JPS59181257A - Ureidobenzamide derivative - Google Patents

Abstract

NEW MATERIAL:A ureidobenzamide derivative shown by the formula I [R1 is H, 1 or 2 alkyl; Y is NHCONHR2(R2 is H, lower alkyl, or aryl which may contain substituent group at nucleus) linked to 2- or 4-position; n is 0 or 1]. EXAMPLE:2-Ureido-N-6-methyl-2-pyridylbenzamide. USE:A drug for lowering blood sugar. PREPARATION:A nitrobenzoyl halide shown by the formula II (X is halogen) is reacted with an amine shown by the formula VI in the presence of an amine to give a nitrobenzamide derivative shown by the formula III, which is reduced by a conventional procedure to give an aminobenzamide derivative shown by the formula V. This compound is further reacted with an isocyanate shown by the formula R2NCO to give a compound shown by the formula I . In the compounds, the 2-ureidobenzamide derivative can also synthesized from isotoic acid anhydride shown by the formula IV and a compound shown by the formula VI.

Description

Detailed Description of the Invention The present invention is based on the following general formula [wherein R1 represents a hydrogen atom or 1 to 2 lower alkyl groups, and Y is a group bonded to the 2- or 4-position -NH0ONHR]
2 (here, 82 means a hydrogen atom, a lower alkyl group, or an aryl group that may have a substituent on the nucleus), and n is 0.
or 1] The present invention relates to a ureidobenzamide derivative represented by:

The compound of the present invention represented by the above formula (1) has an excellent hypoglycemic effect and is useful as a medicine.

The compound of the present invention can be prepared by reacting nitrobenzoyl halide with an amine in the presence of a base, for example, as shown below.
It can be obtained by making an o-benzamide derivative, then reducing it by a conventional method to make an aminobenzamide derivative, and then reacting it with an incyanate. Also 2
-Ureidobenzamide derivatives can also be obtained by reacting isatonic anhydride with amines to obtain 2-ureidobenzamide derivatives, and then reacting with isocyaners.

The formula for this is as follows. In the formula, X means a halogen atom, and the other symbols have the same meanings as above.

[■]Cm) [)1 The reaction between compound (U) and amines is carried out under normal acid amide forming reaction conditions, for example, in an inert solvent such as acetone, tetrahydrofuran, dioxane, etc., preferably in triethylamine, dioxane, etc. 1) O in the presence of a base such as gin
It is carried out at 30°C for 1 to 5 hours.

The compound (V) can be introduced into the compound (V) by a conventional method, for example, by a reduction reaction using a catalyst such as noradium-carbon or Raney nickel.

On the other hand, the reaction between anhydrous isatone [12(IV) and amines is carried out without bath or in a solvent such as dioxane, toluene, xylene, etc., at 50 to 180°C for 1 to 5 hours with stirring, resulting in compound (V). (2-substituted product) can be obtained.

Reaction of compound [■] with isocyanates (carried out under normal urea formation reaction conditions; for example, in the case of R2H, reaction is preferably carried out in an inert solvent such as benzene, toluene, acetone, tetrahydrofuran, dioxane, etc.) is 20~10α1~ in the presence of a base such as triethylamine or pyridine.
It will be done in 48 hours. Moreover, when R2=H, the compound [■] is hydrochloric acid.

It is dissolved in an acidic aqueous solution such as acetic acid, then an alkali cyanate aqueous solution is added under stirring, and the reaction is carried out at 0 to 100°C for 1 to 5 hours.

Example 1: 259.2-amino-6-methylpyridine isatonic anhydride and 16.6 r of 2-amino-6-methylpyridine are heated to 100 DEG C. with stirring in a solvent. Foaming begins after a while, but stirring is continued for another 4 hours at the same humidity. After cooling, the reaction mixture was dissolved in chloroform and subjected to silica gel chromatography, and 2-amino-N-6-methyl-2-pyridylbenzamide 132 was obtained from the chloroform outflow (colorless prism crystals, n-hexane,
(recrystallized from benzene mixed solvent). Yield 37%, melting point 86
~87℃.

This 2.3f was dissolved in 15ml of 5% hydrochloric acid solution, and room temperature (
While stirring, add an excess of 10% potassium cyanate aqueous solution to make alkaline, and continue stirring at the same temperature for 2 hours. The precipitated crystals were collected in a furnace, washed with water, and then recrystallized from methanol.
2.19 of 2-ureido-N-6-methyl-2-pyridylbenzamide (compound 1) was obtained as colorless needle-like crystals.

Yield 77%, melting point 180-181°C.

Elemental analysis value OHN as molecular formula 014H14N402 Theoretical value (Foundation) 62.21 5.22 20.73 Actual value (To) 62.24 5.25 20.76 Example 2゜2-Ami/-N-6-Methyl- To a mixed solution of 2.3 f of 2-pyridylbenzamide and 20 m of acetone, 0.69 g of methyl isocyanate and a catalytic amount of triethylamine are added while stirring at room temperature. After stirring for 24 hours, the precipitated crystals were crushed, washed with water, and recrystallized from acetone to obtain colorless needle-like crystals of 2-(3-methylureido)-N-6-methyl-2-pyridylbenzamide (compound 2). .5f was obtained.

Yield 87%, melting point 135-136°C.

Elemental analysis value Molecular formula 015 HI3 N402 as O
HN Theoretical value (6) 63.36 5.67 19.71" Actual value (foundation) 63.32 5.64 19.74 Example 3゜2-amino-6-methylpyridine 14.6f,) ethylamine 25 4-nitrobenzoyl chloride 2 was added to a mixed solution of 300 d of ril and acetone under water cooling and stirring.
52 gradually. 30 minutes at the same temperature, then 1 hour at room temperature.
After stirring for an hour, the reaction solution was poured into 1.51 g of water, and the precipitated crystals were filtered, washed with water, and recrystallized from methanol to form colorless needle-like crystals of 4-nitro-N-6-methyl-2-pyridyl. Benzamide 20V was obtained. Yield 58%, melting point 231-23
2℃.

Hydrogen is passed through a mixture of 2(1', 1.52 ml of 10% palladium-carbon and 300 ml of ethanol, and catalytic reduction is carried out by a conventional method. After absorbing a total of n amount of hydrogen, the catalyst is removed, and the reaction liquid is concentrated under reduced pressure. The residue was recrystallized from a mixed bath medium of n-hexane and benzene to obtain colorless prismatic crystals of 4-amino-N.
-6-Methyl-2-pyridylbenzamide l 5.7
I got f.

Yield 89%, melting point 136-137°C.

This 2.3f is dissolved in 15 mJ of a 5% hydrochloric acid bath solution, and while stirring at room temperature, an excess of 10% potassium cyanate aqueous solution is added to make it alkaline, and stirring is continued at the same temperature for 2 hours. The precipitated crystals were collected in a furnace, washed with water, and then recrystallized from methanol to obtain 1.9 g of 4-ureido-N-6-methyl-2-pyridylbenzamide (compound 3) as colorless needle-like crystals.

Yield 69%, melting point 225-227°C.

Elemental analysis value Molecular formula 〇14 HI3 0 as N402
, HN Theoretical value (goods) 62.21 5.22 20.73 Actual value (to) 62.23 5.26 20.71 Example 4
゜Methyl isocyanate 0.62 and catalyst i were added to a mixed solution of 2.31 4-amino-N-6-methyl-2-pyridylbenzamide and 20 rrtl of acetone with stirring at room temperature.
Add t of triethylamine. After stirring for 24 hours, the precipitated crystals were collected in a furnace, washed with water, and then recrystallized from acetone to obtain colorless needle-like crystals of 4-(3-methylureido)-N-6-methyl-2-pyridylbenzamide (compound 4) 2 I got .49. Yield 83%, melting point 200-202°C.

Elemental analysis value Molecular formula cts ) (ta 0 as N402) (N Theoretical value (to) 63.36 5.67 19.71
Actual value (to) 63.32 5.61 19.76
Example 46゜Group: 5 mice of the 5-year-old DDY strain (9 males weighing 25-30
f) After fasting for 16 hours, 75 mg/H of alkane was administered intravenously, and 48 hours later, the compound of the present invention (200 m!) was administered intravenously.
Orally administer an aqueous solution or suspension of i'/Mf),
After 0 minutes, blood was collected from Shin Hee.The compound numbers in the table correspond to the compound numbers in the above examples.

Coming to the United States: P<0.05 Future: P<0.01 Coming to the United States: P<0.001 Table 4

Claims (1)

[Claims] General formula [In the formula, R1 represents a hydrogen atom or 1 to 2 lower alkyl groups, and Y is a group bonded to the 2- or 4-position -NH00NH
R, 2 (here, R12 means a hydrogen atom, a lower alkyl group, or an atomyl group which may have a substituent on the nucleus),
n represents O or 1] A ureidobenzamide derivative represented by: