US3878212A - Blood sugar lowering sulfamoyl pyrimidines and asymmetrical carbon atom - Google Patents

Abstract

which have available an asymmetrical C atom C*, the enantiomers exhibit a surprisingly great difference in the blood sugar lowering effect. Thus, one of the enantiomers is generally 30 to 300 times more effective than the other and about twice as effective as the racemate.

Compounds of the sulfamoyl pyrimidine with asymetric carbon atom are provided for the treatment of Diabetes Mellitus. Substituted sulfonamides are suitable for the treatment of Diabetes mellitus. The first clinically tested preparation of this class of substances, N-sulfanilyl-N''-n-butyl urea (Carbutamid), still showed undesirable bacteriostatic side effects. These side effects no longer appear, for example, in N-(4methylbenzenesulfonyl)-N''-n-butyl urea (Tolbutamid) or in N-(5(2-methoxyethoxy)-2-pyrimidinyl)-sulfamoyl-benzene (Glymidin). The clinically employed dose of the last-named compounds is of the order of 0.5 - 1 g daily. The p-substitution of the benzene nucleus in the Glymidin type, in particular the subsitution by aromatic acid amide groups, leads to compounds of considerably increased action, as is evident from Belgian Pat. No. 726,253. It has now been found that in compounds of the general formula I

Description

United States Patent 91 Rufer et al.

[ Apr. 15, 1975 BLOOD SUGAR LOWERING SULFAMOYL PYRIMIDINES AND ASYMMETRICAL CARBON ATOM [76] Inventors: Clemens Rufer, Cimbernstr. 6,

' Berlin 38; Hans Ahrens, Spanische Allee 72a, Berlin 38; Helmut Biere, Joachim-Friedrich-Str. 13, Berlin 31; Eberhard Schroder, Am Rosenanger 22, Berlin 28; Erich Gerhards, Maximiliankorso 20, Berlin 28; Ekkehard Schillinger, Lagardestr. 44a, Berlin 38; Wolfgang Felix Losert, Hauptstr. 118, Berlin 62; Olaf Loge, Bekassinenweg 37, Berlin 27, all of Germany 22 Filed: July 5,1973

21 Appl. No.: 377,944

Related US. Application Data [63] Continuation of Ser. No. 129,948, March 31, 1971,

abandoned.

[30] Foreign Application Priority Data Apr. 28, 1970 Germany 2021962 [52] US. Cl..... 260/256.5 R; 260/556 AR; 424/251 [51] Int. Cl C072 51/42 [58] Field of Search 260/256.5 R

[56] References Cited UNITED STATES PATENTS 3,621,026 l/197l Gutsche et a1. 260/256.5 R

Primary Examiner--Richard J. Gallagher Attorney, Agent, or Firm.loseph F. Padlon [57] ABSTRACT Compoundsof the sulfamoyl pyrimidine with asymetric carbon atom are provided for the treatment of Diabetes Mellitus.

Substituted sulfohamides are treatment of Diabetes mellitus.

suitable for the It has now been found that in compounds of the general formula I 50 -Fornu1a I which have available'an asymmetrical C atom C*, the enantiomers exhibit a, surprisingly great difference in the blood sugar lowering effect. Thus, one of the enantiomers is generally 30 to 300 times more effective than the other and about twice as effective as the racemate.

19 Claims, No Drawings ethylamlde BLOOD SUGAR LOWERING SULFAMOYL PYRIMIDINES AND ASYMMETRICAL CARBON ATOM This is a continuation of application Ser. No. 129,948 filed Mar. 31, 1971, now abandoned.

This invention relates to racemates and optical antipodes of sulfamoyl pyrimidines of the general formula 1, above where C* is an asymmetrical C atom;

X and Y are identical or different and each by itself represents a direct bond or a methylene group;

R and R Hydrogen or halogen atoms, alkyl groups with 1 6 atoms or alkoxy groups with l 4 C atoms;

R, and R are different and represent hydrogen atoms, straightchain or branched alkyl groups, with l 4 C atoms, carboxyl or alkoxycarbonyl groups, with l 4 C atoms;

R; and R are identical or different and represent hydrogen atoms or low alkyl groups with l 4 C atoms;

R,, is a straight-chain or branched alkyl group with l 6 C atoms; and

W is a direct CC bond or an oxygen or sulfur atom, as well as their salts with physiologically tolerable bases.

Testing for blood sugar reduction was done houron on rabbits fasting for 24 hours, over a time interval of 6 hours. The values shown in the following table under BZ (Blood Sugar) indicate the lowest dose of the particular sulfonamide which lowers the blood sugar as much as 1 mg/kg of 4-[N-(5-isopropoxy-2- pyrimidinyl)-su1famoyll-phenylacetic acid--chloro-2- methoxyanilid, one of the most effective compounds from Belgian Pat. No. 726,253. The dosage gradation is: 30, 3, 1, 0.5, 0.25, 0.1, 0.05 mg/kg).

Table do not have a side chain (e.g., Glymidin) are betacytotropically active.

For therapeutical use, the substances according to the invention can be administered by mouth as free sulfonamides, as salts with physiologically acceptable inorganic and/or organic bases, such as hydroxides of sodium, lithium, calcium or ammonium, amines such as methyl glucamine, morpholine, ethanolamine and others, or also in the form of mixtures of the free sulfonamides with a suitable alkali bicarbonate, or respectively carbonate. Especially suitable are bases which in themselves are blood sugar lowering, as for example, butyl biguanide. The confectioning of the substances can be effected without or with the additions, vehicles, taste correctives, etc. common in galenic pharmacy, namely for example in powder form, as tablets, dragees, capsules, pills, or in the form of suspensions or solutions.

The production of the new compounds of the general formula 1 is effected by a) reacting a possibly optically active sulfohalide of the general formula where C*, X, Y, R R R R R and R have the same meaning as above and Q is a halogen atom, preferably chlorine, with guanidine, and condensing the resulting possibly optically active guanidinesulfonyl compound of the general formula with a substituted malonedialdehyde of the general formula O -Q HJLLRb BZ form Name (+) form Racemate 4-[ N-( 5-isopropoxy2-pyrmidinyl sulfamolyll-phenylacetic acid-l-phenyl- 0 l 30 4-[ N-( 5-isopropoxy-2-pyrimidinyl sulfamoyl1-phenylacetic acid-l-phenylpropylamide 4-[N(5-isobutyl-2-pyrimidinyl)- sulfamoyl ]-phenylacetic acid- 1 -phenyl ethylamide 4-[N-( S-isobutyl-Z-pyrimidinyl sulfamoyl] lphenylacetic acid- 1 -phenylpropylamide 4-[N-(5-isobutyl-2-pyrimidinyl)- sulfamoyl ]-phenylacetic acid- 1 (5-fluoro-2-methoxy-phenyl )-ethylamide It is surprising that the increase in blood sugar lowering action is brought about-by a modification of the molecule in the lengthened side chain of the sulfonized benzene nucleus, that is, a point which does not necessarily have anything to do with the beta-cytotropic action of the sulfonamides, since also compounds which where W and R have the same meaning as above, in which the aldehyde groups may also be functionally modified, closing the ring, or

b. reacting the possibly optically active sulfohalide mentioned under a) with a 2-amino-5-W-R pyrimidine, where W and R have the same meaning as above, or

c. Reacting a possibly optically active sulfonamide of the general formula in which C*, X, Y, R R R R R and R have thesame meaning as above, in free form or as alkali salt I with a pyrimidine derivative of the general formula where W and R have the same meaning as above and Q is a halogen atom, preferably chlorine, or

d. reacting an acid chloride of the general formula with a possibly optically active amine of the general formula Where C*, X, Y, R R R R, and R have the same meaning as above, or

e. subjecting a racemate of the general formula 1 to racemate splitting, and possibly transforming the compounds obtained according to a) to e) with physiologically tolerable inorganic or organic bases into the respective salts.

The racemate splitting according to e) can be effected, for example, by formation of diastereomeric salts with strong, optically active bases.

The substituted malonedialdehyde used for the reaction as per a) can be obtained, for example, in that compounds of the general formula CH -W42 IEXAMPLE 1 S-(-)-[N-(5-isopropoxy-2-pyrimidinyl)sulfamoyl]- phenyl-aceticacid-l-phenyl ethylamide.

7.38 g (20 millimole) of 4-[N-(5-isopropoxy-2- pyrimidinyl)-s'ulfamoyl]-phenyl-acetic acid chloride were suspended in 70 ml of chloroform. At 5 10C 4.88 g (40 millimole) of S(-)-1-phenylethylamine were dropped into 20 ml of chloroform. After boiling for one hour, the product is concentrated and recrystallized out of 20 ml of alcohol with 20 ml of water.

Yield 5.3 g 56 percent of the theory of melting point 148C, [alpha],, 29 (c'=l, chloroform).

EXAMPLE 2 R(+)-4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-l-phenyl-ethylamide The compound was produced analogously to example 1 with R(+)-l-phenylethylamine.

Yield: 57 percent of the theory.

Melting point: 148C. [alpha],, =+30 (c 1, ch10- roform).

EXAMPLE 3 4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-phenyl-ethylamide The compound was procured analogously to example 1 with l-phenylethylamine.

Yield: 64 percent of the theory. Melting point: l72174C. (from methylglycol-water). The sodium salt of this compound was obtained in ethanol with an equivalent quantity of sodium alcoholate. Melting point: 285C.

EXAMPLE 4 S(-)-4-[ N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl1- phenylacetic acid-l-phenyl-propylamide The compound was produced analogously to example l with S-(-)-l-phenyl-propylamine. Recrystallization from ethanol, then from a mixture of methylglycol and water 3:1.

Yield: 27 percent of the theory. Melting point: 177C. [alplia] =-37 (c 1, chloroform).

EXAMPLE 5 R(+)-4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-phenyl-propylamide The compound was produced analogously to example 1 with R-(+)-l -phenyl-propylamine. Recrystallization from ethanol.

Yield: 53 percent. Melting point: 178C. [alpha/ +38 (c l, chloroform).

EXAMPLE 6 4[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-phenyl-propylamide The compound was produced analogously to example 1 with l-phenyl-propylamine.

Yield: 57 percent of the theory. Melting point: l73-175C.

EXAMPLE 7 S-(-)-4-[N-(5-isobuty1-2-pyrimidinyl)-su1famoyl]- phenylacetic acid-l-phenyl-ethylamide The compound was produced analogously to example 1 from 4-[N (5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and S-( l phenylethylamine.

Yield: 72 percent of the theory. Melting point: 148C.

[alpha] 29 (c 1, chloroform). The sodium salt of this compound was obtained in ethanol with an equivalent quantity of sodium alcoholate. Melting point 274C.

[alpha] 29 (c 2.6, water).

EXAMPLE 8 R-(+)-4-[N-(5-isobutyl-2-pyrimidinyl) sulfamoyl]- phenylacetic acid-l-phenyl-ethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and R-(+)-1- phenylethylamine.

Yield: 78 percent of the theory. Melting point: 150C.

[alpha],, +29 (c 1, chloroform). Sodium salt: Melting point: 273C. [alpha] =+29 (c 2, water).

EXAMPLE 9 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-phenylethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-phenyl-ethylamine.

Yield: 81 percent of the theory. Melting point: ll4-l16C.

The sodium salt was obtained with an equivalent quantity of sodium alcoholate in ethanol. Melting point: 254C.

EXAMPLE 10 (c l, chloroform).

EXAMPLE 11 I R-(+)-4-[N-(5isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-phenyl-propylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and R-(+)-l-phenylpropylamine and recrystallized twice out of ethanol.

Yield: 51 percent of the theory. Melting point: 198C.

[alpha] +35 (c 1, chloroform).

EXAMPLE l2 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-1phenyl-propylamide The compound was produced analogously to example 1 from 4 -[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid chloride and l-phenyl- 'propylam ine.

Yield: 58 percent of the theory. Melting point: l68-l70C.

EXAMPLE 13 S-()-4-[ N-(S-ethyI-Z-pyrimidinyl)-sulfarnoyl]- phenylacetic acid- 1 phenyl-ethylamine The compound was produced analogously to example, 1 with 4-[N-(5-ethyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and recrystallized twice out of ethanol.

Yield: 64 percent of the theory. Melting point: 169C.

EXAMPLE 14 4-[N-(5-ethyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid- 1 phenyl-ethylamide The compound was produced analogously to example 1 from 4-[N-(5-ethyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-phenylethylamine.

Yield: 47 percent of the theory. Melting point: 122124C.

EXAMPLE 15 S-()-4-[ N-( S-ethoxy-Z-pyrimidinyl )-sulfamoyl]- phenylacetic acid- 1 phenyl-ethylamide The compound was produced analogously to example l with 4-[N-(5-ethoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride. Recrystallization out of ethanol.

Yield: 90 percent of the theory. Melting point: 174C.

[alpha] =.33 (c 1, chloroform).

EXAMPLE 16 4-[N-(5-ethoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid- 1 phenyl-ethylamide The compound was produced analogously to example 1 from 4-[N-(5-ethoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-phenylethylamine.

Yield: 90 percent of the theory. Melting point: l-177C.

EXAMPLE l7 4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid- 1 phenyl-butylamid The compound was produced analogously to example 1 with l-phenylbutylamine and recrystallized out of ethanol.

Yield: 72 percent of the theory. Melting point: 182l83C.

EXAMPLE 1s 4-[N-(5isopropoxy-Zpyrimidinyl)-sulfamoyl]- phenylacetic acid-lphenyI-Z-methylpropylamide The compound was produced analogously to example 1 from 4-[N-(5isopropoxy-Z-pyrimidinyl)-sulfamoyll-phenylacetic .acid chloride and l-phenyl-2- methyl-propylamine and recrystallized from ethanol.

Yield: 58 percent vof the theory. Melting point: 191l93C. I

EXAMPLE l9 4- N-( 5 -isopropoxy-2-pyrimidinyl )-sulfamoyl phenylacetic acid-Z-phenyl-2-butylamide The compound was produced analogously to example l with 2-phenyl-2-butylamine.

Yield: 48 percent of the theory. Melting point:

EXAMPLE 20 4[ N- 5 isopropoxy2-pyrimidinyl )-sulfamoyl] phenylac etic acid-l 5-chloro-2-methoxy phenyl ethylamide The compound was produced analogouslyto example 1 with 1-(5-chloro-2-methoxy-phenyl)-ethylamine.

Yield: 50 percent ofthe theory; Melting'point: 122C Example 21 4-[N-(5 isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-1-(5-chloro-2-methoxy-phenyl)- ethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfa moyl]- phenylacetic acid chloride and l-(5-chloro-2-methoxyphenyl)-ethylamine.

Yield: 70 percent of the theory. Melting point: 122C (from ethanol-water).

EXAMPLE 22 EXAMPLE 23 4-lN-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-(l-(5-fluoro-2-methoxy-phenyl)- ethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-(5-fluoro-2-methoxyphenyl)-ethylamine.

Yield: 66 percent. Melting point: 134C.

EXAMPLE 24 4-[,N-isopropoxy-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid-1-(2,5-dimethoxy-phenyl)- ethylamide The compound was produced analogously to example l with 1-(2,5-dimethoxy-phenyl)-ethylamine.

Yield: 90 percent, Melting point: 176C. 1-(2,5- dimethoxy-phenyl)-ethylamine was obtained analogously to 1-(5-chloro-2-methoxy-phenyl)-ethylamine (see example from 2,5-dimethoxy-acetophenone.

Yield: 27 percent of boiling point 150C at 13 mm EXAMPLE 4-[ N-( 5 ispbutyl 2-pyrimidinyl )-sulfamoyl phenylacetic "acid l-(2,5-dimethoxy-phenyl)- ethylamide i The compound was obtained analogously toexample 1 from, 4-[N(5 isobujtyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-2(2,5-dimethoxy- 8 phenyl)-ethylamine.

Yield: 84 percent. Melting point: 192C.

EXAMPLE 26 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-(4-n-propyl-phenyl)-ethylamide The compound was produced analogously to example 1 from 4-[N (5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-(4-n-propyl-phenyl)- ethylamine.

Yield: 55 percent. Melting point: C.

EXAMPLE 27 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-1-(2-ethoxy-5-methyl-phenyl)- ethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and 1-(2-ethoxy-5-methylphenyl)-ethylamine.

Yield: 45 percent. Melting point: C.

The l-(2-ethoxy-5-methyl-phenyl)-ethylamine was produced as follows:

17.8 g (0.1 mole) of 2-ethoxy-5-methylacetophenone were heated with 22.5 g (0.5 mole) of formamide for 6 hours at -200C. After cooling, the product was diluted with water and extracted three times with 100 ml of ether each time. The organic residue from the ether solution (15.2 g) was heated with 30 g NaOH in 300 ml of water for 3 hours with reflux. After cooling, the separated oil was extracted with 3 X 150 ml of ether, and the organic phase was washed and dried over K CO After removal of the ether, the remaining oil was distilled under high vacuum.

Yield: 10 g (55.8 percent). Boiling point: 99102C at 0.01 mm Hg. Melting point of the picrate: 211C (ethanol) EXAMPLE 28 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-1-(5-chloro-2-methyl-phenyl)- ethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and l-(5-chloro-2-methylphenyl)-ethylamine.

Yield: 60 percent. Melting point: 166C.

The l-(5-chloro-2-methyl-phenyl)-ethy1amine was produced as follows:

To a solution of 0.5 mole methyl magnesium iodide in 300 ml absolute ether there was added drop by drop while stirring a solution of 38 g of 5-chloro-2- methylbenzonitrile (0.25 mole) in 150 ml absolute ether. Then the solution was boiled for about 8 hours with reflux. After cooling, 10 g of lithium alanate were added in portions and the mixture boiled for 3 hours with reflux.

After cooling, the excess lithium alanate as well as Grignards reagent were decomposed by careful addition of about 250 ml of Zn NaOH. After extracting with ether, the combined ether phases were washed and concentrated under vacuum.

Yield: 36.6 g (86 percent). For purification the product was distilled under vacuum. Boiling point: 90C at 1 mm Hg. Melting point of the picrate: 233C (ethanol).

EXAMPLE 29 4-[ N-( -isobutyl-2-pyrimidinyl )-su1famoyl]- phenylacetic acid-N-methyl-l-phenyl ethylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and N-methyl-lphenylethylamine.

Yield: 40 percent of the theory. Melting point: l69l7lC.

EXAMPLE 30 S-(-)-4-[N-(5-isobutyl-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid-1-(5fluoro2-methoxy-phenyl)- ethylamide To 3167 g millimole) of 4-[N-(5-isobutyl-2- pyrimidinyl)-sulfamoyll-phenylacetic acid chloride in 35 ml of chloroform there was added a mixture of 1.86 g (l 1 millimole) of S-()-l-(5-fluoro-2methoxy)- phenyl-ethylamine and 1.1 1 g (l l millimole) of triethylamine in ml of chloroform at 0 5C. drop by drop. After another 2 /2 hours of agitation at 20C, the product was heated to boiling for 1 hour, the solvent evaporated, and the residue suspended in 75 ml of water. After acidification with hydrochloric acid, the product was suction-filtered and recrystallized twice out of ethanol.

Yield: 3.2 g 64 percent of the theory. Melting point 156C, [alpha],, 24 (c l, chloroform).

The splitting of the racemic l-(5-fluoro-2-methoxyphenyl) ethylamine can be effected as follows:

141 g (0.834 mole) of the racemic amine in 200 ml of methanol were added to a boiling solution of 126 g (0.84 mole) of L-(+)-tartaric acid in 1800 ml of methanol. After standing-over night at 20C, the salt was suction filtered; the working up of the mother liquor M is described below. The salt (189 g 0.59 mole) was recrystallized five times from a minimum of hot methanol, 29 g 0.11 mole being obtained. This was dissolved in 150 ml of water, the base being liberated with concentrated sodium hydroxide solution, ether extracted, and distilled. The obtained free, dextrorotating base (14 g 0.083 mole, [alpha],, +29) was added to a suspension of 1.75 g (0.010 mole) of Ni(SCN) in 200 ml of toluene, the mixture being heated for 5 minutes to 85C and left at 20 for 16 hours. After cooling to 0C, the complex was filtered out, the filtrate concentrated and the residue distilled. 8.5 g 0.05 mole of R-(+)-1-(5fluoro-2-methoxy-phenyl)ethylamine of boiling point 113114C at 13 mm Hg was obtained. The rotation of the base without solvent was [alpha],, +36. The above-mentioned mother liquor M was concentrated to 1 liter, filtered, the filtrate was concentrated to dryness, and from the salt the base was liberated as usual, distilled with steam, extracted with benzene, the extract concentrated and the residue distilled; one obtained 34 g 0.2 mole of free, levorotating base.

i The latter was added in 50 ml of methanol to a boiling solution of 27 g (0.18 mole') D-()-tartaric acid in 400 ml of methanol. After standing over night, the salt was suction-filtered. The salt (43 g 0.135 mole) was recrystallized once out of a minimum of hot methanol; one obtained 32 g 0.1 mole. The levorotating base liberated therefrom as usual (14 g 0.083 mole, [alpha],, was further purified with 1.75 g (0.010 mole) Ni(SCN) in 60 ml of toluene and 10 m1 of tertiary butylbenzene as described above. 7.7 g 0.046

mole of S-()- l-( 5-f1uo-2-methoxy-phenyl ethylamine of boiling point l12-l14 C at 13 mm Hg were obtained. The rotation of the base without solvent EXAMPLE 31 R-(+)-4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenlacetic acid- 1-(5-fluoro-2methoxy-phenyl)- ethylamide The compound was produced analogously to example 30 with R-(+)-l-(5-fluoro-2-methoxy-phenyl)- ethylamine and 4-[N-(5isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid chloride. Yield 68 percent of the theory. Melting point 157C. [a1pha],, +24 (c l chloroform).

EXAMPLE 32 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-lmethoxycarbonylbenzylamide The compound was produced analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and Z-phenyl-glycinemethyl ester.

Yield: 65 percent. Melting point 124C.

EXAMPLE 33 S-()-4-[ N-( 5-isobutyl-2-pyrimidinyl )-sulfamoyl phenylacetic acid-l-phenylethylamide 33 g (0.1 mole) of S-()-4-chlorosulfonylphenylacetic acid-l-phenylethylamide were charged in a solution of 15.0 g 2-amino-5-isobutylpyrimidine in ml pyridine and the mixture was heated for 2 hours at 50C. Then 350 ml of water was added and the precipitated product was recrystallized from ethanol.

Yield: 30 g 66 percent of the theory. Melting point: 148C [alpha],, 29 (c=l, chloroform).

S-()-4chlorosulfonylphenylacetic acid- 1 phenylethylamide was obtained as follows: 57 g (0.2 mole) of S-()-4-nitrophenylacetic acicl phenylethylamide (produced from 4-nitrophenylacetic acid chloride with S-()-1-phenylethylamine in pyridine, melting point C, [alpha],, 86 (c-l, in methanol) were hydrated in 500 m1 of dioxane at 70-80C and 50 atm excess pressure in the presence of Raney nickel. After removal of the catalyst by suction, the solvent was distilled off under vacuum and the residue recrystallized from benzene-petroleum ether.

Yield: 45 g 88 percent of the theory. Melting point: 142C, [alpha] 65 =1, in methanol).

25 g of this S-()-4-amino-phenyl-acetic acid-1- phenylethylamide were dissolved in ml of glacial acetic acid plus 25 ml of concentrated hydrochloric acid and admixed with S.5 g of sodium nitrite while cooling to 0 5C. Then the diazonium salt solution was dropped at room temperature into a mixture consisting of 100 m1 of an approximately 1 1 percent sulfur dioxide solution in glacial acetic acid, 6 g of copper(l1) chloride in 10 ml of water, and 100 m1 of benzene. After that, agitation was continued for 5 hours at 30C, the mixture poured on ice, and the precipitated sulfochloride suctioned off, washed with iced water, and dissolved in chloroform was drawn off under vacuum. The crude sulfochloride was coupled with bases without further purification.

EXAMPLE 34 4-[ N-( 5-isobutyl-2-pyrimidinyl )-sulfamoyl]- phenylacetic acid-l-phenyl-ethylamide 34 g of ,4-aminosulfonyl-phenylacetic acid-lphenylethylamide sodium salt and 17.5 g of 2-chloro-5- isobutylpyrimidine were dissolved in 320 ml of dimethyl formamide and stirred for 3V2 hours at 150C. The dimethyl formamide was distilled off and the remaining oil residue was stirred into 500 ml of water. The precipitate was suctioned off and recrystallized out of ethanol.

Yield: 13 percent of the theory. Melting point: 1 l3l 15C.

The starting product. 4-aminosulfonyl-phenylacetic acid-l-phenyl-ethylamide sodium salt, was produced by known methods by dropping the 4-chlorosulfonylphenylacetic acidl-phenylethyl chloride into excess ammonium hydroxide, distilling the excess ammonium hydroxide, drying the amide, and reacting with sodium ethylate. Melting point 300C (with decomposition).

EXAMPLE 35 4-1 N-( 5-isopropylthio-Z-pyrimidinyl )-sulfamoyl phenylacetic acid-l-phenylethylamide.

15 g (44.5 millimole) of 4-chlorosulfonylphenylacetic acid-l-phenylethylamide in 70 ml of acetone were added drop by drop at -5C to a mixture of 11.2 g of guanidine nitrate and 37 g of sodium hydroxide in 40 ml of acetone-water 1:1. After 2 hours, the crude 4-guanidino-sulfonyl-phenylacetic acid-lphenyl-ethyl amide was precipitated with 40 ml of water, suctioned off and dried (7 g).

Besides, 4 g of phosgene were passed into a solution of 2.8 g of dimethyl formamide in 12 ml of toluene (temperature 0C). 3.7 g of isopropyl mercaptoacetaldehyde diethylacetal were added in drops at 5C, the mixture was stirred for 2 hours at 65C, the toluene drawn off under vacuum, and the residue neutralized in 4 ml of methanol with a methanolic sodium methylate solution. The reaction product thus obtained was added to a solution of 0.9 g sodium in 21 ml methanol, the solution admixed with the 7 g of sulfaguanidine (see above) and the mixture heated for 12 hours with reflux. After neutralization with hydrochloric acid (pH 6) the product was suctioned off the common salt, the filtrate evaporated under vacuum, and the residue taken up in water. After acidification with hydrochloric acid one obtains the desired product, which was once more dissolved in sodium hydroxide solution and precipitated with hydrochloric acid.

Yield: 3.2 g 15 percent of the theory. Melting point 125l29C.

lsopropyl mercapto-acetaldehyde-diethyl acetal was obtained as follows: 48 g (250 millimole) of acetylmercapto-acetaldehyde-diethyl acetal were added to a solution of 12.5 g sodium in 175 ml ethanol, the mixture was heated for 15 minutes with reflux and at the boiling heat mixed with 64.6 g of isopropyl bromide without further testing. After another hour of heating with reflux, the product was concentrated under vacuum, added with 300 m1 of iced water, and extracted with ether-benzene 1:1. The organic phases were concentrated and the residue was distilled.

Yield: 42 g 88 percent of the theory. Melting point 90-92C at 13 mm Hg.

EXAMPLE 36 EXAMPLE 37 R-(+)-4-[N-(5-ethoxy-2-pyrimidiny1)-sulfamoyl]- phenylacetic acid- 1 -phenylethylamide The compound was produced analogously to example 10 from 5.5 g (15 millimole) of 4-[N-(5-ethoxy-2- pyrimidinyl)-sulfamoyl]-phenylacetic acid chloride, 1.8 g (18 millimole) of triethylamine and 2.18 g (18 millimole) of R-(+)-l-phenylethylamine and recrystallized from ethanol. Yield: 5.5 g 83 percent of the theory. Melting point: 173C, [alpha] +32 (c l, chloroform).

sulfamoyl1- EXAMPLE 38 S-()-4-[N-(5-ethylmercapto-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-l-phenyl-ethylamide The compound was obtained analogously to example 33 from S-()-4-chlorosulfonyl-phenylacetic acid-lphenylethylamide and S-ethyl mercapto-2-aminopyrimidine.

Yield: 20 percent of the theory. Melting point: 149C.

[alpha],, 44 (0 l, chloroform).

5-ethylmercapto-2-amino-pyrimidine was produced as follows: To 38.4 g of ethylmercapto-acetaldehydediethylacetal, produced analogously to the isopropyl mercapto compound in example 35 with ethylbromide,

Yield: 88 percent of the theory, boiling point at 13 mm Hg (84-86C), there were added 42 g of PCL at 3035C and then 45 ml of dimethylformamide at 1520C. The mixture was heated for 90 minutes at 65C, admixed with 50 ml of methanol at 2030C, brought to pH 8 with sodium ethylate solution (21g Na in 200 ml ethanol), and the solution added drop by drop to a mixture consisting of 40 g guanidine nitrate in 60 ml methanol and 7.6 g sodium in 80 ml methanol, at 3035C. Within 2 hours the solvent was distilled off, the residue dissolved in 350 ml water, extracted with chloroform, and the concentrated extract recrystallized twice out of m1 CC1 Yield: 7.9 g 25 percent of the theory. Melting point: 116C. I

EXAMPLE 39 ethylmercapto-Z-aminO-pyrimidine.

Yield: 20 percent of the theory. Melting. point: 149C. H

[alpha],,""= +46 (c l, chloroform).

EXAMPLE 4O 4-[ N-( -isobutyl-2-pyrimidinyl )-sulfamoyl phenylacetic acid- 1 -carboxy-benzylamide The compound was obtainedby saponification of the methyl ester (example 32) with 2n aqueous potash lye for 2 hours at 30C and subsequent acidification.

Yield: 81 Jaercent of the theory. Melting point: 192C.

EXAMPLE 41 4-[N-(5isobutyl-2-pyrimidinyl-sulfamoyl]- phenylacetic acid-l-methyl-2-phenylethylamide The compound was obtained analogously to example 1 from 4-[N-(5-isobutyl-2-pyrimidinyl)-su1famoyl]- phenylacetic acid chloride and l-methyl-2- phenylethylamine Yield: 50 percent of the theory. Melting point: 146C.

EXAMPLE 42 4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-Z-phenylpropylamide The compound was obtained analogously to example 1 from 4-[N-(5-isobutyI-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid chloride and Z-phenyl-propylamine.

Yield: 94 percent of the theory. Melting point: 212C.

EXAMPLE 43 R-(+)-4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-2-phenylpropylamide The production was effected analogously to example 42 by means of R-(+)-2-phenylpropylamine.

EXAMPLE 44 S-(-)-4-[N-(S-isobutyl-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid-2-phenylpropylamide The production was effected analogously to example 42 by means of S-()-2-phenylpropylamine.

EXAMPLE 45 (+)-2-( 4- N-( 5-isopropoxy-2-pyrimidinyl sulfamoyl]-phenyl) )-propionic acid- 1 -R- phenylethylamide The compound was obtained analogously to example 1 from 2-( 4-[ N-( 5-isopropoxy-2-pyrimidinyl sulfamoyl]-phenyl))-propionic acid chloride and R-(+)-1-phenylethylamine.

Yield: 50 percent of the theory. Melting point: 100C.

[alpha],, +l5 (c 1 chloroform).

The acid chloride was prepared as follows:

27.0 g of 2-penylpropionic acid chloride were charged drop by drop in 80 ml of dimethylamine solution (40 percent aqueous) while stirring at to +l5C.

'1 EL-5d N Stirring was continued for 1 hour at +l5C, then leaving stand over night. The solution was shaken out with chloroform and the organic phase concentrated. The 29.0 g: of 2-phenylpropionic acid dimethylamide 5 thus obtained were dissolved in' 150 ml of perchloroethylene, and 75 m] of chlorosulfonic acid were added drop by drop at 55C while stirring. Agitation was continued for 45 minutes at 60-65C, the product being slowly placed on ice, while much heat tone occurred. The iced water was diluted with 200 ml of chloroform and thoroughly stirred. The organic phase was concentrated.

Yield: 38 g.

21.1 g of 2-amino-5-isopropoxy-pyrimidine 138 millimole) were dissolved in 80 ml of pyridine, and while stirring 38.0 g 138 millimole) of the sulfochloride were added. Agitation was continued for 2 hours at 60-65C, the solution was charged in 400 ml of iced water and acidified with hydrochloric acid. After succrude product was saponifled. The crude acid amide was heated for 8 hours with reflux in 60 ml of 10 percent sodium hydroxide solution. After treatment of the alkaline solution with carbon, the product was acidified with 20 percent hydrochloric acid while stirring and cooling, and sanctioned off. The product was prepurified by reprecipitation with dilute ammonia and dilute hydrochloric acid and treatment with carbon. The dried crude product was recrystallized from 150 ml of ethanol-water 9:1.

Yield: 14.3 g. Melting point: l61-l63C.

From this the acid chloride was obtained with thionyl chloride in the usual manner.

EXAMPLE 46 (-)-2-(4-[N-(5-isopropoxy-2-pyrimidinyl)- sulfamoyl]-phenyl)-propionic phenylethylamide The compound was obtained analogously to example 45 by means of S-(-)-1-phenylethylamine.

Yield: 71 percent of the theory. Melting point: 99C.

[alpha],, 15 (0 l, chloroform) We claim:

1. Racemates and optical antipodes of sulfamoyl pyrimidines of the general formula wherein C* is an asymmetric C atom,

X and Y are identical or different and each by itself represents a direct bond or a methylene group except that X and Y cannot both be a direct bond.

acid- 1 -s- R, and R hydrogen or halogen atoms, alkyl groups with l 6 C atoms or alkoxy groups with l 4 C atoms,

R, and R are different and represent hydrogen atoms, straight-chain or branched alkyl (with l4 C atoms), carboxyl or alkoxy carbonyl groups (with 1-4 C atoms) R and R are identical or different and represent hydrogen atoms or low alkyl groups with l4 C atoms,

tion-filtering and repeated rewashing with water the R; a straight-chain or branched alkyl group with 1-6 C atoms, and

W a direct C-C bond or an oxygen or sulfur atom, as well as their salts with physiologically tolerable bases.

2. A compound as set forth in claim 1, which is S(-) 4-[N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid- 1 -phenyl-propylamide.

3. A compound as set forth in claim 1, which is R(+)- 4-[ N-( 5-isopropoxy-Z-pyrimidinyl )-sulfamoyl phenylacetic-l-phenyl-propylamide.

4. A compound asset forth in claim 1, which is 4-[N- (5-isopropoxy-2-pyrimidinyl )-sulfamoyl -phenylacetic acid-l-phenyl-propylamide.

5. A compound as set forth in claim 1, which is S(-)- 4-[N-(5-isobutyl-2-pyrimidinyl )-sulfamoyl]- phenylacetic acid-l-phenyl-propylamide.

6. A compound as set forth in claim 1, which is R(+)- 4-[N-(S-isobutyl-Z-pyrimidinyl)-sulfamoyl]- phenylacetic acid-l-phenyl-propylamide.

7. A compound as set forth in claim 1. which is 4-[ N- (S-isobutyl-Z-pyrimidinyl )-sulfamoyll-phenylacetic acid- 1 -phenyl-propylamide.

8. A compound as set forth in claim 1, which is 4-[N- (5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-l-phenyl-butylamide.

9. A compound as set forth in claim 1, which is 4-[N- (5-isopropoxy-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-1-phenyl-Z-methyl-propylamide.

10. A compound as set forth in claim 1, which is 4- [N-( 5-isopropoxy-2-pyrim idinyl )-sulfamoyl]- phenylacetic acid-Z-phenyl-2-butylamide.

11. A compound as set forth in claim 1, which is'4- [N-( S-isobutyl-Z-pyrimidinyl )-sulfamoyl]-phenylacetic acid-l-(5-fluoro-2-methoxy-phenyl)-ethylamide.

12. A compound as set forth in claim 1, which is 4-[ N-( S-isobutyl-Z-pyrimidinyl )-sulfamoyl phenylacetic acid-l-(5-fluoro-2-methoxy-phenyl)- ethylamide.

13. A compound as set forth in claim 1, which is R- (+)-4-[ N-( S-isobutyl-Z-pyrimidinyl )-sulfamoyl]- phenylacetic acid- 1 5-fluor-2-methoxy-phenyl ethylamide.

14. A compound as set forth in claim 1, which is 4- N-(5(-isobutyl-2-pyrimidinyl)-sulfamoy1]- phenylacetic acid- 1 -methoxy-carbonyl-benzylamide.

15. A compound as set forth in claim 1, which is 4- [N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid- I -carboxy-benzylamide.

16. A compound as set forth in claim 1, which is 4- [N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]-phenylacetic acid-l-methyl-Z-phenyl-ethylamide.

17. A compound as set forth in claim 1, which is 4- [N-(5-isobutyl-2-pyrimidinyl)-sulfamoyll-phenylacetic acid-phenylpropylamide.

18. A compound as set forth in claim 1, which is R- (+)-4-[N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl]- phenlacetic acid-Z-phenylpropylamide.

19. A compound as set forth in claim 1, which is S ()-4-[N-(5-is0butyl-2-pyrimidinyl)-sulfamoyl]- phenylacetic acid-2-phenylpropylamide.

Claims (19)

1. RACEMATES AND OPTICAL ANTIPODES OF SULFAMOYL PYRIMIDINES OF THE GENERAL FORMULA

2. A compound as set forth in claim 1, which is S(-)-4-(N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-propylamide.

3. A compound as set forth in claim 1, which is R(+)-4-(N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic-1-phenyl -propylamide.

4. A compound as set forth in claim 1, which is 4-(N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-propylamide.

5. A compound as set forth in claim 1, which is S(-)-4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-propylamide.

6. A compound as set forth in claim 1, which is R(+)-4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-propylamide.

7. A compound as set forth in claim 1, which is 4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-propylamide.

8. A compound as set forth in claim 1, which is 4-(N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-butylamide.

9. A compound as set forth in claim 1, which is 4-(N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-phenyl-2-methyl-propylamide.

10. A compound as set forth in claim 1, which is 4-(N-(5-isopropoxy-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-2-phenyl-2-butylamide.

11. A compound as set forth in claim 1, which is 4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-(5-fluoro-2-methoxy-phenyl)-ethylamide.

12. A compound as set forth in claim 1, which is S-(-4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-(5-fluoro-2-methoxy-phenyl)-ethylamide.

13. A compound as set forth in claim 1, which is R-(+)-4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-(5-fluor-2-methoxy-phenyl)-ethylamide.

14. A compound as set forth in claim 1, which is 4-(N-(5(-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-methoxy-carbonyl-benzylamide.

15. A compound as set forth in claim 1, which is 4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylaceTic acid-1-carboxy-benzylamide.

16. A compound as set forth in claim 1, which is 4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-1-methyl-2-phenyl-ethylamide.

17. A compound as set forth in claim 1, which is 4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-phenylpropylamide.

18. A compound as set forth in claim 1, which is R-(+)-4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenlacetic acid-2-phenylpropylamide.

19. A compound as set forth in claim 1, which is S-(-)-4-(N-(5-isobutyl-2-pyrimidinyl)-sulfamoyl)-phenylacetic acid-2-phenylpropylamide.