DE2009385C3 - 2-Benzenesulfonamidopyrimidines and process for their preparation - Google Patents

Description

CH = CH- / C = CH

III)

= CH-ZC =

ι R ₂

in which R ₁ , R--, R ₃ and π have the same meaning as in claim 1, in a manner known per se with a benzenesulfonyl compound of the general formula III

> - SO.X

(Uli

in the R ₄ the same meaning as in the claim! and X is a halogen atom or a reactive group capable of forming a -SO ₂ NH- group, is reacted at a temperature ranging from room temperature to about 120 C ^c.

"> e £ <* nsta ⁿ d of the invention are 2-Benzolsulfonamidopyrimidine of the general formula 1

SO ₁ NH

in which R ₁ and R ₃ each represent a hydrogen atom, a chlorine or bromine atom or a methyl group, R ₂ and R ₄ each represent a hydrogen atom or a methyl group and η denotes the number 0 or 1.

The sulfonamide derivatives represented by the above general formula 1 have a substantial one Ability to lower blood sugar.

The invention further relates to a process for the preparation of the compounds of the general Formula I by the known implementation of a 2-aminopyrimidine compound of the general Formula Il so

N-

H ₁ N-

CH = CH- / C = CH

- R,

-R,

in which R ₁ . R ₂ , R, and / 1 have the same meaning as above, with a benzene sulfonyl compound of the general formula III

SC) A

Hh

in which R _{4 has} the same meaning as above and X is a halogen atom, such as chlorine or grain, or a reactive group which is capable of forming a SO1N1 group, at a temperature of room temperature up to about 120 ° C.

A reactive group that is capable of bridging an —SO ₂ NH group is, for example, a mixed acid anhydride, an ester radical or a cyanide group. The reaction can be carried out in the absence or presence of an inert solvent such as, for example, dioxane. Acetone, tetrahydrofuran, dimethylformamide. Diethylformiamide or dimethylacetamide and in the presence of an acylation catalyst. such as pyridine. Picoline, lutidine, quinoline. Dimethylaniline. Triethylamine or sodium acetate are run.

The reaction is carried out first at room temperature and then at an elevated temperature of about 60 to 120 ° C carried out. If desired, the Temperature lower or higher can be selected. The reaction proceeds quickly with the formation of a yellow one or brown reaction mixture from which crystals quickly precipitate. After the reaction has ended the crystals are separated from the reaction mixture in a conventional manner. For example, will the reaction mixture is cooled, producing the desired Product is obtained in the form of a precipitate, then the product is filtered off. washed and dried. The crude product can be obtained from an organic solvent such as Alhyleneglykolmonomet hy lather or Dimethylformamid, be recrystallized.

The starting materials of the general formula 11 are obtained one in such a way that one optionally substituted in 5-Stelhing 2-amino-4-meth \! pvnmidin

ler general formula IV

(IV)

in which R _{3 has} the same meaning as above, with a phenylaldehyde compound of the general formula V

in which R ₁ , R ₂ and η have the same meaning as above, reacts with acetic anhydride in acetic acid in the presence of sulfuric acid.

The pharmacological properties of some typical compounds of the general formula 1 according to the invention were investigated as follows:

Alloxane monohydrate dissolved in distilled water was given to mice weighing 20 to 25 g Tail vein injected intravenously at a dosage of 75 mg / kg.

On the seventh day after the administration of the alloxant, 0.02 ml of blood was withdrawn by capillary action

ίο vein tissue removed from the base of the eyes of the mice, each 16 hours before and after administration of the test substance in the specified sections without Food were kept. In this experiment, the Tesl substance was administered intraperitoneally in one dose of 100 mg / kg administered. The blood sugar level was then determined and the decrease in the Blood sugar calculated according to the following relationship:

Decrease in blood sugar concentration (%) = -

A - 50

100,

m the A denotes the sugar level before the administration of the test substance and ß denotes the sugar level after the administration of four test substances.

The test results can be seen in Table 1 below:

table

connection

CH = CH

H ₃ C- <V- SO ₂ NH (example 1)

H ₃ C - <V-SO ₂ NH- (example 2)

CH = CH

> —Br

N ^:

CH = CH-CH = CH

SO ₂ NH

(Example 3)

N <=

N-

H ₃ C-fV- SO ₂ NH -! Example 4)

CH = CH-CH = CH

CH ₃

CH = CH-CH = CH-f decrease
the blood sugar concentration

1%)

95.1 ± 5.5

U ± 6.3

71.7 ± 9.9

75.8 ± 17

CH,

<f V- SO ₃ NH -Ά V-CH ₃ S3.3 t 18.S

(Example 5)

continuation

connection

SO ₁ NH

CH = CH - CH = CH - Z

CH ₃

(Example 6)

S0, NH - C - NH - C ₄ H,

Il ο

Tolbutamide: N'-lp-ToluenesulfonylKN ^ fn-ButyD-urea reduction
the blood sugar concentration

73.6 ± 5.6

53.7 ± 17.3

As can be seen from Table 1, the blood sugar lowering ability is the new compounds according to the invention are superior to that of tolbutamide. At the same time, when administered to mice, in no toxicities were observed at a dose of 2 g / kg / day.

The following is the preparation of the invention Compounds explained by means of examples.

example 1

Production of 2- (p-toluenesulfonamido | -
4-styrylpyrimidine of the formula VI

CH ----- CH -; '- ■

N-

-SCKNH-

(Yl)

N "

A mixture of 0.6 g of 2-amino-4-styrylpyrimidine. 0.65 g of p-toluenesulfonyl chloride and 7 ml of pyridine was added heated slowly and held at 90 to 100 ° C. for 7 hours. After cooling the reaction mixture the crystals formed therein were filtered off and washed with water and ethanol. By recrystallization from dimethylformamide, 0.6N needle-shaped crystals were obtained. M.p. 254 to 25SV.

Elemental analysis CmH ₁₇ O ₂ N ₂ S:

Calculated ... C 64.94. H 4.XK "":

experimental

found C 65.00. H 5.05 "...

Example 2

Production of 2-amino-5-hrom-4-> i \ r \ l-p \ rimidin the formula Yl!

H, N-

CH - ■■ CH

Mr

(VM

2.95 g of 2-amino-4-methyl-5-bromopyrimidine were dissolved in 30 ml of glacial acetic acid for 2 seconds and 6 ml of this solution conc. Sulfuric acid added while cooling with ice. Then 1.68 g of benzaldehyde were obtained at 25 to 27 ° C and 2.5 ml of acetic anhydride are added and the reaction mixture is kept at 50 to 60 ° C. for 8 hours heated. The yellow crystals precipitated from the reaction mixture were collected by filtration. The crystals thus obtained were suspended in 90 ml of water and neutralized with aqueous ammonia: yellow crystals with a melting point of 149 to 150 ° C. were obtained as the crude product. Yield: 3 g (69%). Recrystallization from ethanol gave uclbc needle-shaped crystals. 151 to 153 C.

Elemental analysis C ₁₂ H ₁₀ N ₃ Br:

Calculated .. C 52.19. H 3.65%;
uefundcn .... C 51.94. H 3.89%.

Production of 2- (p-toluenesulfonamido) -

5-bromo-4-styr \ lp \ rimidine of the formula VIII

CH = CH- ί

; - SO-, NH-

Br

(VlIIi

0.5 g of 2-amino-5-bromo-4-slyrylpyrimidine. 2 ml of l'yridir. and 0.31 g of p-toluenesulfonyl chloride were mixed and reacted at 90 to 100 ° C for 6 hours. The from the Rcaktionsgemiscr Precipitated crystals were filtered off and dried Washed water and methanol; gellx crude crystals which melted at 258 to 26 ° C. were obtained. Out Loot: 0.49 g (49.1%). Through recrystallization au; Dimethylformamide was obtained pale crystals \ on prismatic form. M.p. 265 to 265.5 C.

Elemental analysis C ',,, 11 ,,, O ₂ N, SBr:

Calculated ... C 53.03. H 3.75 ",,:

experimental

found C 52.97. H 3.86 ° ...

Example 3

Preparation of 2-amino-4-14-phenyl, 3-butadienyl) pyrimidine of the formula IX

CH = CH-CH = CH

(IX)

1.0 g of 2-amino-4-methyl-pyrimidiri were dissolved in ΊΟ ml of glacial acetic acid and 2 ml of conc. Sulfuric acid, 1.45 g of cinnamaldehyde and 0.9 ml bssigsäureanhydrid added and incubated for 1 hour at 55 to 60 ⁰ C heated; reddish-violet crystals precipitated out. The reaction mixture was kept at the same temperature for an additional 6 hours. The reaction mixture was then cooled and the crystals passed through

s Filtration and washing with acetic acid recovered. The crystals thus obtained were suspended in water and neutralized with ammonia solution to give coarse yellow crystals. Yield: 1.0 p. (49%). Obtained by recrystallization from ethanol

ίο one yellow crystals in platelet form, m.p. 196 to 197 ^P C.

Elemental analysis C ₁₄ H ₁₃ N ₃ :

Calculated ... C 75.31, H 5.87%:
found .... C 75.39, H 5.87%.

Preparation of 2- (benzoisulfonamido) -4-14-phenyl-1,3-butadienyl) pyrimidine of the formula X

= CH-CH =

SO, NH

N = -

(X)

0.7 g of 2-amino-4- (4-phenyl-1,3-butadienyl) pyrimidine, 2 ml of pyridine and 0.61 g of benzenesulfonyl chloride were mixed and at 90 to 100 "C for 4 hours brought to reaction. The crystals precipitated from the reaction mixture were filtered off and washed with Washed water and methanol; yellow crude crystals with a melting point of 276 to 27 ° C. were obtained. Yield: 0.87 g (76.5%). By circulating baking from ethylene glycol monomethyl ether yellow crystals of prismatic shape, melting point 285 ° to 286 ° C., were obtained.

Elemental analysis C ₁₈ H _{; 5} O ₂ N ₂ S.

C 64.08. H 4.48%;

Calculated ...
experimental
found

C 64.24, H 4.65%.

B e i s ρ i e!

Preparation of 2-amino-5-methyl-4- (4-phenyl-1,3-butadienyl) -pyrimidine of formula XI

H ₂ N- <

N-

CH = CH-CH = -CH -

CH,

(XI)

N ^{= /}

2.0 g of 2-amino-4,5-dimethylpyrimidine were dissolved in 20 ml of glacial acetic acid; to this solution were 4 ml conc. Sulfuric acid was added with simultaneous ice cooling. The sulfuric acid fell out of the mixture Salt of 2-amino-4,5-dimethyl-pyrimidine. To this mixture were added dropwise at room temperature 2.2 g of cinnamaldehyde were added and the reaction mixture was then heated to 50 to for 12 hours 55'C heated. The crystals precipitated from the reaction mixture were separated by filtration.

suspended in water and made alkaline with ammonia solution; this gave: yellow crude crystals with a melting point of 169 to 170.degree. Yield: 1.4 g (36.3%). By Umkristallisalion from aqueous ethanol to give yellow crystals of prismatic shape and a melting point obtained. 175-176 C. ^r

Elemental analysis C ₁₅ H ₁₅ N ₃ :

Calculated ... C 75.92, H 6.37%:
found .... C 76.17, H 6.47%.

Preparation of 2- (toluenesulfonamido) -5-methyl-4- (4-phenyl-1,3-butadienyU-pyrimidine of the formula XII

H ₃ C

SO ₂ NH

CH = CH-CH = CH

0.35 g of 2-amino-5-methyl-4- (4-phenyl-1,3-buta-mixture, crystals precipitated by filtration

dieny1) pyrimidine, 0.8 ml of pyridine and 0.31 g of p-toluene-65 obtained and washed with water and acetone

sulfonyl chloride were mixed and at 90 to 100 C to give yellow ^r Rohkristallc mp. 274 bi

Reacted for 6 hours. After 275 ^r C. Yield: 0.38g (65.6%). By Umkrislalli

The reaction mixture was cooled and the dimethylformamide obtained from the acid was yellow

ίο

crystals of prismatic shape. Melting point 27S to 79 = C.

ilemcnlaranalysis C ₂₂ H ₂ IO ₂ N, S:

Calculated ... C 67.49. H 5.41%: determined .... C 67.40. H 5.56 °.,.

Example 5

Preparation of 2-amino-5-methyl-4- [4- (4-methyl-phenyl) -1.3-butadienyl] -pyrimidine of the formula ΧΪ11

CH-CH-CH = CH -f V-CH,

H ₂ N- <y-CHj

(XIl

5.0 g of 2-ainino-4,5-dimethylpyrimidine were dissolved in 45 ml of glacial acetic acid and 10 ml of conc. Sulfuric acid was added while cooling with ice. 6.5 g of p-methylcinnamaldehyde and 4.5 ml of acetic anhydride were then added at room temperature and the reaction was carried out at 55 to 60 ° C. for 5 hours. The precipitated from the reaction mixture crystals were filtered, suspended in water and made alkaline with ammonia solution. Thereby obtaining 2.5 g (24 ⁷ '\> l yellow coarse crystals by recrystallization from \\ a \\ - rieem ethanol yielded crystals in cclbc Platelet form, m.p. 179 to 181 C.

Elemental analysis C _lh H, -N ,:

Calculated ... C 76.46. H 6.82 ",,:
found .... C 76.2 ?. H 7.12 ° ,,.

Production of
2- (Benzo! Sulfona! Nido) -5-methyl-4- [4- (4-methylpheny!) - 1- butadienyl] pynmidine of the formula XlY

CH = CH-CH = -CH

\ V- SO, NH - ~ i V-CH,

0.7 g of 2-amino-5-methyl-4- [4- (4-methylphenyl-1,3-butadienyl] pyrimidine. 2 ml pyridine and 0.54 g (XlYl

Yield of 0.65 g (5.5%). By recrystallization from ethylene glycol monomethyl ether was obtained

Benzene sulfonyl chloride was mixed and 6.5 hours 30 yellow crystals in needle shape. M.p. 271 to

the long at 90 to 100 C reacted with each other. After cooling the reaction mixture the crystals precipitated from the mixture were separated by filtration and washed with methanol Wash: the same raw crystals were obtained in a 273 C.

Elemental analysis C ₂₂ H ₂₁ O ₂ N ₁ S:

Calculated ... C 67.49. H 5.41 ",
determined C 67.37. H 5.47 ",

Example 6

Preparation of 2-amino-4- [3-methyl-4- (4-chlorophenyl) -1.3-butadienylj-pyrimidine of the formula XY

^No.

1.0 g of 2-amino-4-methylpyrimidine were dissolved in 10 ml of glacial acetic acid: 2 ml of conc. Sulfuric acid added, whereby the white-colored sulfuric acid salt of 2-amino-4-methy] p \ nmidins was precipitated from the mixture. Then 0.9 ml of acetic anhydride and 1.5 g of 2-methyl-p-chloro-cinnamaldehyde were added added at room temperature and the reaction run through for 7.5 hours at 50 to 55 C (XY-.

leads. The crystals precipitated from the reaction mixture were filtered off, suspended in water and neutralized with ammonia solution, whereby cclbc crude crystals were obtained which melted at Pd up to 177.5 ° C.

Yield: 0.76 g (30.4%). By crystallization from methanol, pale yellow prismatic crystals were obtained. M.p. 179 to ISO C.

Production of
2- (Benzol sulfonamido) -4- [3-meth \ l-4- (4-chlorophenyl | -l.3-butadienyl] pyrimidine of the formula XY

CH = CH-C = CH
CH ₃

Cl

(XYD

0.4 g of 2-amino-4- [3-methyl-4- (4-chlorophenyl) -1.3-bu ^ adicnyl] pyrimidine. 0.5 ml Dimeilnlanilin to 0.29 g ~ benzenesulfonyl chloride were mixed and at 90 to 100 "C for 5.5 hours with each other / u

12th

Brought reaction. After the reaction mixture was cooled, the crystals precipitated from the mixture were filtered off and washed with water and methanol; yellow crude crystals were obtained. which melted at 257 to 260 ^{0 C.} Bulge: 0.47 g (70%). Recrystallization from ethylene glycol monomethyl ether gave yellow crystals of prismatic shape, melting point 274 to 275 C.

Elemental _{analysis C 2} , H ₁₈ O ₂ N ₃ ClS:

Calculated ... C 61.23. H 4.40%;
determined .... C 61.53, H 4.60%.

The same procedure as in Example 2 bc was used for those in the table below Keep the listed 2-aminopyrimidine compounds:

CH,

CH,

CH,

CH,

CH,

H, N

Table 2

CH = CH- / C = CH

-R ₁

π R ₂ Rj 0 CH, 0 - Cl 1 CH ₃ H 1 CH, Cl 1 CH, Br 1 CH, CH, 0 - H 0 - CH, 1 H H 1 CH, CH, 1 CH, H 0 _ H 0 - Br

Melting point CC)

209-209.2

179-179.2

151-152

179-180

193-194

158-161

152-153

170-173

175-176

170-173

184-185

198-198.2

188 189

Look color the crystal Working out Pale yellow shape % Pale yellow prismatic 80.0 Pale yellow platelet-shaped 71.0 Pale yellow needle-shaped 38.0 Pale yellow prismatic 30.4 Pale yellow romboetric 29.4 Pale yellow platelet-shaped 13.0 yellow prismatic 86.0 yellow prismatic 90.0 yellow prismatic 36.3 yellow prismatic 12.1 yellow platelet-shaped 41.4 yellow needle-shaped 69.0 nade'.fbrmig 77.8

Using the same method as described in Example 1, those listed in Table 3 below were used led to 2-benzenesulfonamidopyrimidine derivatives substituted in the 4-position:

Table 3

CH,

CH,

Br

Br

Br

Br

CH,

/ V

SO, NH

π R ₂ R ₃ R ₁ 0 H H 0 - H H 0 - H CH, 0 - H H 0 - H H 0 - H CH, 1 H H CH, I. CH, H CH, 1 CH, H H 1 CH, H CH, 1 CH ₃ H CH, 0 - CH, H

Melting point
C)

252-253

273-274

279-280

283-285

-289

284-285

264-265

253-254.5

265-266

252-253

239-240

289-290

Appearance of the crystal
Color shape

Pale yellow

yellow

yellow

yellow

yellow

yellow

yellow

yellow

yellow

yellow

yellow

Pale yellow

platelet-shaped

prismatic

prismatic

needle-shaped

needle-shaped

needle-shaped

prismatic

needle-shaped

granular

needle-shaped

needle-shaped

prismatic

yield

60.5 86.4 63.5 85.5 69.3 74.3 69.3 64.0 64.5 67.0 43.1 66.2

η 13th R ₂ * Ra 2009 385 Ό
4 14 Appearance of the crystals color shape yield continuation Pale yellow platelet-shaped % R ₁ O CH ₃ CH ₃ Melting point Pale yellow prismatic 57.8 O - CH ₃ H (Ο Pale yellow prismatic 51.8 H O - CH ₃ CH ₃ 276-277 yellow prismatic 59.5 CH, 1 H CH ₃ H 302-305 yellow prismatic 49.0 CH., 1 H CH ₃ CH ₃ 298-300 yellow acicular 65.6 H 1 H CH ₃ H 293-294 yellow prismatic 58.5 H 1 H CH ₃ CH ₃ 278-279 Pale yellow acicular 59.2 CH ₃ 1 CH ₃ CH ₃ CH ₃ 277-278 Pale yellow fibrous 69.6 CH ₃ 1 CH ₃ CH ₃ H 272-274 Yellowish brown powdery 18.7 H 1 CH ₃ CH ₃ CH ₃ 243-245 Yellowish white prismatic 53.4 CH, r \
U - Br CH ₃ 237-239 Pale yellow prismatic 49.1 CH ₃ O - Br CH ₃ 220-223 yellow prismatic 85.5 H O - CH ₃ CH ₃ 265-266 65.2 Br over 315 Br 311-312

Claims (2)

Claims: 1. 2-benzenesulfonamidopyrimidines of the general formula I. SO, NH in which R ₁ and R ₃ each represent a hydrogen atom, a chlorine or bromine atom or a methyl group, R ₂ and R ₄ each represent a hydrogen atom or a methyl group and η denotes the number 0 or 1. 2. Process for the preparation of the 2-benzenesulfonamidopyrimidines according to claim 1, characterized in that a 2-aminopyrimidine compound of the general formula II