NO133138B

NO133138B -

Info

Publication number: NO133138B
Application number: NO713870A
Authority: NO
Inventors: C Rufer; H Ahrens; H Biere; E Schroeder; E Gerhards; E Schillinger; W F Losert; O Loge
Original assignee: Schering Ag
Priority date: 1971-10-05
Filing date: 1971-10-19
Publication date: 1975-12-08
Also published as: JPS4844272A; DK136034B; DE2150279A1; AU4735672A; IL40514A; ZA727126B; CH568982A5; DE2150279C2; CA977755A; GB1403264A; NL7213535A; IL40514A0; SE385213B; DD103442A6; AT319952B; NO133138C; DK136034C

Description

Analogifremgangsmåte ved fremstilling av sulfamoyl- Analogous method for the production of sulfamoyl-

pyrimidiner med blodsukkersenkende virkning. pyrimidines with a blood sugar-lowering effect.

I henhold til hovedpatent nr. 131.835 fremstilles forbindelser med den generelle formel: 'hvor Cft er et asymmetrisk carbonatom, A er According to main patent no. 131,835, compounds are prepared with the general formula: 'where Cft is an asymmetric carbon atom, A is

hvor R.^og R o er hydrogen, halogen, alkyl med 1-6 carbonatomer eller alkoxy med 1-4 carbonatomer, where R.^ and R.sub.o are hydrogen, halogen, alkyl with 1-6 carbon atoms or alkoxy with 1-4 carbon atoms,

X og Y, som er like eller forskjellige, er en direkte binding eller methylen, X and Y, which are the same or different, are a direct bond or methylene,

R og R^er forskjellige, og er hydrogen, rettkjedet eller forgrenet alkyl med 1-4 carbonatomer, carboxyl eller alkoxycarbonyl med 1-4 carbonatomer, R and R^ are different, and are hydrogen, straight-chain or branched alkyl with 1-4 carbon atoms, carboxyl or alkoxycarbonyl with 1-4 carbon atoms,

R^og R^, som er like eller forskjellige, er hydrogen eller alkyl med 1-4 carbonatomer, R^ and R^, which are the same or different, are hydrogen or alkyl of 1-4 carbon atoms,

R^er rettkjedet eller forgrenet alkyl med 1-6 carbonatomer, og R^ is straight-chain or branched alkyl with 1-6 carbon atoms, and

W er en direkte C-C-binding eller oxygen eller svovel, W is a direct C-C bond or oxygen or sulphur,

og salter derav med fysiologisk godtagbare baser. and salts thereof with physiologically acceptable bases.

Disse forbindelser er egnet til behandling av diabetes mellitus. These compounds are suitable for the treatment of diabetes mellitus.

Foreliggende oppfinnelse er en videreutvikling av oppfinnelsen ifølge hovedpatentet, og angår fremstillingen av racemater og optiske antipoder av sulf amo<y>lp<y>rimidmer av formel I hvor C , X, Y, R^, R^, R^og W er som angitt i hovedpatentet, og A kan foruten den i hoved-pat entet angitte betydning være en nafthyl-, pyridyl-, 1-methyl-indolyl- eller 2-fenylfenylgruppe, The present invention is a further development of the invention according to the main patent, and relates to the production of racemates and optical antipodes of sulf amo<y>lp<y>rimidmers of formula I where C , X, Y, R^, R^, R^ and W are as specified in the main patent, and A may, in addition to the meaning specified in the main patent, be a naphthyl, pyridyl, 1-methyl-indolyl or 2-phenylphenyl group,

Rg kan foruten å være som i hovedpatentet, også være cyano eller trifluormethyl, eller R^kan være en med substituenten A forbundet alkylengruppe med 2 eller 3 carbonatomer slik at der dannes indan eller tetrahydronafthaien, og In addition to being as in the main patent, Rg can also be cyano or trifluoromethyl, or R^ can be an alkylene group with 2 or 3 carbon atoms connected to the substituent A so that indane or tetrahydronaphthalene is formed, and

R^kan, foruten å være som angitt i hovedpatentet, være en direkte binding til substituenten A, R^ can, in addition to being as indicated in the main patent, be a direct bond to the substituent A,

med det forbehold at en av substituentene A, Rn eller Re må være som ovenfor spesielt angitt, with the proviso that one of the substituents A, Rn or Re must be as specifically indicated above,

såvel som salter av disse forbindelser med fysiologisk godtagbare baser . as well as salts of these compounds with physiologically acceptable bases.

Prøvingen på blodsukkersenkende virkning skjedde over et tids-rom på 6 timer på kaninunger som hadde sultet i 24 timer. Den laveste dose f.eks. for 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-l-a-nafthylethylamid, som senker blodsukkeret like meget som 1 mg/kg 4~[N-(5~isopropoxy-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-5-klor-2-methoxanilid, en av de mest virksomme forbindelser fra belgisk patent nr. 726.253»ligger for (+)-formen ved 3, for (-)-formen på 0,1. (Doseavtrapning: 30, 3»1»0,5, 0,25, 0,1, 0,05 mg/kg). The blood sugar-lowering effect was tested over a period of 6 hours on baby rabbits that had been starved for 24 hours. The lowest dose e.g. for 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-α-naphthylethylamide, which lowers blood sugar as much as 1 mg/kg 4~[N-(5~isopropoxy-2-pyrimidinyl)- sulfamoyl]-phenylacetic acid-5-chloro-2-methoxanilide, one of the most effective compounds from Belgian Patent No. 726,253" is for the (+) form at 3, for the (-) form at 0.1. (Dose tapering: 30, 3»1»0.5, 0.25, 0.1, 0.05 mg/kg).

Det er overraskende at stigningen i den blodsukkersenkénde virkning fremkalles ved en forandring av molekylet i den forlengede sidekjede på den sulfonerte benzenkjerne, altså på et sted som ikke ubetinget har noe å gjøre med den p-cytotrope virkning av sulfon-amidet, da også forbindelser som ikke har en sidekjede (f.eks. glymidin) er (3-cytotrop virksomme. It is surprising that the increase in the blood sugar-lowering effect is caused by a change in the molecule in the extended side chain of the sulphonated benzene nucleus, i.e. in a place which does not necessarily have anything to do with the β-cytotropic effect of the sulphonamide, then also compounds which do not have a side chain (eg glymidine) are (3-cytotropic active.

Ved terapeutisk anvendelse kan fremgangsmåteforbindelsene administreres pr. os som frie sulfonamider som salter med fysiologisk godtagbare uorganiske og/eller organiske baser, som f.eks. natrium-, lithium-, calcium- eller ammoniumhydroxyd, aminer som methylglucamin, morfolin, ethanolamin o.a., eller også i form av blandinger av de frie sulfonamider med et egnet alkalimetall-»bicarbonat eller -carbonat. Særlig egnet er baser som selv virker blodsukkersenkénde, som f.eks. butylbiguanid. Konfeksjoneringen av forbindelsene kan skje uten eller med de i den galeniske farmasi vanlige tilsetninger, bærere, smakskorrigenser etc, og f.eks. i pulverform, som tabletter, dragéer, kapsler, piller, i form av sus-pensjoner eller oppløsninger. For therapeutic use, the process compounds can be administered per os as free sulfonamides as salts with physiologically acceptable inorganic and/or organic bases, such as e.g. sodium, lithium, calcium or ammonium hydroxide, amines such as methylglucamine, morpholine, ethanolamine etc., or also in the form of mixtures of the free sulphonamides with a suitable alkali metal bicarbonate or carbonate. Particularly suitable are bases that themselves have a blood sugar-lowering effect, such as e.g. butyl biguanide. The confection of the compounds can take place without or with the usual additives, carriers, taste corrections etc. in galenic pharmacy, and e.g. in powder form, such as tablets, dragées, capsules, pills, in the form of suspensions or solutions.

Fremstilling av de nye forbindelser av formel I skjer som ifølge hovedpatentet ved at Production of the new compounds of formula I takes place as according to the main patent by

a) et eventuelt optisk aktivt sulfohalogenid av den generelle formel: a) an optional optically active sulfohalide of the general formula:

hvor C<*>, X, Y, Å, R^, R^, R^ og R^er som ovenfor angitt, og Q er halogen, fortrinnsvis klor, omsettes med guanidin eller et salt derav, og at den dannede, eventuelt optisk aktive guanidinsulfonyl-forbindelse av den generelle formel: ;hvor betydningen av substituentene er som ovenfor angitt, kondenseres under ringslutning med et substituert malondialdehyd av den generelle formel: ;hvor W og R^er som ovenfor angitt, idet aldehydgruppen også kan være funksjonelt endret, eller b) det under a) anførte eventuelt optisk aktive sulfonhalogenid omsettes med et 2-amino-5-W-R^-pyrimidin, hvor W og R^er som ovenfor angitt, eller c) et eventuelt optisk aktivt sulfonamid av den generelle formel: ;hvor C , X, Y, A, R^, R^, og R_ er som ovenfor angitt', i fri form eller som alkalimetallsalt, omsettes med et pyrimidinderivat av den generelle formel: ;hvor W og Rg er som ovenfor angitt, og Q er halogen, fortrinnsvis klor, eller d) et syreklorid av den generelle formel: ; hvor W, R^og Ry er som ovenfor angitt, omsettes med et eventuelt ;optisk aktivt amin av den generelle formel: ; ; hvor C A, X, Y, A, R^, R^og R^er som ovenfor angitt, eller ;e) et racemat av den generelle formel I underkastes en racemat-spaltning, ;og at de under a) til e) erholdte forbindelser eventuelt overføres til et fysiologisk godtagbart salt med en uorganisk eller organisk base. ;Racematspaltningen ifølge e) kan eksempelvis skje ved dann-else av diastereomere salter med sterke, optisk aktive baser. ;Eksempel 1 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-1-tet ralylamid ;Til en oppløsning av 20 mmol 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyreklorid i 70 ml aceton tildryppes ,ved 10°C en oppløsning av 22 mmol triethylamin og 22 mmol 1-aminotetralin i 30 ml aceton. Efter 16 timer ved 20°C og 90 minutters kokning av-kjøles blandingen, bunnfallet avsuges og omkrystalliseres fra alkohol. ;Utbytte: 4,5 g med smeltepunkt 174°C. ;Eksempel 2 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-f enyleddiksyre-1-indanylamid ;Fremstillingen skjedde analogt med eksempel 1 med 1-amino-indan. ;Utbytte: 5,8 g med smeltepunkt 154°C. ;Eksempel 3 ;R(+) -4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyrel-1-a-naf thylet hylamid ;Fremstillingen skjedde analogt med eksempel 1 medR(+)-l-a-nafthylethylarain, og omkrystalliseringen skjedde fra aceton-vann 1:1. Utbytte: 3, 79med smeltepunkt 172°C. ;[a]p° = +27° (c=l, kloroform). ;Eksempel 4 ;S(-)-4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-1-a-naf thylethylamid ;Fremstillingen skjedde analogt med eksempel 1 med S(-)-l-a-nafthylethylamin, og omkrystalliseringen skjedde fra aceton:vann 1:1. Utbytte: 4,0 g med smeltepunkt 172°C. ;[a]^° = -23,7° (c=l, kloroform). ;Eksempel 5 ;S(-)-4-[N-(5-neopentyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-1-g- nafthylethylamid ;2-amino-5-neopentylpyrimidin ble fremstilt som generelt be-skrevet for 2-amino-5-alkylpyrimidiner (Arzneimittelforschung 14, 373 (1964)). ;56 mmol av dette utgangsmateriale ble behandlet i lOO ml pyridin med 4-klorsulfonyl-fenyleddiksyre i 2 timer ved 8o°C. Felning med vandig saltsyre, forsåpning av dimethylamidfunksjonen ;med 3%-ig natronlut (6 timers kokning), varmfiltrering og felning med saltsyre ga efter omkrystallisasjon fra methylglycol-alkohol 14,2 g 4-[N-(5-neopentyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre med smeltepunkt 250°C. Omsetning av 19 mmol av det tilsvarende syreklorid (fremstilt med thionylklorid) med 28 mmol (S)-l-a-nafthylethylamin og 20 mmol triethylamin i 100 ml kloroform (1 times kokning), avdampning av oppløsningsmiddel, suspendering i vandig saltsyre og omkrystallisasjon fra pyridin-vann og derpå fra isopropanol-aceton-vann ga produktet med 46% av det teoretiske utbytte, smeltepunkt 166°C. ;[a]p° = -25° (c=l, kloroform). ;Eksempel 6 ;S (-)-4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-1-g- naf thylethylamid ;Fremstillingen skjedde analogt med eksempel 1 med 4~[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyreklorid og (S)-1-a-nafthylethylamin. ;Utbytte: 43% av det teoretiske, smeltepunkt l83°C. ;Eksempel 7 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-1-(2-pyridyl) - ethylamid ;Fremstillingen skjedde analogt med eksempel 1 med l-(2-pyridyl)-ethylamin. Acetonet ble imidlertid avdestillert, residuet suspendert i fortynnet saltsyre og ekstrahert med kloroform. Efter avdampning av kloroformen ble residuet opptatt i vandig natrium-bicarbonatoppløsning, blandingen ble filtrert, filtratet syret, bunnfallet avsuget og opptatt i vandig ammoniakk. Oppløsningen ble filtrert over kull og syret med 20%-ig eddiksyre til pH 6. Bunnfallet ble omkrystallisert fra alkohol-vann. ;Utbytte: 1,2 g med 1,4% vann, smeltepunkt 84°C. ;Eksempel 8 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-1-(2,2,2-trifluor)- fenylethylamid ;Fremstillingen skjedde analogt med eksempel 1 med 1-fenyl-2,2,2-trifluorethylamin. ;Utbytte: 30% av det teoretiske, smeltepunkt l68°C. ;Eksempel 9 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-f enyleddiksyre-1-cyano-benzylamid ;Fremstillingen skjedde analogt med eksempel 1 med 2-fenyl-glycin-nit ril. ;Utbytte: 13% av det teoretiske, smeltepunkt l4o°C. ;Eksempel 10 ;4-[N- (5-isobut yl-2-py r imidinyl) -sulf amoyl ] -f enyleddiksyre-l-( 2-f enyl)- fenylethylamid ;Fremstillingen skjedde analogt med eksempel 1 med l-(2-bifenyl)-ethylamin, som ble erholdt fra 2•-fenyl-acetofenon ved reduserende aminering med ammoniumformiat ifølge Wallach-Leuckart. Utbytte: 23% av det teoretiske med smeltepunkt 98°C. ;Eksempel 11 ;4-[N-(5-neopenty1-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-l-(N-methyl- 3- indolyl)- ethylamid ;Fremstillingen skjedde analogt med eksempel 1 med l-(l-methyl-3- indolyl)-ethylamin. ;Eksempel 12 ;4- [N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-fenyleddiksyre-2 *-methyl- where C<*>, X, Y, Å, R^, R^, R^ and R^ are as indicated above, and Q is halogen, preferably chlorine, is reacted with guanidine or a salt thereof, and that the formed, optionally optically active guanidinesulfonyl compound of the general formula: ;where the meaning of the substituents is as indicated above, is condensed under ring closure with a substituted malondialdehyde of the general formula: ;where W and R^ are as indicated above, the aldehyde group may also be functionally modified . ;where C , X, Y, A, R^, R^, and R_ are as indicated above', in free form or as an alkali metal salt, is reacted with a pyrimidine derivative of the general formula: ;where W and Rg are as indicated above, and Q is halogen, preferably chlorine, or d) an acid chloride of the general formula: ; where W, R^ and Ry are as stated above, is reacted with an optional optically active amine of the general formula: ; where C A, X, Y, A, R^, R^ and R^ are as indicated above, or ;e) a racemate of the general formula I is subjected to a racemate cleavage, ;and that those under a) to e) obtained compounds optionally transferred to a physiologically acceptable salt with an inorganic or organic base. The racemate cleavage according to e) can for example take place by forming diastereomeric salts with strong, optically active bases. ;Example 1 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-tetraylamide ;To a solution of 20 mmol of 4-[N-(5-isobutyl-2-pyrimidinyl)- sulfamoyl]-phenylacetic acid chloride in 70 ml of acetone is added dropwise, at 10°C, to a solution of 22 mmol of triethylamine and 22 mmol of 1-aminotetralin in 30 ml of acetone. After 16 hours at 20°C and 90 minutes of boiling, the mixture is cooled, the precipitate is suctioned off and recrystallized from alcohol. Yield: 4.5 g with melting point 174°C. ;Example 2 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-indanylamide ;The preparation took place analogously to example 1 with 1-amino-indane. Yield: 5.8 g with melting point 154°C. ;Example 3 ;R(+)-4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid 1-a-naphthyl amide ;The preparation took place analogously to example 1 with R(+)-1-a- naphthylethylaraine, and the recrystallization took place from acetone-water 1:1. Yield: 3.79 with melting point 172°C. ;[a]p° = +27° (c=1, chloroform). ;Example 4 ;S(-)-4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-a-naphthylethylamide ;The preparation took place analogously to example 1 with S(-)-l-a- naphthylethylamine, and the recrystallization took place from acetone:water 1:1. Yield: 4.0 g with melting point 172°C. ;[a]^° = -23.7° (c=1, chloroform). ;Example 5 ;S(-)-4-[N-(5-neopentyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-g-naphthylethylamide ;2-amino-5-neopentylpyrimidine was prepared as generally described for 2-amino-5-alkylpyrimidines (Arzneimittelforschung 14, 373 (1964)). 56 mmol of this starting material was treated in 100 ml of pyridine with 4-chlorosulfonyl-phenylacetic acid for 2 hours at 80°C. Precipitation with aqueous hydrochloric acid, saponification of the dimethylamide function with 3% caustic soda (boiling for 6 hours), hot filtration and precipitation with hydrochloric acid gave, after recrystallization from methylglycol alcohol, 14.2 g of 4-[N-(5-neopentyl-2-pyrimidinyl) )-sulfamoyl]-phenylacetic acid with a melting point of 250°C. Reaction of 19 mmol of the corresponding acid chloride (prepared with thionyl chloride) with 28 mmol of (S)-1-α-naphthylethylamine and 20 mmol of triethylamine in 100 ml of chloroform (boiling for 1 hour), evaporation of solvent, suspension in aqueous hydrochloric acid and recrystallization from pyridine- water and then from isopropanol-acetone-water gave the product with 46% of the theoretical yield, melting point 166°C. ;[a]p° = -25° (c=1, chloroform). ;Example 6 ;S (-)-4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-g-naphthylethylamide ;The preparation took place analogously to example 1 with 4~[N-(5 -isopropoxy-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid chloride and (S)-1-α-naphthylethylamine. Yield: 43% of the theoretical, melting point 183°C. ;Example 7 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-(2-pyridyl)-ethylamide ;The preparation took place analogously to example 1 with 1-(2-pyridyl)-ethylamine . However, the acetone was distilled off, the residue suspended in dilute hydrochloric acid and extracted with chloroform. After evaporation of the chloroform, the residue was taken up in aqueous sodium bicarbonate solution, the mixture was filtered, the filtrate acidified, the precipitate suctioned off and taken up in aqueous ammonia. The solution was filtered over charcoal and acidified with 20% acetic acid to pH 6. The precipitate was recrystallized from alcohol-water. Yield: 1.2 g with 1.4% water, melting point 84°C. ;Example 8 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-(2,2,2-trifluoro)-phenylethylamide ;The preparation took place analogously to example 1 with 1-phenyl-2 ,2,2-trifluoroethylamine. Yield: 30% of the theoretical, melting point 168°C. ;Example 9 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-cyano-benzylamide ;The preparation took place analogously to example 1 with 2-phenyl-glycine-nitrile. ;Yield: 13% of the theoretical, melting point 14o°C. ;Example 10 ;4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-l-(2-phenyl)-phenylethylamide ;The preparation took place analogously to example 1 with l-( 2-biphenyl)-ethylamine, which was obtained from 2•-phenyl-acetophenone by reductive amination with ammonium formate according to Wallach-Leuckart. Yield: 23% of the theoretical with a melting point of 98°C. ;Example 11 ;4-[N-(5-neopenty1-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-(N-methyl-3-indolyl)-ethylamide ;The preparation took place analogously to example 1 with l-(l- methyl-3-indolyl)-ethylamine. ;Example 12 ;4- [N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-2*-methyl-

indolinid indolinide

Fremstillingen skjedde analogt med eksempel 1 med 2-methyl- The preparation took place analogously to example 1 with 2-methyl-

indolin. indoline.

Utbytte: 40% av det teoretiske med smeltepunkt 171°C (hydrat). Yield: 40% of the theoretical with melting point 171°C (hydrate).

Claims

Analogy method according to patent no. 131,835 by developing

position of new sulfamoylpyrimidines with blood sugar-lowering action, and which have the general formula:

where C , X, Y, R^, Rg, R-, and W are as stated in the main patent, A can, in addition to being as stated in the main patent, also be a naphthyl, pyridyl, 1-methyl-indolyl or 2-phenylphenyl group, In addition to being as in the main patent, R„ can also be cyano or trifluoromethyl, or R^ can be one with the substituent A attached alkylene group with 2 or 3 carbon atoms so that indan is formed or the tetrahydronaphthalene, and R- can, besides being as indicated in the main patent, be a direct bond to the substituent A, with the proviso that one of the substituents A, R^ or R- must be as above specifically stated, as well as salts of these compounds with physiologically acceptable bases, characterized by a) an optional optically active sulfohalide of the general formula:

where C A, X, Y, A, R^, R^, and R. are as indicated above, and Q is halogen, preferably chlorine, is reacted with guanidine or a salt thereof, and the obtained, optionally optically active guanidinesulfonyl compound of the general formula:

where the substituents have the same meaning as above, are condensed under ring closure with a substituted malondialdehyde of the general formula:

where W and Rg are as stated above, since the aldehyde group may be functionally changed, or b) the optionally optically active sulfohalide listed under a) is reacted with a 2-amino-5-W-R^-pyrimidine, where W and Rg are as stated above , or c) an optional optically active sulfonamide of the general formula:

where C , X, Y, A, R^, R^, R- and R_ are as indicated above, in free form or as an alkali metal salt, reacted with a pyrimidine derivative of the general formula: where W and Rg are as indicated above, and Q is halogen, preferably chlorine, or d) an acid chloride of the general formula: where W, R^ and R_ are as indicated above, reacted with an optional optically active amine of the general formula:

where C* X, Y, A, R_, Ri and R- are as indicated above, or e) a racemate of the general formula I is subjected to a racemate resolution, and that optionally the compound obtained under a) to e) is transferred to a corresponding salt with a physiologically acceptable inorganic or organic base.