IL27621A - N1-(2-or 6-cyclopropyl-4-pyrimidinyl)-sulphanilamide derivatives and their preparation - Google Patents

Description

Geigy A.6, - la - 27621/2 The invention consists in new -(or -6)-cyclopropyl-4-pyriaidinyl)-sulphanilamide derivatives, of the general formula wherein one of and ^ is cyclopropyl and the other one is hydrogen, chlorine or a low alk l, alkoxy or alky thio group, is a lower alkyl or alkoxy group or chlorine; and thei salts with Inorganic or organic bases. ft~(4~ Pyrimidiny1)-sulphanilamide derivatives of the general formula above, unsubstituted or alkyl and/or alkoxy sub-stituted in the pyrimidine ring are known* These known compounds have antibacterial activity and are used in the treatment of infectious diseases* As compared with the known compounds aforesaid, the new compounds according to the invention, which are characterized by the cyclopropyl substltuent in the 2-or 6- position of the pyrimidine ring, have been found to possess superior antibacterial properties. Thus, the effect against streptococcus haemolytious £ 113 of the 5-methox -6-cyclP ropyl and 5-chloro-6-cyclopropyl-pyrim-idine sulphanilamide has been compared with that of the corresponding 2,6-dimethoxy compound which out of the group of known compounds is the one most commonly used, - lb - 27621/2 and it has been found that the curative dose 0T)^Q (i.e. the amount in tag/kg of body weight of the teat animal which cures 50 of the number of test animals infected with¾e above bacteria) is about four times smaller for the compounds of the invention than for the known compound. Moreover, in application in man the compounds according to the invention have a half-life period (i.e. the period required for the decomposition of one-Half of a given amount of the substance in the body) Of about four times longer than that of the aforesaid known compounds, which means that the antibacterial effect is accordingly more long-lasting.

In the compounds of general formula I ,' R, , R? and R as alkyl groups are, e.g. the methyl, ethyl, propyl or the iso-propyl group and, as alkoxy groups they are, e.g. the methoxy, ethaxy, propoxy or the isopropoxy group. In addition, as alkylthio groups, and R2 are, e.g. the methylthio or the ethylthio group.

These new compounds are produced by reacting a compound of the general formula II with a compound of the general formula III A0 - Z wherein X represents the amino group or a nitrogen-containing group which can be converted into the amino group, one of the two symbols A-^ and A2 represents the imino group -NH- and the other represents the direct bond, and Y and Z represent reactive radicals which can be split off together, and R- R2 and R3 have the meanings given above, the reaction optionally being performed in the presence of an binding agent acid to form a compound of general formula IV wherein R^, R25 R3 and X have the meanings given above, if necessary converting the group X in the above reaction product into the free amino group, and/or, if desired, reacting a reaction product containing a chlorine atom as radical R-^ or R2 with a metal compound of a -low alkanol or alkane thiol, or reducing the reaction product until the chlorine atom is elimi nated. ; hen A-^ is the imino group and A2 is the direct bond, Y is, e.g. a monovalent cation, particularly an alkali metal ion, and Z is then, e.g. a chlorine atom or a group of the formula IVa I CH^ - N - Ac (IVa) / \ CH3 CH3 wherein Ac represents a monovalent anion, particularly a chlorine ion.

In addition, Z can be, e.g. the cyanamino or nitroamino group or when neither R^ nor R^ is an alkylthio group, Z can be a low alkylsulphonyl group.

On the other hand, when is the direct bond and A2 is the imino group, then Y is, e.g. a chlorine atom or an acyloxy radical, e.g. a radical of the general formula IV b and Z is a hydrogen atom, whilst X in this case is preferably not a free amino group. Also, free sulphonic acids (A-L being the direct bond and Y = OH) can be reacted with 4-acetamido-pyrimidine derivatives (A2 = NH and Z = CH3~GO) , for example in a low alkanol, whereby the latter is partially distilled off.

The reactions of compounds of general formula II with those of general formula III are performed, e.g. in a suitable organic solvent such as dimethyl formamide, acetamide, N,N-dimethyl acetamide or dimethyl sulphoxide, while heating. When an acid is formed as liberated compound Y-Z, then the reaction is performed in the presence of an acid binding agent such as pyridine or trimethylamine , in methylene chloride.

Any necessary subsequent conversion of the group X of the reaction product of general formula IV into the free amino group is, depending on the type of this group, in the broadest sense a hydrolysis or reduction. Radicals X which can be converted into the amino group by hydrolysis are, e.g. acylamino radicals such as the acetamido radical, low alkoxy-carbonylamino radicals, such as the methoxycarbonylamino radical, the benzyloxy- or phenoxycarbonylamino radical, or substituted methylene amino groups such as the benzylidene amino radical or the p-dimethylaminobenzylidene amino radical.

The hydrolysis of corresponding compounds of general in an acid medium such as by heating in dilute methanolic hydrochloric acid, or under alkaline conditions, e.g. by means of dilute sodium hydroxide solution, at temperatures between ° and 100°. Radicals which can be converted into the amino group by reduction are, e.g. the nitro group, the benzyloxy- carbonylamino radical or the benzylidene amino radical or substituted azo radicals such as, e.g. the phenylazo or p-dimethyl amino ■ phenylazo radical or the azo group of the compound of the general formula Ila wherein A-^ and Y have the meanings given above.

Generally, the reduction of these reducible or cleav- able groups can be performed catalytically , e.g. with hydrogen in the presence of Raney nickel in an inert solvent, but there are also non-catalytically methods being used.

The reduction of the nitro group to the amino group may be carried out by means of iron in acetic acid or hydrochloric acid. The benzyloxycarbonylamino group is reduced e.g. with sodium in liquid ammonia. The reductive cleavage of the azo group can be performed e.g. with sodiumdithionite in ethanol or water, further with zinc in glacial acetic acid or in hydrochloric acid, or with tin (II) chloride in hydrochloric acid.

Reactions of compounds of general formula IV wherein R-^ and R£ are chlorine, with metal compounds, particularly alkali metal compounds such as sodium compounds, of low alkanols are most simply performed in the corresponding alkanols as solvents while heating, e.g. at the boiling temperature or ata raised temperature in a closed vessel. Also, dimethyl ., sulphoxide or dimethyl formamide, for example, can be used as solvents. The same solvents are also suitable for the reactions with heating., of compounds of general formula IV wherein R^ or represent s chlorine with alkyl mercaptides, particularly with alkali metal alkyl mercaptides. A chlorine atom R-^ or R£ is eliminated by reduction, e.g. by catalytic hydrogenation in the presence of a base. For example, palladium on barium sulphate is used as catalyst and aqueous sodium hydroxide solution is used as reaction medium. The compounds of general formula IV used in the' reactions mentioned above can be direct products of the main reaction or they can be obtained from such products by conversion of the group X into the free amino group. Optionally, a chlorine atom R-^ or R£ can be replaced by hydrogen in the same step as the reduction of a group X suitable therefor, e.g. the nitro group.

To produce starting materials of the general formula III wherein A2 is the direct bond, Z is a chlorine atom, a trimethyl ammonium ion or a low alkylsulphonyl group, R2 is the cyclopropyl group, 3 is a low alkyl or alkoxy group and R^ has the meaning given in formula I, for example, low -alkyl or -alkoxy derivatives of β-οχο-cyclopropane propionic acid alkyl esters, particularly the methyl or ethyl esters ar.e used as starting materials. These esters are con-densed with thiourea, low 0-alkyl isoureas, S-alkyl isothioureas or with amidines of low alkanoic acids such as formamidine or acetamidine, to form 5-alkyl or 5-alkoxy derivatives of 2-mercapto-6-cyclopropyl- , 2-alkoxy-6-cyclopropyl- , 2-alkylthio 6-cyclopropyl- , 6-cyclopropyl- or 2 methyl-6-cyclopropyl-4-pyrimidinols. The low 5-alkyl or 5-alkoxy derivatives of 6-cyclopropyl-2-thiouracil ( 6-cyclopropyl-2-mercapto-4-pyrimidinol) can be reduced, e.g. with Raney nickel in the presence of ammonia, to form 5-alkyl- or 5-alkoxy-6-cyclo-propyl-4-pyrimidinols , or they can be alkylated, e.g. with dialkyl sulphates or low alkyl halides in the presence of potassium carbonate, to form 5-alkyl- or 5-alkoxy-2-alkylthio-6-cyclopropyl-4-pyrimidinols, or they can be converted, e.g. by boiling with 10% { by weight) of chloracetic acid, into 5-alkyl- or 5-alkoxy-6-cyclopropyl uracils.

On treating the 5-alkyl- or 5-alkoxy-6-cyclopropyl- 4-pyrimidinols mentioned above with phosphorus oxychloride, e.g. in the presence of diethyl aniline, the corresponding 5-alkyl- or 5-alkoxy- 4-chloro-6-cyclopropyl pyrimidines embraced by general formula III are obtained, and by treating the 5-alkyl- or 5-alkoxy- 6-cyclopropyl uracils analogously, the 5r-alkyl- or 5-alkoxy- 2,4-dichloro-6-cyclopropyl pyrimidines which are also embraced by that formula, are obtained. On reacting the 4-monochlorine compounds mentioned above with tri-methylamine, N- ( 6-cyclopropyl-4-pyrimidinyl) - ,N ,N-trimethyl ammonium chlorides substituted in the 2-position by R-^ - with the exception of the cyclopropyl radical - and in the 5-position by alkyl or alkoxy groups are obtained as further starting materials of the general formula III. Corresponding starting materials having a low alkylsulphonyl radical as radical Z which can be split off are produced, e.g. by reacting 5-alkyl- or -alkoxy-4-chloro-6-cyclopropyl pyrimidines, 5-alkyl- or 5- or 2,5-dialkyl- 4-chloro-6-cyclopropyl pyrimidines with alkali metal salts of low alkane thiols and oxidising the 4-alkylthio compounds obtained, e.g. with peracetic acid.

The a-alkyl-p-oxo-cyclopropane propionic acid alkyl esters mentioned as condensation components for the pyrimidine ring closure reaction are obtainable, e.g. from β-οχο-cyclo-propane propionic acid alkyl esters and alkyl iodides in the presence of a low sodium alcoholate, and the corresponding a-alkoxy- -oxo-cyclopropane propionic acid alkyl esters are obtained from a-diazo-p-oxo-cyclopropane propionic acid alkyl esters and a low alkanol in the presence of copper and boron trifluoride etherate.

Starting materials of the general formula III wherein A2 represents the direct bond, Z is a chlorine atom, R2 is the cyclopropyl group, R^ is represented by chlorine and R-^ has the meaning given in formula I, are produced by reacting 6-cyclopropyl-4-pyrimidinol with N-chloro-succinimide and treating the obtained 5-chloro-6-cyclopropyl-4-pyrimidinol e.g. with a mixture consisting of phosphorus oxychloride and dimethylformamide , in order to obtain 6-cyclopropyl-4 , -dichloro-pyrimidine.

A second group of starting materials of the general formula III wherein Ag represents the direct bond, Z is a chlorine atom, a trimethyl ammonium ion or a low alkylsulphonyl group, R3 is a low alkyl or alkoxy group, R-^ is the cyclopropyl group and R2 has the meaning given in formula I, are produced by first condensing cyclopropane carboxamidine with low a-alkyl or a a-alkoxy derivatives of low alkanoyl acetic acid alkyl esters or with low -alkyl malonic acid alkyl esters to form 5-alkyl- or 5-alkoxy- 2-cyclopropyl-4-pyrimidinols , 2-cyclopropyl-5 , 6-dialkyl-4-pyrimidinols , 2-cyclopropyl-5-alkoxy-6-alkyl-4-pyrimidinols or 2-cyclopropyl-5-alkyl-4 , 6-pyrimidine diols. By reacting these hydroxy compounds with inorganic acid chlorides such as phosphorus oxychloride or thionyl chloride, compounds embraced by general formula III containing chlorine as radical Z, namely 5-alkyl- or 5-alkoxy- 2-cyclopropyl-4-chloro pyrimidines, 2-cyclopropyl-5,6-dialkyl-4-chloro pyrimi-dines, 2-cyclopropyl-5-alkoxy-6-alkyl-4-chloro pyrimidines or 2-cyclopropyl-5-alkyl-4 ,6-dichloro pyrimidines are obtained. The latter compounds can be reacted, for example, with equimolar amounts of alkali metal compounds of low alkanols or alkane thiols to form 2-cyclopropyl-5-alkyl-6-alkoxy-4-chloro pyrimi-dines or 2-cyclopropyl-5-alkyl-6-alkylthio-4-chloro pyrimidines. Starting materials of general formula III having other reactive radicals Z are obtained from the 4-monochloro compounds mentioned above, e.g. by reaction with trimethylamine to form 4-trimethyl ammonium compounds or by reaction with alkali metal salts of low alkane thiols and oxidation of the 4-alkyl-thio compounds obtained to form 4-alkylsulphonyl compounds, i e.g. with peracetic acid.

The low -alkoxy-β-οχο derivatives of low aliphatic carboxylic acid alkyl esters, particularly methyl or ethyl esters, used for the pyrimidine ring closure reaction, can be produced, for example, from corresponding -diazo- -oxo-car-boxylic acid alkyl esters in a low alkanol in the presence of copper and borontrifluoride etherate.

A third group of starting materials of the general formula III wherein A2 is the imino group, Z is hydrogen and R- R2 and R^ have the meanings given in formula I, i.e. 5-alkyl, 5-alkoxy or 5-chloro derivatives of 4-amino-6-cyclopropyl or 4-amino-2-cyclopropyl pyrimidines which are substituted in the 2- or 6- position according to the definition of R-^ or R2 , are obtained from those compounds already mentioned of general formula III which contain a chlorine atom or a low alkylsulpho-nyl group in the 4-position, by reacting these compounds with ammonia.

However, in some of the above cyclisation reactions, -cyano ketones can be used instead of oc-aeyl acetic acid alkyl esters of cyanoacetic acid alkyl esters can be used instead of malonic acid dialkyl esters. In this way, 4-amino-pyrimidines or 4-amino-6-pyrimidinols respectively, which are embraced by general formula III, can be obtained. Starting materials of the general formula III are obtained from the latter by conversion into substituted 4-amino-6-chloro pyrimidines and, optionally, further conversion into substituted 4-amino-6-alkoxy pyrimidines or 4-amino-6-alkylthio pyrimidines, the conversion of hydroxyl groups into chlorine atoms and the conversion of chlorine atoms into alkoxy or alkylthio groups being perfermed analogously to the production of the first two groups of starting materials of general formula III. The 4-amino - pyrimidine derivatives obtained can be converted into 4-nitroamino pyrimidine derivatives, e.g. with nitric acid, these derivatives being a fourth group of starting materials of general formula III.

The compounds of general formula I obtained by the processes according to the invention are then converted, if desired, into their salts with inorganic or organic bases.

These salts are produced, e.g. by reacting compounds of general formula I with the equivalent' amount of a base in a suitable aqueous/organic or organic solvent such as methanol, ethanol, ether, chloroform or methylene chloride.

Instead of the free compounds of general formula I, their salts with bases can be used as medicaments. Suitable salts are those the cations of which have no physiological action of their own in the usual dosages. It is also of advantage if the salts to be used as medicaments crystallise well and are not or only slightly hygroscopic. Suitable salts are, e.g. sodium, potassium, magnesium, calcium and ammonium salts as well as salts with ethylamine , dimethylamine , diethyl-amine, triethylamine , ethylenediamine , choline, benzylamine, dibenzylamine , pyridine, piperidine, morpholine, N-ethyl-piperidine, aminoethanol, diethylaminoethanol , diethanolamine , triethanolamine and 1- ( 2-hydroxyethyl) -piperidine .

The new sulphanilamide derivatives corresponding to general formula I are suitable for the preparation of medicaments for internal or external use, 'e.g. for the treatment of infections caused by gram positive bacteria such as Staphylococci, Streptococci, Pneumococci as well as by gram negative bacteria such as Salmonella typhi,, Escherichia coli and Klebsiella pneumoniae.

- - The new active substances are administered orally and parenterally. The daily dosages of the free bases or of pharmaceutically acceptable salts thereof vary between 100 and 5,000 mg for adult patients. Suitable dosage units such as tablets or ampoules preferably contain 100 - 700 mg of an active substance according to the invention or of a pharmaceutically acceptable salt thereof. In addition, corresponding amounts of other forms for applications,, such as syrups, ointments or powders, can be used.

Dosage units for oral administration preferably contain between 60% and 90% of a compound of general formula I or of a pharmaceutically acceptable salt of such a compound as active substance. They are produced by combining the active substance with, e.g. solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights, to form tablets.

Ampoules for parenteral, particularly intramuscular, administration preferably contain a water soluble salt of an active substance in a concentration of, preferably, 5 - 10%, in aqueous solution, optionally together with suitable stabilising agents and buffer substances.

The following prescription further illustrates the production of tablets: 100,000 kg of N - ( 5-methoxy-6-cyclopropyl-4-pyrimidinyl) -sulphanilamide are mixed with 13,000 kg of dry corn starch and 13,000 kg of lactose. The mass obtained is mixed with 3,000 kg glycerol and 5,000 kg of gelatine in distilled water, whereupon this mass is kneaded during 20 minutes.

As soon as it is evenly moistened, it is granulated through a sieve (25 mesh/sq.cm) and dried. The dried granulates are sieved again (60 mesh/sq.cm) and then mixed during one hour with 7,500 kg of potato starch, 7,500 kg of talcum and 1,000 kg of magnesium stearate. The mass obtained is pressed into I'OOO'OOO tablets each weighing 150 mg and containing 100 mg of active substance.

The following examples further illustrate the production of the new compounds of general formula I and of hitherto undescribed intermediate products, but they in no way limit the scope of the invention. The temperatures are given in ; degrees Centigrade.

Example 1 a) 17.6 g of a-diazo-p-oxo-cyclopropane propionic acid ethyl ester (cf. L.J. Smith and S. Mc enzie, J. Org. Ghem. 15, 74 (1950)) are dissolved in 135 ml of dry methanol. This solution, with the addition of 1 g of copper powder and 4 drops of borontrifluoride etherate, is heated at a bath temperature of 60-70°. At first there is strong nitrogen development which has been completed after 2 hours. The reaction mixture is then filtered and the filtrate is concentrated to dryness. The oil which remains is fractionated, whereupon the pure a-methoxy-β- · oxo-cyclopropane propionic acid ethyl ester is obtained, B.P. 60-61°/0.1 Torr. b) 2.25 g of sodium are added to 45 ml of dry ethanol- and then 8.75 g of thiourea and 12.25 g of the ester obtained accor-ding to example la) are added. The mixture is then refluxed for 7 hours. The ethanol is distilled off under vacuum, the residue is dissolved in 25 ml of warm water and the solution is decoloured with 1 g of active charcoal. The charcoal is filtered off and the pH of the filtrate is adjusted to 6 with 5N hydro-chloric acid. The suspension obtained is left to stand for 1 hour at.0° after which the crude 2-mercapto-5-methoxy-6-cyclo-propyl-4-pyrimidinol is filtered off under suction. It is washed with water and dried in vacuo, whereupon it melts at 208-210° with decomposition. Recrystallisation of the crude product from ethanol yields the pure compound which melts at 211-213° with decomposition. c) 8 g of the crude mercapto compound produced according to example lb) are added to 100 ml of distilled water and 10 ml of 25% (% by weight) of aqueous ammonia. The mixture obtained is heated to 70-80° while stirring, 24 g of Raney nickel in the form of a moist paste are added in portions and then the suspension is heated for 1 1/2 hours in a bath of 110-120° while stirring is continued. The precipitate is filtered off and washed twice with hot water. The filtrates are evaporated to dryness in vacuo and the residue is dried over phosphorus pentoxide. The crude 5-methoxy-6-cyclopropyl-4-pyrimidinol obtained melts at 113-116°. Sublimation of the crude product at 90-100°/0.1 Torr yields the pure compound; it melts at 120 - . 122° . d) 5.7 g of the crude 5-methoxy-6-cyclopropyl-4-pyr imidi-nol are added to 36 ml of ice cold phosphorus oxychloride and then 2.6 ml of Ν,Ν-dimethyl aniline are- added. The mixture obtained is stirred for 1 1/2 hours at a bath temperature of 90^100° whereupon the excess phosphorus oxychloride is distilled off in vacuo and the residue is poured onto ice. The suspension obtained is extracted three times with 50 ml of ether each time, the ether extract is washed first with water, then with 5% (% by weight) of sodium hydrogen carbonate solution and again with water, dried over sodium sulphate and concentrated. The residue, crude, oily 4-chloro-5-methoxy-6-cyclo- ■ propyl pyrimidine, is used directly for the following reaction,, sodium e) A mixture of 10.7 g of/sulphanilamide se&Lwg^. ■ 40 ml of dimethyl sulphoxide, 4.61 g of the crude chlorine compound obtained according to example Id) and 0.6 g of tri-methylamine, dissolved in 6 ml of dimethyl formamide, is heated for 48 hours at a bath temperature of 60 - 70° while stirring. The solution obtained is concentrated under high vacuum and, the residue is stirred with water and ether. The pH of the aqueous phase is adjusted to 8 - 9 with solid carbon dioxide and the excess sulphanilamide which precipitates is filtered off. After acidifying the filtrate with 5N hydrochloric acid until the pH is 5 - 6, the crude N"*"- ( 5-methoxy-6-cyclopropyl-4-pyrimidinyl) -sulphanilamide is obtained therefrom. It is recrystallised once from aqueous ethanol and once from acetic acid ethyl ester/hexane whereupon it melts at 201-203°. Thin layer chromatography gives the Rf value of 0.65 (Silicagel Merck G; solvent: chloroform .methanol 4:1).

Example 2 sodium 34.9 g of/sulphanilamide ee«L4«ai and 32„5 g of acetamide are mixed, the mixture is melted at 160° and left to cool to 90°. 14.6 g of N-(6-cyclopropyl-5-methoxy-4-pyrimidinyl)-N,N,N~ trimethyl- ammonium chloride (obtained from 6-cyclopropyl-5-methoxy-4-chloropyrimidine and trimethylamine) are then added, the whole is stirred for 10 minutes at 100°, the mixture is allowed to cool and stirred with water. The pH of the solution is adjusted to 8 - 9 with solid carbon dioxide and the precipitated sulphanilamide is filtered off. 6N-hydrochlo c" acid is added to the filtrate until the pH is 5 - 6 and the crude N -( 5-methoxy-6-cyclopropyl-4-pyrimidinyl) -sulphanilamide is filtered off under suction. It is identical with the product obtained according to example 1.

Example 3 a) 4.6 g of sodium are reacted in 120 ml of dry ethanol. At 55°, 31.2 g of β-οχο-cyclopropane propionic acid ethyl ester are added dropwise to the solution obtained. Two minutes after this addition, 31.2 g of methyl iodide are added dropwise and, after completion of the exothermic reaction, the mixture is refluxed for 1 hour. It is then cooled to 30° and concentrated in vacuo. The residue is mixed with 10 ml of water and the suspension obtained is extracted three times with ether. The ether extract is washed once with water, dried over sodium sulphate and evaporated. The yellow oil which remains is distilled and pure a-methyl--oxo-cyclopropane propionic acid ethyl ester is obtained, B.P. 90-95°/12 Torr. b) The crude 2-mercapto-5-methyl-6-cyclopropyl-4-pyrimi-dinol (M.P. 220-220° , with decomposition), is obtained analogously to example lb) from 5.8 g of sodium in 115 ml of dry ethanol, 28.6 g of the ester prepared according to example 3a) and 21.4 g of thiourea. Recrystallisation of the crude product from aqueous ethanol yields the pure compound which melts at 232-234° (with decomposition) . c) 18.8 g of the mercapto compound obtained according to example 3b) in 268 ml of water and 26.8 ml of 25 ( by weight) of aqueous ammonia, are desulphurised with 61.5 g of Raney nickel by the method described in example lc) . The crude 5-methyl-6-cyclopropyl-4-pyrimidinol obtained melts at 180-182°, Sublimation of the crude product yields the pure compound which melts at 184-186°. d) 13.3 g of the crude 5-methyl-6-cyclopropyl-4-pyrimi-dlnol, 93 ml of phosphorus oxychloride and 7 ml of dimethyl aniline are reacted analogously to example 3d) to yield 4-chloro-6-cyclopropyl-5-methyl pyrimidine. After evaporation of the ether, the chlorine compound remains as a slightly greasy crystal mass; it melts at 80-82°. e) 5 g of the crude compound produced according to example sodium 3d) are added to a suspension of 14.6 g of/sulphanilamide : ;· ; : SKxi iWR- . in 30 ml of dimethyl sulphoxide and 0.36 g of tr imethylamine , dissolved in 4 ml of dimethyl formamide. The mixture is stirred at a bath temperature of 60° and gradually turns into a brown solution. After 90 hours, this is concentrated under high vacuum and the residue is worked up as described in example le). The crude N^-( 5-methyl-6-cyclopropyl-4-pyrimidinyl) -sulphanilamide obtained melts at 229-232°, Recrystallisation of the crude product from aqueous ethanol and a little dimethyl formamide yields the pure compound which melts at 237-239°. Thin layer chromatography gives the Rf value of 0.6 (Silicagel Merck G; solvent: chloroform : methanol 4:1).

Example 4 a) 5.95 g of acetamidine hydrochloride are added to a mixture of 10.7 g of a-methyl-p-oxo-cyclopropane propionic acid ethyl ester (produced according to example 3a)) and 3 ml of absolute ethanol and the whole is stirred well. 2.52 g of pulverised sodium hydroxide and 2.5 ml of dry ethanol are then added, stirring being continued from time to time until the sodium hydroxide has. dissolved,, The mixture, in a crystal to stand in a vacuum desiccator under 12 Torr, the sulphuric acid being renewed each day. After about one week, the reaction mixture is dry whereupon it is thoroughly pulverised and mixed with 2-5 of sodium carbonate and 2.5 g of sodium bicarbonate,, This mixture is then continuously extracted with benzene., for . about 18 hours and the benzene extract is concentrated,, The . crude, crystalline 6~cyclopropyl-2 , 5-dimethyl-4-pyrimidinpl melts, at 218-220°, b) 7.0 g of the above crude hydroxy compound are stirred for 45 minutes at a bath temperature of 90° with 54 ml of phosphorus oxychloride and 6.37 ml N,N-niiethy1-aniline. The brown solution formed is concentrated to dryness under 12 Torr, Ice is added to the residue which is then extracted three times with ether. The ether extract is then, washed, first with dilute ice cold sodium bicarbonate solution, then with water and dried over sodium sulphate. After distilling off the ether, the oily 4-chloro-6-.cyclopropyl -2 , 5-dimethyl-pyrimidine remains. This is used directly for further reaction. sodium c) A mixture of 14.8 g of/sulphanilamide 44 ml of dimethyl sulphoxide, 4..65 g of the crude chlorine compound obtained according.: to 4 b) and 0.53 g of trimethylamine in 5 ml of dimethyl formamide are heated for 14 hours at a bath temperature of 50-60° and for 60 hours at 60-70°. The product is worked up as described in example 1 e) . After- crystallisation from aqueous alcohol, N"*"- (6-cyclopropyl-2 , -dimethyl-4-pyrimi-dinyl) -sulphanilamide is obtained, M.P. 185-187°.

- - Example 5 a) A solution of 15.5 g of O-methyl isourea hydrochloride in 50 ml of dry methanol and a solution of 6.45 g of sodium in 70 ml of dry methanol are added drop ise to each other, care being taken by a cooling bath that the temperature does not rise above -5°. 17.0 g of a-methyl-p-oxo-cyclopropane propionic acid ethyl ester are then added and the reaction mixture is stirred for 2 to 3 days at 20-25° and then heated for 3 hours at a bath temperature of 70-80°. It is then concentrated in vacuo, the residue is rubbed with 100 ml of water and acidified to pH 4 with 2N hydrochloric acid. The precipitated 6-cyclo-propyl-2-methoxy-5-methyl-4-pyrimidinol can be used directly for the further reactions. In the crude state it melts at 205-207°. b) 8 g of the crude product obtained as described above are reacted for 30 minutes at a bath temperature of 90° with 56 ml of phosphorus oxychloride and 6.6 g of N,N-diethyl aniline. A sample of the crude product obtained is recrystal-lised from hexane and the pure 4-chloro-6-cyclopropyl-2-methoxy-5-methyl-pyrimidine melts at 61-62°. c) 8.3 g of the 4-chlorine compound and 17.2 g of sodium sulphanilamide &Θ Ϊ¾Β» in 72 ml of dimethyl sulphoxide and 0.88 g of trimethylamine in 8 ml of dimethyl formamide are reacted as described in example 1 e) for 16 hours at a bath temperature of 40° and then for 40 hours at a bath temperature of 60°. The pure ^- (6-cyclopropyl-2-methoxy-5-methyl-4-pyrimidinyl) -sulphanilamide obtained from aqueous ethanol melts at 213-214°.

Example 6 a) 6.8 g of 6-cyclopropyl-4-pyrimidinol (produced analogously to example 3 b) and c)) are suspended in 15 ml of glacial acetic acid and 0.3 ml of acetanhydride. On heating for a few minutes at 80° a clear solution is obtained. The solution is allowed to cool to 50 - 55° and 8.3 g of N-chlorosuccinimide are added in portions. The whole is stirred for 3 hours at a bath temperature of 60° and, after cooling to about 20°, it is filtered and the residue is washed with water. The crude 5-chloro-6-cyclopropyl-4-pyrimidinol melts at 218-220°. b) 6 g of the crude compound obtained as described above, are added to an ice cooled mixture of 3 ml of phosphorus oxy-chloride and 0.6 ml of dimethyl firmamide. The whole is stirred for 45 minutes at a bath temperature of 110°. A red solution is formed which is concentrated under 12 Torr. The residue is poured onto ice and extracted several times with 50 ml of hexane each time. After distilling off the solvent, the oily 6-cyclopropyl-4 , 5-dichloropyrimidine remains. c) A.mixture of 5.6 g of 6-cyclopropyl-4 , 5-dichloropyrimidine, 14.3 g of sulphanilamide sodium, 30 ml of dimethyl formamide and a solution of 0.3 g trimethylamine in 3 ml of dimethyl formamide is stirred for 2 hours at a bath temperature of 60°. Another 0.3 g of trimethylamine in 3 ml of dimethyl formamide are then added and the mixture is stirred for another 13-14 hours at a bath temperature of 70°. The dark brown suspension formed is evaporated to dryness under a pressure of 0.1 Torr. The residue is dissolved in water, the pH of the solution is adjusted to 9..Ό with carbon dioxide and Sa the solution is stirred for 2 hours. Unused sulphanilamide is filtered off, the filtrate is washed once with ether and the pH of the filtrate is adjusted to 6.0 with 5N hydrochloric acid. After 1 hour, the precipitated crude product is filtered off and recrystallised from 2-methoxy-ethanol/water . N^- ( 5-chloro-6-cyclopropyl-4-pyrimidinyl) -sulphanilamide is obtained, M.P. 202-203°.

Example 7 a) 20.85 g of cyclopropyl carboxamidine hydrochloride are dissolved in 60 ml of dry methanol and the solution is cooled to -5°. First a solution of 8.04 g of sodium in 81 ml of dry methanol is added while continuously stirring and then 30.6 g of methyl malonic acid diethyl ester are added. The temperature is allowed to rise to 20° within about 2 hours whereupon stir-ring is continued for another 2 days. The product is left to stand for 4 days at 20°, then heated for 1 1/2 hours at a bath temperature of 50-60° after which the solvent is distilled off under vacuo. 100 ml of water are added to the residue and the pH is adjusted to 4 - 5 with 2N hydrochlic acid. The precipita--te is filtered off under suction, washed twice with water and dried over phosphorus pentoxide in a vacuum desiccator. The 2-cyclopropyl-5-methyl-4 , 6-pyrimidine diol did not melt at over 300°. b) 15 g of the pyrimidine obtained according to -a) are added to a mixture of 145 ml of phosphorus oxychloride and 16 ml of pyridine and the whole is heated for 2 hours at a bath temperature of 100°. The excess phosphorus oxychloride is then distilled off at 12 Torr at a bath temperature of 60° whereupon water is added to the residue. The reaction is exothermic; the temperature is kept under 20° by the addition of ice. The mixture is extracted with hexane, the hexane extract is washed once with water and dried over sodium sulphate.

After removal of the solvent, the crude, crystalline 2- cyclopropyl-4 , 6-dichloro-5-methyl-pyrimidine remains. c) 74 ml of dry ethanol are saturated with methyl mercaptan while cooling with ice and 7.45 g of the above crude product are dissolved in the cold solution. A solution of 0.99 g of sodium methylate in 17 ml of dry ethanol is added dropwise within 20 minutes while stirring and then the mixture is stirred for 18 hours at 20°. The suspension is evaporated under vacuum ■ at 30° and the residue obtained is extracted with about 40° warm hexane. After concentrating the extract, the crystalline crude product remains. Recrystallised from a little petroleum ether, the 2-cyclopropyl-4-chloro-5-methyl-6-methylthio- pyrimidine melts at 49-51°. sodium d) A mixture of 6.67 g of/ sulphanilamide swti-tair, 30 ml of dimethyl sulphoxide and 0.1. g of trimethylamine dissolved in 6 ml of dimethyl formamide, and 3.35 g of the pyrimidine compound produced under c) is heated for 62 hours at a bath temperature of 60°. The reaction mixture is worked up according to example 1 e). Crystallisation of the crude product from methoxyethanol/water , yields pure N^~- ( 2-cyclopropyl-5-methyl- 6-methylthio-4-pyrimidinyl) -sulphanilamide , M.P. 229-230°.

Claims (10)

HAVING HOW particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is: What we claim is:

1. New sulphanllamide derivatives of the general formula I wherein R-^ and independently of each other represent hydrogen, chlorine atoms, low alkyl, alkoxy or alkylthio groups or the cyclopropyl group, one of the symbols R-^ and ^ being the cyclopropyl group, and R2 represents a low alkyl or alkoxy group or a chlorine atom.

2. Compounds of the general formula I given in Claim 1 and their salts with inorganic and organic bases.

3. N"*"- (5-methoxy-6-cyclopropyl-4-pyrimidinyl) -sulphanllamide and the salts thereof.

4. N"*"- (5-methyl-6-cyclopropyl-4-pyrimidinyl) -sulphanllamide and the salti thereof.

5. N'1"-(6-cyclopropyl-2 , 5-dimethyl-4-pyrimidinyl) -sulphanllamide and the salt* thereof.

6. N1- ( 5-chloro-6-cyclopropyl-4-pyrimidinyl) -sulphanllamide and the saltj thereof.

7. New sulphanllamide derivatives of the general formula I as defined in Claim 1, substantially as herein described with reference to and as illustrated in any of the foregoing examples.

8. Process for the production of new sulphanilamide derivatives according to Claim 1, which comprises reacting a compound of the general formula II with a compound of the general formula III wherein X represents the amino group or a nitrogen-containing group which can be converted into the amino group, one of the two symbols and represents the imino group and the other represents the direct bond, and Y and Z represents reactive radicals which can be split off together , and R-p R2 and have the meanings given above, the reaction optionally being performed in an acid binding agent, to form a compound of the general formula IV 25 - GB etc. wherein R-^, I^, R3 and X have the meanings given above, if necessary converting the group X of the. reaction product into the free amino group and/or, if desired, reacting a reaction product containing a chlorine atom , as radical R-^ or Rg with a metal compound Of a low alkanol or alkane thiol, or reducing it to eliminate the chlorine atom R-^ or R2.

9. New sulphanilamide compounds of the general formula I whenever prepared by the process Of claim 8 as defined in. claim 1', substantially as herein described with reference to and as illustrated in any of the foregoing examples.

10. A pharmaceutical preparation in dosage unit form comprising a compound claimed in claim 1 and at least one inert pharmaceutical carrier. Dated this 15th day of March 1967. For the Applicants, Dr. Riinhold Cohn & 30.1.67/Hb/dZ - 26 - GB etc.