,2,4-α-18111010-5- (3 * -iodobenzyl) pyrimidine, m.p. 220.5 ”222 °. Yield 51% i) by the method of a) β-anilino-of-1-iodobenzylacrylonitrile was converted to 2, U-diamino-5- (U'-iodobenzyl) pyrimidine, m.p. 2U6-2U8 ° C. Yield 66% by the method of j) a) β-anilino-α-2-bromobenzylacrylonitrile was converted to 2,2'-diamino-5 '(2'-bromobenzyl) pyrimidine, m.p. 2U8-250 ° C. Yield 30%.

10 59403

Example 2

The procedure was as in Example 1a), but using β- (p-methylanilino) -o ((3,5-trimethoxybenzyl) acrylonitrile, which was converted to 2,1 + -diamino-5- (3 ', 5, -trimethoxybenzyl) pyrimidine by heating at reflux for 2 hours Yield 90% mp 200 ° C.

Example 3

The procedure was as in Example 1a), but using β- (p-chloroanilino) -O ((3,1 *, 5, -trimethoxybenzyl) acrylonitrile modified to 2,1 + -diamino-5 - (3 ', U', 51 -trimethoxybenzyl) pyrimidine by heating under reflux for 2 hours, yield 90%, mp 200 ° C.

Example 1+

The procedure was as in Example 1a), but using N- (p-methoxyanilino) - <X (3,1 +, 5-trimethoxybenzyl) acrylonitrile, which was converted to 2,1 + -diamino-5- (3 ', 5'-trimethoxybenzyl) pyrimidine. by refluxing for U 1/2 hours. Yield 90% \ m.p. 200 ° C.

Example 5

The procedure of Example 1a) was repeated using [5-anilino-ol-S, N-dimethoxybenzylacrylonitrile (29 g) to give 2,14-diamino-5- (3 ', 1''-dimethoxybenzyl) pyrimidine. Yield 93% \ m.p. 230-233 ° C.

Example 6

The procedure of Example 1a) was repeated using β-anilino-1H-piperonylacrylonitrile (28 g) to give 2,6-diamino-5-piperonylpyrimidine. Yield 90% \ m.p. 252-253 ° C (recrystallized from denatured ethanol).

Example 7

The procedure of Example 1a) was repeated using β-anilino-o-2-methyl-1,5-dimethoxybenzylacrylonitrile (16 g) and after refluxing for 18-20 hours, 2,4-diamino-5- (2'-methyl) was obtained. -1 + ', 5'-dimethoxybenzyl) pyrimidine. Yield 92% \ m.p. 230-231 ° C.

Example 8

The work-up as in Example 1a) was repeated using β-anilino-o ((3'-dimethoxy-5-bromobenzyl) acrylonitrile (62 g) to give 2, k-diamino-5- (31'-dimethoxy-5 '). bromobenzyl) pyrimidine Yield 68% mp 203.5-205 ° C.

Example 9

The work-up of Example 1a) was repeated using β-anilino-of-p-benzyloxybenzylacrylonitrile (25 g) to give, after refluxing for 1 hour, 2,1 + -diamino-5- (p-benzyloxybenzyl) -pyrimidine. Weight 20.5 g · This was converted to its acetate salt by treatment with acetic acid. Yield 92%; mp. 202-20U ° C.

11 59403

Example 10/3-Morpholino-α-3,1 +> 5-trimethoxybenzylacrylonitrile (32 g), guanidine carbonate (3I + g) and dimethyl sulfoxide (50 ml) were heated together at 160 ° C for 1 hour with good stirring. The reaction mixture was cooled and poured into ice water (200 ml) to give 2,1 + -diamino-5- (3 ', 1' ', 5') - trimethoxybenzyl) pyrimidine, which was collected and washed with water and acetone. Yield 80 m.p. 196-198 ° C.

Example 11

The treatment of Example 10 was repeated using β-N-methylpiperazine-Sino-O ((3,1 +, 5-trimethoxybenzyl) acrylonitrile to give 2,1 + -diamino-5- (3 ', 1 +', 51-trimethoxybenzyl) Yield 75% mp 198-200 ° C.

Example 12

The work-up of Example 10 was repeated using N-piperidino-of-1,1 ', 5-trimethoxybenzylacrylonitrile to give 2,1 + -diamino-5- (3', 1 + ', 5'-trimethoxybenzyl) pyrimidine. Yield 73 m.p. 200 ° C.

Example 13

The treatment of Example 10 was repeated using β-pyrrolidino-3,1,5-trimethoxybenzylacrylonitrile to give 2,1 + -diamino-5- (3 ', 1' ', 5'-trimethoxybenzyl) pyrimidine. Yield 69% \ m.p. 200 ° C.

Example ll +

The work-up of Example 10 was repeated using 1-benzylamino-α-3,5-trimethoxybenzylacrylonitrile to give 2,1 + -diaraino-5- (3 ', 1 * 1'5'-trimethoxybenzyl) pyrimidine. Yield 73% \ m.p. 200 ° C.

Example 15

The treatment of Example 10 was repeated using β-morpholino-o (-3,1'-dimethoxybenzylacrylonitrile to give 2,1 + -diamino-5- (3 ', 1 +' - dimethoxybenzyl) pyrimidine. Yield 78 mp 230-233 ° C.

Example 16

The work-up of Example 10 was repeated using β-morpholino-β-piperonylacrylonitrile to give 2,1 + -diamino-5-piperonylpyrimidine. Yield 75% i m.p. 252-253 ° C.

Example 17

The work-up of Example 10 was repeated using β-morpholino-of-3,1 + -dimethoxy-5-bromobenzylacrylonitrile to give 2,1 + -diamino-5- (3,1'-dimethoxy-4-bromobenzyl) -pyrimidine. 5% mp 203-205 ° C.

Example 18

A solution of guanidine in ethanol / methanol was prepared by dissolving guanidine hydrochloride (II + g) in ethanol / methanol (about 95/5) (80 ml), adding sodium methylate (10 g) with stirring and filtering off the salt formed. To the solution was added β-methylamino-of- (3,1+, 5-trimethoxybenzyl) acrylonitrile and 59403 (13 g). The mixture was heated under reflux for 13 days and then cooled. The resulting solid was collected by filtration, washed successively with cold ethanol, acetone and ether and dried to give 12 g (8%) of 2, ia-diamino-5- (3,5,5-trimethoxybenzyl) pyrimidine, m.p. 196-200 ° C.

Claims (3)

13 59403 A process for the preparation of therapeutically useful 2,1 + -diamino-5-benzylpyrimidines of the general formula R 1 nh 2 2 y-1-v N - N 2 - / '-N 12.3 wherein R, R and R are the same or different and each is a hydrogen or halogen atom or a methyl, methoxy or benzyloxy group, or R and R may together form a methylene dioxide group when R is a hydrogen atom, characterized in that the N-amino-O-benzylacrylonitrile of the formula R1 y \ / cb 5 h ^ _ / ~ CH2 “C ^ c„ - ^ R6 <VIII) R 12 3 56 and R 1 are as defined above, and the group NR 7 R is a secondary amino group in which one of R 1 and R 2 is a hydrogen atom and the other is a methyl, benzyl, naphthyl or phenyl group optionally substituted by one or more halogen atoms or a methyl or methoxy group, tr g ...... or R 1 and R 2 together with the adjacent nitrogen atom form a morpholmo, pyrrolidino, piperidino or N-methylpiperazino group n, is reacted with guanidine or an acid addition salt thereof. Process according to Claim 1, characterized in that the β-anilino-β- (3,5-trimethoxybenzyl) acrylonitrile is reacted with guanidine to give trimethoprim. Process according to Claim 1, characterized in that the β-amino-β-benzylacrylonitrile has a β-amino substituent other than β-anilino and that this compound is reacted with guanidine in the form of a carbonate in a polar, aprotic solvent such as dimethyl sulfoxide, preferably at reflux temperature.