GB2116962A - Nitriles; pyrimidines - Google Patents

Abstract

2,4-Diamino-pyrimidines of the formula I <IMAGE> (R1-3 = H, alkyl, alkoxy, aralkoxy, alkylthio or two = alkylenedioxy) and their salts are prepared by reacting a compound of formula II <IMAGE> with guanidine or a salt thereof. The starting materials are prepared by reacting the corresponding compound in which the m-phenylenediamine residue is replaced by a piperazine ring with m-phenylenediamine, and the piperazine derivatives are prepared by reacting the corresponding aldehyde with N,N'-bis-(cyanoethyl)piperazine.

Description

SPECIFICATION New process for the manufacture of diamino-pyrimidines The present invention relates to a novel and improved process for the manufacture of 2,4-diamino pyrimidines of formula I

wherein R1, R2 and Rs each independently represent a hydrogen atom, a lower alkyl, lower alkoxy, aryllower alkoxy or loweralkylthio radical or any two neighbouring groups of the three groups R1, R2 and 133 may together form an alkylenedioxy radical and the remaining third a hydrogen atom, a lower alkyl, lower alkoxy, aryllower alkoxy, or loweralkylthio radical and their salts.

The lower alkyl groups are e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl or n-heptyl groups, preferably however, methyl, ethyl or n-propyl groups.

The lower alkoxy groups are e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy or n-heptyloxy, preferably, however methoxy, ethoxy or n-propyloxy groups.

When the two of the three groups, R1, R2 and 133 together represent an alkylene dioxy group, the alkylene radicals are ethylene or preferably a methylene radical forming ethylenedioxy or preferably a methylenedioxy-group.

Aryllower alkoxy groups are naphthyl or preferably phenyl lower alkoxy groups wherein lower alkoxy groups have the same meaning as defined earlier preferably they are benzyloxy radicals. In these groups the aryl ring may be substituted by one or more lower alkyl groups e.g. methyl or ethyl groups, lower alkoxy groups e.g. methoxy or ethoxy groups or halogen atoms e.g. chlorine and bromine atoms.

Loweralkylthio groups are e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl thio groups.

The term 'lower' used herein before or hereinafter in connection with the definition of organic compounds, groups and radicals, signifies that such compounds, groups and radicals contain up to an including 7 carbon atoms, preferably up to 4 carbon atoms.

2,4-Diaminopyrimidines described in this application all possess antibacterial properties. Among the compounds for which the present process is useful is the antibacterial agent 2,4-diamino-5-(3',4',5trimethoxybenzyl)-pyrimidin (trimethoprim) which has a broad spectrum of activity against the majority of gram positive organisms. Investigations into the antimicrobial activity of 2,4-diamino-pyrimidines have opened up new biochemical concepts which had far-reaching effects on the development of chemotherapeutic agents. Thus the combination of these compounds with sulfonamides have resulted in the introduction of potent antimicrobial agents capable of inhibiting two essential steps in the metabolic pathways in microorganisms. Such a sequential blockade has been responsible for the synergistic effect in potency as well as increase in breadth of therapeutic usefulness.

Thus the antibacterial effect of these combinations covers a wide spectrum of gram-positive and gram-negative organisms such as Staphylococcus, Streptococcus, Diplococcus, Corynebacterium, Clostridium, Pseudomonas, Enterococcus, Klebsiella, Neisseria, Salmonella, Proteus, etc. Similarly 2,4diaminopyrimidines are useful alone or in combination with other agents against certain protozoal infections, particularly certain strains of malaria, e.g. multiresistant strains of P.falciparum.

The potentiation of the activity of other antibacterial and antiprotozoal agents by 2,4-diaminopyrimidines may be demonstrated by in-vitro methods or by in-vivo experiments against experimental infections in animal models.

The invention relates especially to a process of manufacture of compounds of formula I, wherein R1, R2 and R3 each independently represents hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio or any two neighbouring groups of the three R1, 132 or R3 form a methylenedioxy- or ethylenedioxy radical and the remaining third substituent hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio or propylthio.

The invention relates especially to a process of manufacture of compounds of formula I, wherein R1, 132 and 133 each independently represents hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio or two of the three substitutents R1, R2 or 133 form a methylenedioxy- or ethylenedioxy radical and the remaining third substituent one of the meaning given for R1, R2 and 133.

Among the compounds prepared according to the process of this invention, in addition to 2,4-diamino-5 (3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim), particularly valuable as antibacterial agents and sulpha synergists are 2,4-diamino-5-(2-ethyl-4,5-methylenedioxybenzyl)-pyrimidine, 2,4-diamino-5-(2 methyl-4,5-methylenedioxybenzyl)-pyrimidine, 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl)-pyrimidine, 2,4-diamino-5-(2-methoxy-4,5-methylenedioxybenzyl)-pyrimidine,2,4-diam ino-5-(2,3-dimethoxy-4-methyl benzyl)-pyrimidine,2,4-diamino-5-(2-ethoxy-4,5-methylenedioxybenzyl)-pyrimidine,2,4-diamino-5-(2,4- dimethoxy-5-methylmercaptobenzyl)-pyrimidine,2,4-diamino-5-(3-methoxy-4,5-ethylenedioxy-benzyl)- pyrimidine and 2,4-diamino-5-(4-methoxy-5-methylmercaptobenzyl)-pyrimidine which in addition to possessing antibacterial activity themselves, synergise the antimicrobial activity of sulfonamides such as sulphamethoxazole, sulphadiazine or sulphaphenazole to the extent of 8 to 16 times.

In view of the importance of this class of compounds, several processes are known for their manufacture.

However, essentially all these processes utilise the concept of condensation of a ss-substituted propionitrile with an optionally substituted benzaldehyde in the presence of a strong base followed by condensation with guanidine in the form of an appropriate salt. Various modifications of this process have also been reported in German patents Nos. 1 445 176, 1 795 586,1 1 620729, 1 545966 and 1 545967.

It has now been found that compounds of the formula I wherein the substituents R1, R2 and R3 have earlier defined meanings, can be manufactured by a novel process involving a conceptually new approach and utilising hither-to unknown starting compounds.

Thus it has surprisingly been found that compounds of formula I may be obtained by reacting a compound of formula II

wherein Ra, R2 and 133 have the meanings defined under formula I, with guanidine or a salt thereof and optionally converting an obtained compound of formula I in its free form into an acid addition salt or converting an obtained compound of formula I as an acid addition salt into the free form thereof.

The free guanidine used for the reaction may be prepared in situ from a guanidine salt, for example from guanidine hydrochloride by reacting it with a base as for example an alkali-metal alkoxide in a lower alkanol such as sodium methoxide in methanol. The reaction is carried out in a very easy manner and the product is obtained in an excellent yield without contamination with polymers and coloured impurities.

Depending on the reaction conditions and/or the isolation procedure, the compounds of this invention may be obtained in the free form or in the form of their acid addition salts, salts are likewise included in the present invention.

Resulting salts can be converted in a known manner into other salts or into the corresponding free compounds, for example, by treating with bases, such as alkaline reagents, or suitable ion-exchange resins.

Acid addition salts may also be used as intermediates, for examples, by converting a free compound into a salt thereof, isolating the latter and liberating the free compound from the isolated salt or for identification purposes. They are primarily pharmaceutically acceptable, non-toxic acid addition salts such as those with inorganic acids, e.g. hydrochlooric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or with organic acids, such as aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic or sulphonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicyclic, embonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethylenesulfonic, halogenobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or N-cyclohexylsulfamic acid. Salts with acids, such as those mentioned above, are obtained, by usual method, for example by treatment of the free compound with an acid or with a suitable exchange preparation.

In view of the close relationship between the compounds in free form and in the form of their salts, whenever the free compounds or the salts are mentioned above or hereinafter, the corresponding salts and free compounds, respectively, are, whenever applicable and suitable likewise concerned.

The invention further includes any modification of the procedure, in which an intermediate product resulting at any stage of the process is used as the starting material and any remaining steps are carried out, or the process is discontinued at any stage, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, such as a salt thereof. The invention also includes any resulting new intermediate compounds.

Advantageously, one uses starting material, which lead to the preferred compounds previously mentioned.

Compounds of formula II are prepared by reaction of compounds of formula Ill

with m-phenylene diamine in refluxing lower alkanols such as isopropanol. Compounds of formula III in turn are obtained by reacting suitably substituted aromatic aldehydes with piperazine-1 ,4-bis-(propionitrile) (Farmatsiya 18(1968), p.8-17) of formula IV

in presence of a base such as sodium alkoxide, as for example sodium methoxide or Triton (Registered Trade Mark) B in dimethyl sulfoxide under mild conditions.

The 2,4-diamino-5-benzylpyrimidines of the formula I or their pharmaceutically acceptable acid addition salts may be used in enteral e.g. oral or for rectal application. For this purpose they are in the form of pharmaceutical preparations which contain them in the free form or in the form of their salts in admixture or conjunction with an organic or inorganic solid or liquid pharmaceutical excipientfor example, water, sugars, e.g. lactose, fructose, glucose or saccharose, starches, e.g. corn starch, wheat starch, rice starch or arrowroot, stearyl alcohol, stearic acid or salts thereof, such as calcium stearate or magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, propyleneglycol, polyethylene-glycols or any other known medicinal excipients.The pharmaceutical preparations may be in solid form, e.g. as tablets, dragees, capsules or suppositories, or in liquid form, e.g. as solution, suspensions or emulsions. They may be sterilised and/or may contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts for regulating the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. The pharmacetutical preparations are formulated according to usual methods.

The free compounds or their pharamaceutically acceptable salts may also be used in veterinary medicine, for example in the form of pharmaceutical preparations suitable for veterinary purposes, as well as in the form of animal feed additives using, for example, the conventional extending or diluting agents and feed respectively.

The following examples for the synthesis of compounds of the formula I illustrate the invention.

Temperatures are given in degrees centigrade.

Example 1: 2,4-diamino-5-(3',4', 5,-t,,methoxybenzy/)pyrimidine a) To a solution of guanidine, obtained by treating 50 g of guanidine hydrochloride with sodium methoxide, (prepared using 15 g of sodium in 250 ml of methanol) 50 g of N,N'-bis[(2-cyano-2-3',4',5'trimethoxybenzyl)-vinyl]-1,3-benzenediamine are gradually added. The mixture is refluxed with stirring for 12 hours. The mixture is cooled and the crystalline solid collected by filtration. It is purified by dissolving in dilute acetic acid and reprecipitating with ammonia solution to yield colourless crystalline solid of the formula

which melts at 197-1980.

The starting material is prepared by one of the following procedures.

b) A mixture of 238 g of N,N'-bis[(2-cyano-2-3',4',5'-trimethoxybenzyl)vinyl]piperazin and 81 g of m-phenylene diamine dihydrochloride in 2.5 litres of isopropanol is refluxed with stirring for 4 hours.

Concentrated hydrochloric acid is added to maintain the pH at 5-6. The mixture is cooled and the solid filtered and purified by washing with distilled water. The off-white crystalline solid N,N'-bis[(2-cyano-2 3',4',5'-trimethoxybenzyl)vinyl]-1 ,3-benzene-diamine of or the formula

melts at 185-187".

c) To a suspension of sodium methoxide (prepared from 7.1 g of sodium and methanol) in 500 ml of dimethylsulfoxide is added 95 g of piperazin-1 ,4-dipropionitrile. The mixture is warmed to 50-55 with stirring for 5 minutes. Thereafter 198 g of 3,4,5-trimethoxybenzaldehyde are added to the mixture and stirred at 70-75" for 2.5 hours. The mixture is cooled and diluted with 2 litres of water. The solid is collected and washed with 600 ml of methanol to yield crystalline solid N,N'-bis[(2-cyano-2-3',4',5'-trimethoxy- benzyl)vinyl]-piperazine of the formula

which melts at 222-223".

N,N'-bis[(2-cyano-2-3',4',5'-trimethoxybenzyl)vinyl]-piperazine can also be obtained by altering the method.

d) To 50 ml of dimethyl sulfoxide, containing 5 ml of 40 % methanolicsolution of Triton B, are added 9.5 g of piperazine-1 4-dipropionitrile. The mixture is warmed to 50-55 with stirring for 5 minutes. 19.8 g of 3,4,5-trimethoxybenzahdehyde are added to the mixture and the temperature raised to 70-750. The mixture is diluted with 200 ml of water, after stirring for 2.5 hours at 70-75 . The solid is cooled, washed with 60 ml of methanol to yield crystalline solid which melts at 222-223 .

Claims (8)

1. Process for the production of 2,4-diamino-pyrimidines of the general formula I

wherein Rr, 132 and 133 each independently represent a hydrogen atom, a lower alkyl, lower alkoxy, aryllower alkoxy or loweralkylthio radical or any two neighbouring groups of the three groups R1, R2 and 133 may together form an alkylenedioxy radical and the remaining third a hydrogen atom, a lower alkyl, lower alkoxy, aryllower alkoxy, or loweralkylthio radical and their salts, characterised by reacting a compound of formula II

wherein Ra, 132 and 133 have the meanings defined under formula I, which guanidine or a salt thereof and optionally converting an obtained compound of formula I in its free form into an acid addition salt or converting an obtained compound of formula I as an acid addition salt into the free form thereof.

2. Process as defined in claim 1, characterised that the reaction of a compound of formula II with a guanidine salt is carried out in presence of a base.

3. Process as defined in claim 1 or 2, characterised that the reaction of a compound of formula II with a guanidine salt is carried out in the presence of an alkali-metal alkoxide in an alkanol.

4. Process as defined in any of claims 1 to 3, characterised that the reaction of a compound of formula II with guanidine hydrochloride is carried out in the presence of sodium methoxide in methanol.

5. Compounds of the general formula II

wherein R1, R2 and 133 have the meanings as defined under formula I.

6. Process for the production of compounds of formula II, characterised by reacting a compound of formula III

with m-phenylene diamine in a lower alkanol.

7. The compounds of the general formula las defined in claim 1 whenever prepared by the process of claim 1.

8. A process as claimed in claim 1, substantially as hereinbefore described with reference to Example 1.