JPS59175467A - Ureidobenzamide derivative - Google Patents

Abstract

NEW MATERIAL:An ureidobenzamide derivative shown by the formula I (R1 is H, lower alkyl, or lower alkoxy; R2 is H, halogen, lower alkoxy, or 1-2 lower alkyl; n is 0 or 1). EXAMPLE:3-Ureido-N-2-pyridylbenzamide. USE:A drug having blood sugar lowering action. PREPARATION:For example, a 3-nitrobenzoyl chloride shown by the formula IIis reacted with an amine in the presence of a base, to give a 3-nitrobenzamide derivative shown by the formula III, which is then reduced to give a 3-aminobenzamide derivative shown by the formula IV, which is reacted with an alkali cyanate in an acidic aqueous solution, to give the desired compound shown by the formula I .

Description

【発明の詳細な説明】 本発明は次の一般式 （式中Ｒ１は、水素原子、低級アルキル基又は低級アル
コキシ基を示し、Ｒ２は水素原子、ハ田ゲン原子、低級
アルコキシ基又は１〜２個のａ基を示し、ｎは０又は１
を示す。）で表わされるウレイドベンズアミドｍ２ｉ体
に関する。Detailed Description of the Invention The present invention relates to the following general formula (wherein R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and R2 represents a hydrogen atom, a hydrogen atom, a lower alkoxy group, or 1 to 2 a group, n is 0 or 1
shows. ) is related to the ureidobenzamide m2i form.

上式ＣＩ）で表わされる本発明の化合物は優れた血糖降
下作用を有し、医薬として有用である。The compound of the present invention represented by the above formula CI) has an excellent hypoglycemic effect and is useful as a medicine.

本発明の化合物は例えば以下に示すように３−二トロベ
ンゾイルクロライドとアミン類とを塩基の存在下反応さ
せ３−二Ｆロベンズアミド誘導体とし、次いでこれを常
法により還元して３−アミノベンズアミド誘導体とした
後、酸性水浴液中、シアン酸アルカリと反応させること
により得ることができる。The compound of the present invention can be produced, for example, by reacting 3-nitrobenzoyl chloride with an amine in the presence of a base to obtain a 3-2F lobenzamide derivative as shown below, and then reducing this by a conventional method to form a 3-aminobenzamide. It can be obtained by making it into a derivative and then reacting it with an alkali cyanate in an acidic water bath.

これを式示すれば以下のとおりである。尚、式中Ｘは、
ハロゲン原子、Ａはアルカリ金属原子を意味し、その他
の記号は前記と同一の意味を有する。The formula for this is as follows. In addition, in the formula, X is
The halogen atom and A mean an alkali metal atom, and the other symbols have the same meanings as above.

〔■〕〔皿〕 化合物ＣＩＩＪとアミノピリジン角との反応＋１、ｊ１
ａ常の酸アミド形成反応条件により行われ、例え（ま′
アセトン、テトラヒドロフラン、ジオキ″ｖ−ン等の不
活性溶媒中打丁しくはトリエチルアミン、ピリジン等の
塩基の存在下０〜３０℃、１〜５時ＩＩ号で行われる。[■] [Dish] Reaction between compound CIIJ and aminopyridine angle +1, j1
a It is carried out under conventional acid amide formation reaction conditions, e.g.
The reaction is carried out in an inert solvent such as acetone, tetrahydrofuran, diquine, etc., or in the presence of a base such as triethylamine, pyridine, etc. at 0 to 30° C. at 1 to 5 o'clock No. II.

化合物〔■〕は常法により、例えばノぐラジウム−炭素
、ラネイニッケル、二酸化白金等の触媒を用いる還元反
応により容易に化合物〔■〕に導くことができる。Compound [■] can be easily converted into compound [■] by a conventional method, for example, by a reduction reaction using a catalyst such as noradium-carbon, Raney nickel, or platinum dioxide.

化合物〔■〕とシアン酸塩との反応は、通常の尿素形成
反応条件により行われ、例えば化合物■を塩酸、酢酸等
の酸性水浴液に溶解し、次いでシアン酸アルカリ水浴液
を加え、０〜１００℃、１〜５時間で行われる。The reaction between compound [■] and cyanate is carried out under the usual urea formation reaction conditions. For example, compound (■) is dissolved in an acidic water bath solution such as hydrochloric acid or acetic acid, then an alkaline cyanate bath solution is added, and the It is carried out at 100°C for 1 to 5 hours.

実施例１゜ ２−アミノピリジン２８．２ｆ、）リエチルアミン４５
ｍｇ及びアセトン６００ｍｇの混合浴液に、水冷（Ｗ押
下、３−ニトロベンゾイルクロライド５５゜８２を徐々
に加える。同温度で３０分、次いで室温で１時間攪拌後
、反応浴液を３℃の水Ｑこ注ぎ、析出する結晶を戸数し
、水洗後メタノールより再結晶して無色針状晶の３−ニ
トロ−Ｎ−２−ピリジルベンズアミド５８．５７を得た
。収率８０％。Example 1゜2-aminopyridine 28.2f,) ethylamine 45
3-nitrobenzoyl chloride was gradually added to a mixed bath solution containing 600 mg of acetone and 600 mg of acetone. The precipitated crystals were collected, washed with water, and then recrystallized from methanol to obtain 58.57 ml of 3-nitro-N-2-pyridylbenzamide in the form of colorless needles. Yield: 80%.

融点１５６〜１５７℃。この１５．９ｆ、１０％パラジ
ウム−炭素１．５１及びエタ／−ル３００　ｙｔｔの混
液に水素を通じ、常法により接触還元する。計算量の水
素を吸収後触媒を除去し、反応液を減圧０；１縮し、残
置をエタノールよりｐ１糸吉晶して包（包金ト状晶（Ｄ
　３−アミノ−Ｎ−２−ピ１）ジルベンズアミド７．２
Ｌ？を得た。収率５２％、融点１１３〜１１５℃。この
６．４２を５％塩酸溶液５０ｙ、、Ｊ＆こ溶解し、室温
（ひ押下、過剰の１０％シアン酸力１ノウム水溶液を加
えてアルカリ性とし、同温度で２１時間攪指ミを続ける
。析出した結晶を戸数し、水洗後メタノールから再結晶
して無色針状晶の３−ウレイド−Ｎ−２−ピリジルベン
ズアミド（イし合物ｉ）５．５７を得た。収率７２％、
融点２２３〜２２４℃。Melting point: 156-157°C. Hydrogen was passed through this mixture of 15.9 f, 10% palladium-carbon 1.51 and 300 ytt of ethanol, and catalytic reduction was carried out by a conventional method. After absorbing the calculated amount of hydrogen, the catalyst was removed, the reaction solution was concentrated under reduced pressure 0;
3-Amino-N-2-py1)zylbenzamide 7.2
L? I got it. Yield 52%, melting point 113-115°C. Dissolve this 6.42 in 50 ml of 5% hydrochloric acid solution, press down at room temperature, make alkaline by adding an excess of 10% cyanic acid, and continue stirring for 21 hours at the same temperature. Precipitation. The resulting crystals were separated, washed with water, and then recrystallized from methanol to obtain colorless needle-like crystals of 3-ureido-N-2-pyridylbenzamide (Ishi compound I) at a yield of 5.57. Yield: 72%.
Melting point 223-224°C.

元素分析値　分子式０１３　ＨＩ３　Ｎ４　ｏ２として
０　　　　　　）Ｉ　　　　　　Ｎ Ｊフｊ１　ｉ倫イ直σ功　　　　６０．９３　　　　４
．７２　　　　２］、、８７実１ｊｌｌ値（Ｍ　　　６
０．９０　４．７５　２１．８８」−記と同様にして表
１の化合物を得）こ。Elemental analysis value Molecular formula 013 HI3 N4 0 as o2 ) I N J Fu j1 i Lun I Direct σ Gong 60.93 4
．． 72 2],, 87 real 1jll value (M 6
0.90 4.75 21.88'' - The compound shown in Table 1 was obtained in the same manner as described above.

実施例２゜ １ｇＹ−５匹の５週令ＤＤＹ系マウス（ｉＩｆ：　、体
重２５〜３０Ｓ’）を１６時間絶食後、アロキサン７５
ｐｒｇ　／　ｋｇを静脈内に投与し、４８時間後に、本
発明化合物（２００１１ｒｇ／＃）の水浴液又はけん濁
液を経口投与し、１５０分後に心臓から採血し、グルコ
ースオキシダーゼ法により血中糖量を測定した。Example 2 After fasting for 16 hours, 1gY-5 5-week-old DDY mice (iIf, weight 25-30S') were treated with alloxan 75.
prg/kg was administered intravenously, 48 hours later, a water bath solution or suspension of the compound of the present invention (20011rg/#) was orally administered, and 150 minutes later, blood was collected from the heart and the blood sugar level was determined by the glucose oxidase method. was measured.

測定結果を表２に例示する。The measurement results are illustrated in Table 2.

なお、表中の化合物番号は、実施例１の化合物９１７号
に対ルーしている。Note that the compound numbers in the table correspond to compound No. 917 of Example 1.

Claims (1)

【特許請求の範囲】 ＮＨこ０ＮＨ２ （式中Ｒ１は、水素原子、低級アルキル基又は低級アル
コキシ基を示し、Ｒ２は水素原子、ハロゲン原子、低級
アルコキシ基又は１〜２個の低級アルキル基を示し、ｎ
は０又は１を示す。）で表わされるウレイドベンズアミ
ド誘導体。[Claims] NH0NH2 (in the formula, R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and R2 represents a hydrogen atom, a halogen atom, a lower alkoxy group, or 1 to 2 lower alkyl groups) ,n
indicates 0 or 1. ) A ureidobenzamide derivative represented by