JP3866323B2 - Novel N-benzylbenzamide derivatives - Google Patents
Novel N-benzylbenzamide derivatives Download PDFInfo
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- JP3866323B2 JP3866323B2 JP09757296A JP9757296A JP3866323B2 JP 3866323 B2 JP3866323 B2 JP 3866323B2 JP 09757296 A JP09757296 A JP 09757296A JP 9757296 A JP9757296 A JP 9757296A JP 3866323 B2 JP3866323 B2 JP 3866323B2
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- methyl
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- benzylbenzamide
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Description
【０００１】
【発明の属する技術分野】
本発明は抗真菌剤の合成原料として有用な、新規Ｎ−ベンジルベンズアミド誘導体に関する。
【０００２】
【従来の技術】
水虫に代表される表在性真菌症は、生活が西洋化して靴の着用時間が増加したのに相まって、未だに確実な治療法及び治療薬が見いだされていないこともあり、現代に於ける克服されていない疾病の一つに数えられている。その為、抗真菌作用について、多くの化合物がスクリーニングにかけられた。しかしながら、ｉｎ ｖｉｔｒｏ或いは動物レベルに於いて活性が見いだされた物質でも、実際の臨床段階においてはドロップアウトするものが少なくなく、満足いく結果は今のところ得られたものは極めて少ない。即ち、新規の抗真菌作用を有する母核の発見が待たれていた。この様な状況下本発明者等は一般式（ＩＩ）に示される化合物が優れた抗真菌作用を有することを見いだした。例えば、一般式（ＩＩ）に表される化合物の内、４−ターシャリーブチル−Ｎ−メチル−Ｎ−（２−フェニルベンジル）ベンジルアミン（抗真菌剤１）、４−ターシャリーブチル−Ｎ−メチル−Ｎ−（３−フェニルベンジル）ベンジルアミン（抗真菌剤２）、４−ターシャリーブチル−Ｎ−メチル−Ｎ−（４−フェニルベンジル）ベンジルアミン（抗真菌剤３）、４−ターシャリーブチル−Ｎ−ジフェニルメチル−Ｎ−メチルベンジルアミン（抗真菌剤４）は、表１に示す様にトリコフィトン・メンタグラファイトに対して優れた抗真菌作用を示す。一般式（ＩＩ）に表される化合物は新規化合物であり、従ってその製造方法は知られていない。又、本発明の化合物である、一般式（Ｉ）に表される化合物も文献未記載の新規化合物である。
【０００３】
【化５】
（但し、式中Ｒ１、Ｒ４はそれぞれ独立に水素原子又は置換基を有していても良い炭素数６〜１８の芳香族炭化水素を表し、Ｒ２、Ｒ３はそれぞれ独立に炭素数１〜４のアルキル基を表し、ｍ、ｎはそれぞれ独立に１〜４の整数を表す。）
【０００４】
【化６】
【０００５】
【化７】
【０００６】
【化８】
【０００７】
【化９】
【０００８】
【表１】
【発明が解決しようとする課題】
本発明は、この様な状況下為されたものであり、抗真菌剤である、一般式（ＩＩ）の化合物を合成するのに有用な原料を提供することを課題とする。。
【００１０】
【課題を解決するための手段】
本発明者らは、この様な状況に鑑み、一般式（ＩＩ）の合成原料の開発研究について鋭意努力を重ねた結果、一般式（Ｉ）に示す化合物群が有用な原料になりうることを見いだし、発明を完成させるに至った。以下、本発明について詳細に説明する。
【００１１】
【化１０】
（但し、式中Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８はそれぞれ独立に、水素原子、炭素数１〜４のアルキル基又はフェニル基を表し、且つ、これらの置換の少なくとも１個はフェニル基であるものとする。）
【００１２】
一般式（Ｉ）に示す化合物は、リチウムアルミニウムハイドライド等で還元することにより、一般式（ＩＩ）の化合物へと導くことが出来る。一般式（Ｉ）の化合物はアミンと酸クロライドの反応により、市販の試薬より容易に得ることが出来る。従って、一般式（Ｉ）の化合物は一般式（ＩＩ）の化合物の有用な合成原料であるといえる。
【００１３】
【発明の実施の形態】
本発明の化合物は、一般式（Ｉ）に表されるＮ−ベンジルベンズアミド誘導体である。一般式（Ｉ）に表される化合物は、次に示す反応式１に従って合成できる。即ち、安息香酸誘導体から導いた、Ｎ−メチルベンジルアミン誘導体に、対応するハロゲン化物をトリエチルアミン等の塩基存在下反応させればよい。かくして得られた化合物は、例えば、シリカゲルカラムクロマトグラフィーや再結晶などの通常の精製手段で精製することが出来る。この様な一般式（Ｉ）に表される化合物としては、例えば、Ｎ−メチル−Ｎ−（２−フェニルベンジル）−４−ターシ
ャリーブチル安息香酸アミド（化合物１）、Ｎ−（４−ターシャリーブチルベンジル）−Ｎ−メチル−４−フェニル安息香酸アミド（化合物２）、Ｎ−（ジフェニルメチル）−Ｎ−メチル−４−ターシャリーブチル安息香酸アミド（化合物３）等が好適に例示できる。これらの一般式（Ｉ）に表される化合物は、リチウムアルミニウムハイドライドの様な還元剤をエーテル等の溶媒中で反応させることにより容易に一般式（ＩＩ）に表される化合物へと導くことが可能である。
【００１４】
【化１１】
【００１５】
【化１２】
【００１６】
【化１３】
【００１７】
【化１４】
【００１８】
【実施例】
実施例１
製造例
クロロホルム１００ｍｌにｏ−フェニル安息香酸１０ｇ、塩化チオニル１８．７ｇを混合し４時間加熱還流した。反応物を減圧濃縮し、これを氷冷下４０％メチルアミン水溶液４０ｍｌに滴下した。混合物を室温まで戻し、４日間攪拌し反応させた。２Ｎ塩酸を加え反応を止め、クロロホルムで抽出し有機層を飽和炭酸水素ナトリウム溶液で洗浄した。有機層を取り溶媒を溜去し、Ｎ−メチル−２−フェニル安息香酸アミドを得た。これをエーテル中０．５４ｇのリチウムアルムニウムハイドライドで還元し、１．４６ｇのＮ−メチル−２−フェニルベンジルアミンを得た。これと１．４５ｇのｐ−ターシャリーブチル安息香酸から誘導した酸クロライドをベンゼン中でトリエチルアミンの存在下反応させ、反応液に水とクロロホルムを加え抽出し、有機層を取り、希塩酸、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水の順で洗浄した。溶媒を溜去し黄色結晶として、Ｎ−メチル−Ｎ−（２−フェニルベンジル）−４−ターシャリーブチル安息香酸アミド（化合物１）を２．４２ｇ得た。ＮＭＲ（溶媒：重クロロホルム）は次の通りであった。
１Ｈ−δｐｐｍ；１．３１（９Ｈ，ｓ）、２．８１（３Ｈ，ｄ）、４．６３（２Ｈ，ｄ）７．００〜７．４１（１３Ｈ，ｍ）
【００１９】
（例２）製造例
例１と同様にｐ−フェニル安息香酸２．４７ｇより、４−ターシャリーブチル−Ｎ−メチル−Ｎ−（４−フェニルベンジル）安息香酸アミド（化合物２）を白色結晶として１．５８ｇ得た。１Ｈ−ＮＭＲスペクトル（δｐｐｍ、重クロロホルム）は次に示すとおり。
（ＮＭＲ）
１．２６（９Ｈ，ｓ）、２．９９（３Ｈ，ｄ）、４．６５（２Ｈ，ｄ）、７．１４〜７．５９（１３Ｈ，ｍ）
【００２０】
（例３）製造例
例１と同様に、４．０６ｇのクロロジフェニルメタンより、４−ターシャリーブチル−Ｎ−ジフェニルメチル−Ｎ−メチル安息香酸アミド（化合物３）を白色結晶として１．４８ｇ得た。（収率：４８．９％）１Ｈ−ＮＭＲスペクトル（δｐｐｍ、重クロロホルム）は次に示す通り。
（ＮＭＲ）
１．１６（９Ｈ，ｓ）、２．７２（３Ｈ，ｓ）、７．０１〜７．２５（１４Ｈ，ｍ）
【発明の効果】
本発明によれば、抗真菌剤の原料として好適な新規Ｎ−ベンジルアミド誘導体が提供できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel N-benzylbenzamide derivative useful as a raw material for the synthesis of antifungal agents.
[0002]
[Prior art]
Superficial mycosis, such as athlete's foot, has been overcome in the present age, because there are still no reliable treatments and medicines available because of the westernization of life and the increased wearing time of shoes. It is counted as one of the diseases that have not been done. Therefore, many compounds have been screened for antifungal activity. However, there are not many substances that have been found to be active in vitro or at the animal level but drop out in the actual clinical stage, and very few results have been obtained so far. That is, the discovery of a mother nucleus having a novel antifungal action has been awaited. Under such circumstances, the present inventors have found that the compound represented by the general formula (II) has an excellent antifungal action. For example, among the compounds represented by the general formula (II), 4-tertiarybutyl-N-methyl-N- (2-phenylbenzyl) benzylamine (antifungal agent 1), 4-tertiarybutyl-N- Methyl-N- (3-phenylbenzyl) benzylamine (antifungal agent 2), 4-tertiarybutyl-N-methyl-N- (4-phenylbenzyl) benzylamine (antifungal agent 3), 4-tertiary Butyl-N-diphenylmethyl-N-methylbenzylamine (antifungal agent 4) exhibits excellent antifungal activity against trichophyton menta graphite as shown in Table 1. The compound represented by the general formula (II) is a novel compound, and therefore its production method is not known. Moreover, the compound represented by general formula (I) which is the compound of the present invention is also a novel compound not described in any literature.
[0003]
[Chemical formula 5]
(However, in the formula, R1 and R4 each independently represent a hydrogen atom or an aromatic hydrocarbon having 6 to 18 carbon atoms which may have a substituent, and R2 and R3 each independently have 1 to 4 carbon atoms. Represents an alkyl group, and m and n each independently represents an integer of 1 to 4.)
[0004]
[Chemical 6]
[0005]
[Chemical 7]
[0006]
[Chemical 8]
[0007]
[Chemical 9]
[0008]
[Table 1]
[Problems to be solved by the invention]
The present invention has been made under such circumstances, and an object thereof is to provide a raw material useful for synthesizing the compound of the general formula (II) which is an antifungal agent. .
[0010]
[Means for Solving the Problems]
In view of such circumstances, the present inventors have made intensive efforts for the development and research of synthetic raw materials of general formula (II), and as a result, the compounds shown in general formula (I) can be useful raw materials. It has been found and the invention has been completed. Hereinafter, the present invention will be described in detail.
[0011]
Embedded image
(However, in the formula, R1, R2, R3, R4, R5, R6, R7, R8 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group, and at least one of these substitutions. Each shall be a phenyl group.)
[0012]
The compound represented by the general formula (I) can be led to the compound represented by the general formula (II) by reduction with lithium aluminum hydride or the like. The compound of general formula (I) can be easily obtained from a commercially available reagent by the reaction of an amine and an acid chloride. Therefore, it can be said that the compound of general formula (I) is a useful synthetic raw material of the compound of general formula (II).
[0013]
DETAILED DESCRIPTION OF THE INVENTION
The compound of the present invention is an N-benzylbenzamide derivative represented by the general formula (I). The compound represented by the general formula (I) can be synthesized according to the following reaction scheme 1. That is, an N-methylbenzylamine derivative derived from a benzoic acid derivative may be reacted with a corresponding halide in the presence of a base such as triethylamine. The compound thus obtained can be purified by ordinary purification means such as silica gel column chromatography or recrystallization. Examples of such a compound represented by the general formula (I) include N-methyl-N- (2-phenylbenzyl) -4-tertiarybutylbenzoic acid amide (compound 1), N- (4-tersia). Preferable examples include (L-butylbenzyl) -N-methyl-4-phenylbenzoic acid amide (Compound 2), N- (diphenylmethyl) -N-methyl-4-tertiarybutylbenzoic acid amide (Compound 3), and the like. These compounds represented by the general formula (I) can easily lead to compounds represented by the general formula (II) by reacting a reducing agent such as lithium aluminum hydride in a solvent such as ether. Is possible.
[0014]
Embedded image
[0015]
Embedded image
[0016]
Embedded image
[0017]
Embedded image
[0018]
【Example】
Example 1
Production Example 10 g of o-phenylbenzoic acid and 18.7 g of thionyl chloride were mixed with 100 ml of chloroform and heated to reflux for 4 hours. The reaction product was concentrated under reduced pressure and added dropwise to 40 ml of a 40% aqueous methylamine solution under ice cooling. The mixture was returned to room temperature and stirred for 4 days to react. The reaction was stopped by adding 2N hydrochloric acid, extracted with chloroform, and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was removed and the solvent was distilled off to obtain N-methyl-2-phenylbenzoic acid amide. This was reduced with 0.54 g of lithium aluminium hydride in ether to give 1.46 g of N-methyl-2-phenylbenzylamine. This was reacted with 1.45 g of acid chloride derived from p-tertiary butylbenzoic acid in benzene in the presence of triethylamine, extracted by adding water and chloroform to the reaction solution, and the organic layer was taken, diluted hydrochloric acid, saturated bicarbonate Washing was carried out in the order of aqueous sodium solution, water and saturated brine. The solvent was distilled off to obtain 2.42 g of N-methyl-N- (2-phenylbenzyl) -4-tertiarybutylbenzoic acid amide (Compound 1) as yellow crystals. NMR (solvent: deuterated chloroform) was as follows.
1H-δ ppm; 1.31 (9H, s), 2.81 (3H, d), 4.63 (2H, d) 7.00 to 7.41 (13H, m)
[0019]
(Example 2) In the same manner as in Production Example 1, from 2.47 g of p-phenylbenzoic acid, 4-tertiarybutyl-N-methyl-N- (4-phenylbenzyl) benzoic acid amide (Compound 2) was obtained as white crystals. 1.58 g was obtained. The 1H-NMR spectrum (δ ppm, deuterated chloroform) is as shown below.
(NMR)
1.26 (9H, s), 2.99 (3H, d), 4.65 (2H, d), 7.14-7.59 (13H, m)
[0020]
(Example 3) In the same manner as in Production Example 1, 1.48 g of 4-tertiarybutyl-N-diphenylmethyl-N-methylbenzoic acid amide (Compound 3) was obtained as white crystals from 4.06 g of chlorodiphenylmethane. . (Yield: 48.9%) 1H-NMR spectrum (δ ppm, deuterated chloroform) is as shown below.
(NMR)
1.16 (9H, s), 2.72 (3H, s), 7.01 to 7.25 (14H, m)
【The invention's effect】
According to the present invention, a novel N-benzylamide derivative suitable as a raw material for an antifungal agent can be provided.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09757296A JP3866323B2 (en) | 1996-03-27 | 1996-03-27 | Novel N-benzylbenzamide derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09757296A JP3866323B2 (en) | 1996-03-27 | 1996-03-27 | Novel N-benzylbenzamide derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09255643A JPH09255643A (en) | 1997-09-30 |
| JP3866323B2 true JP3866323B2 (en) | 2007-01-10 |
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ID=14195962
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP09757296A Expired - Fee Related JP3866323B2 (en) | 1996-03-27 | 1996-03-27 | Novel N-benzylbenzamide derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3866323B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2247675C (en) * | 1998-09-17 | 2009-05-05 | Pola Chemical Industries, Inc. | Antifungal agents |
| UA90691C2 (en) * | 2004-09-29 | 2010-05-25 | Баер Шеринг Фарма Акциенгезельшафт | Process for the preparation of 4-{ 4-[({ [4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide |
-
1996
- 1996-03-27 JP JP09757296A patent/JP3866323B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH09255643A (en) | 1997-09-30 |
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