JP2549931B2 - Pyrimidobenzimidazole derivative - Google Patents
Pyrimidobenzimidazole derivativeInfo
- Publication number
- JP2549931B2 JP2549931B2 JP2005913A JP591390A JP2549931B2 JP 2549931 B2 JP2549931 B2 JP 2549931B2 JP 2005913 A JP2005913 A JP 2005913A JP 591390 A JP591390 A JP 591390A JP 2549931 B2 JP2549931 B2 JP 2549931B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- acid
- examples
- pyrimidobenzimidazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明はピリミドベンズイミダゾール誘導体及びその
塩に関する。TECHNICAL FIELD The present invention relates to a pyrimidobenzimidazole derivative and a salt thereof.
従来の技術 本発明のピリミドベンズイミダゾール誘導体及びその
塩は文献未載の新規化合物である。2. Description of the Related Art The pyrimidobenzimidazole derivative and its salt of the present invention are novel compounds which have not been published in the literature.
発明が解決しようとする課題 本発明は、後記するように医薬品として有用な化合物
を提供することを目的とする。DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention aims to provide a compound useful as a pharmaceutical as described below.
課題を解決するための手段 本発明によれば、下記一般式（１）で表わされるピリ
ミドベンズイミダゾール誘導体が提供される。Means for Solving the Problems According to the present invention, a pyrimidobenzimidazole derivative represented by the following general formula (1) is provided.
〔式中R1は置換基としてハロゲン原子、低級アルキル
基、低級アルコキシ基及びヒドロキシ基から選ばれる基
を１〜３個有することのあるフェニル基を、R2は水素原
子、ニトロ基、低級アルキル基、低級アルケニル基、低
級アルコキシカルボニル基又はベンジル基をそれぞれ示
し、ｎは０又は１を示す。〕 上記一般式（１）で表わされる本発明の化合物及びそ
の塩は、抗菌、抗ウイルス、抗炎症、抗リウマチ等の薬
理作用を示し、従って抗菌剤、抗ウイルス剤、抗炎症
剤、抗リウマチ剤等の医薬品として有用である。 [Wherein R 1 is a phenyl group which may have 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group as a substituent, and R 2 is a hydrogen atom, a nitro group or a lower alkyl group. Group, lower alkenyl group, lower alkoxycarbonyl group or benzyl group, respectively, and n represents 0 or 1. The compounds of the present invention represented by the above general formula (1) and salts thereof exhibit pharmacological actions such as antibacterial, antiviral, antiinflammatory and antirheumatic, and therefore antibacterial agents, antiviral agents, antiinflammatory agents and antirheumatic agents. It is useful as a drug such as an agent.
本明細書において、低級アルキル基としては、例えば
メチル、エチル、プロピル、イソプロピル、ブチル、イ
ソブチル、tert−ブチル、ペンチル、ヘキシル基等の直
鎖又は分枝鎖状低級アルキル基を例示できる。In the present specification, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.
低級アルコキシ基としては、例えばメトキシ、エトキ
シ、プロポキシ、イソプロポキシ、ブトキシ、イソブト
キシ、tert−ブトキシ、ペンチルオキシ、ヘキシルオキ
シ基等を例示できる。Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy groups and the like.
低級アルケニル基としては、例えばビニル、アリル、
２−ブテニル、３−ブテニル、１−メチル−２−プロペ
ニル、２−ペンテニル、３−メチル−２−ブテニル、２
−ヘキセニル基等を例示できる。Examples of lower alkenyl groups include vinyl, allyl,
2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 3-methyl-2-butenyl, 2
Examples thereof include a hexenyl group.
低級アルコキシカルボニル基としては、例えばメトキ
シカルボニル、エトキシカルボニル、プロポキシカルボ
ニル、ブトキシカルボニル、tert−ブトキシカルボニ
ル、ペンチルオキシカルボニル、ヘキシルオキシカルボ
ニル基等を例示できる。Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl groups and the like.
ハロゲン原子には、弗素原子、塩素原子、臭素原子及
び沃素原子が包含される。The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
本発明のピリミドベンズイミダゾール誘導体は、各種
の方法により製造することができる。その具体例を下記
反応工程式に示す。The pyrimidobenzimidazole derivative of the present invention can be produced by various methods. A specific example is shown in the following reaction process formula.
〔式中R1及びR2は前記に同じ。R2aは水素原子、低級ア
ルキル基、低級アルケニル基、低級アルコキシカルボニ
ル基又はベンジル基を、R3は低級アルキル基をそれぞれ
示す。〕 上記反応工程式−１に示す化合物（２）と化合物
（３）との反応は、塩基の存在下、無溶媒又は適当な溶
媒中で行われる。ここで用いられる塩基としては、例え
ばナトリウムメトキシド、ナトリウムエトキシド、カリ
ウム−tert−ブトキシド等の金属アルコキシドや、水素
化ナトリウム、水素化リチウム等の金属水素化物等を例
示できる。之等は通常化合物（３）に対して0.3〜３モ
ル量程度使用できる。また溶媒を用いる場合、該溶媒と
しては、例えばN,N−ジメチルホルムアミド（DMF）、ベ
ンゼン等の不活性溶媒を使用することができる。 [In the formula, R 1 and R 2 are the same as defined above. R 2a represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl group or a benzyl group, and R 3 represents a lower alkyl group. The reaction of the compound (2) shown in the above reaction process formula-1 with the compound (3) is carried out in the presence of a base, without solvent or in a suitable solvent. Examples of the base used here include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, and metal hydrides such as sodium hydride and lithium hydride. These can usually be used in an amount of about 0.3 to 3 mol based on the compound (3). When a solvent is used, an inert solvent such as N, N-dimethylformamide (DMF) or benzene can be used as the solvent.
反応は、一般に約25〜200℃程度の温度範囲にて、約
５〜24時間程度を要して行われ、かくして目的化合物
（1a）を得ることができる。The reaction is generally performed in a temperature range of about 25 to 200 ° C. for about 5 to 24 hours, and thus the target compound (1a) can be obtained.
〔式中R1及びｎは前記に同じ。〕 上記反応工程式−２に示す化合物（1b）のニトロ化反
応は、常法に従って、例えばニトロ化剤として亜硝酸
塩、硝酸、硝酸−硫酸、硝酸−酢酸等を用い、無溶媒又
は適当な溶媒中で実施できる。 [Wherein R 1 and n are the same as defined above. The nitration reaction of the compound (1b) shown in the above reaction process formula-2 is carried out according to a conventional method, for example, using nitrite, nitric acid, nitric acid-sulfuric acid, nitric acid-acetic acid, etc. as a nitrating agent without a solvent or a suitable solvent. Can be done in.
上記ニトロ化剤は、通常原料化合物に対して大過剰量
使用される。溶媒としては酢酸、硫酸等を使用するのが
好ましい。反応温度としては一般に約０〜30℃程度の範
囲を採用するのがよい。The above nitrating agent is usually used in a large excess amount with respect to the raw material compound. It is preferable to use acetic acid, sulfuric acid or the like as the solvent. As the reaction temperature, it is generally preferable to adopt a range of about 0 to 30 ° C.
上記各反応工程式に示す方法により得られる目的化合
物は、慣用の分離手段により容易に単離精製できる。該
手段としては例えば溶媒抽出、再結晶、カラムクロマト
グラフィー等を例示できる。The target compound obtained by the method shown in each of the above reaction schemes can be easily isolated and purified by a conventional separation means. Examples of the means include solvent extraction, recrystallization, column chromatography and the like.
また、本発明化合物（１）は、これに常法により水素
化ナトリウム、水素化リチウム等の金属水素化物等で処
理することにより、容易に医薬的に許容される金属塩と
することができる。更に本発明化合物（１）は、これに
常法に従い適当な酸性化合物を付加反応させることによ
り、容易に医薬的に許容される酸付加塩とすることがで
きる。該酸付加塩を形成し得る酸性化合物としては、例
えば塩酸、硫酸、リン酸、臭化水素酸等の無機酸及びシ
ュウ酸、マレイン酸、フマール酸、リンゴ酸、酒石酸、
クエン酸、安息香酸、ベンゼンスルホン酸等の有機酸を
例示できる。Further, the compound (1) of the present invention can be easily converted into a pharmaceutically acceptable metal salt by treating the compound (1) with a metal hydride such as sodium hydride or lithium hydride by a conventional method. Furthermore, the compound (1) of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting the compound (1) of the present invention to an addition reaction with an appropriate acidic compound according to a conventional method. Examples of the acidic compound capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid,
Organic acids such as citric acid, benzoic acid and benzenesulfonic acid can be exemplified.
上記金属塩及び酸付加塩は、遊離形態の本発明化合物
と同様の薬理活性を有しており、本発明はかかる金属塩
及び酸付加塩をも包含する。The above metal salts and acid addition salts have the same pharmacological activity as the free form compound of the present invention, and the present invention also includes such metal salts and acid addition salts.
実施例 以下、本発明を更に詳しく説明するため、本発明化合
物の製造のための原料化合物の製造例を参考例として挙
げ、次いで本発明化合物の製造例を実施例として挙げ
る。Examples Hereinafter, in order to explain the present invention in more detail, Production Examples of the starting compounds for producing the compounds of the present invention will be described as Reference Examples, and then Production Examples of the compounds of the present invention will be described as Examples.
実施例 １ ３−ｎ−プロピル−４−ヒドロキシ−10−ベンジル−２
−オキソ−２−ピリミド［2,1−ｂ］ベンズイミダゾー
ルの製造 １−ベンジル−２−アミノベンズイミダゾール5g及び
ナトリウムメトキシド318mgをｎ−プロピルマロン酸ジ
エチル48mlに懸濁させ、150℃で９時間撹拌した。反応
終了後放冷し、析出した粗結晶を取してエーテルを洗
浄した。この粗結晶を一旦クロロホルムに溶かし、水で
洗浄後、無水硫酸マグネシウムで乾燥させ、濃縮し、得
られる結晶を更にエーテルで洗浄して、目的化合物3.95
gを得た。Example 1 3-n-propyl-4-hydroxy-10-benzyl-2
Preparation of -oxo-2-pyrimido [2,1-b] benzimidazole 5 g of 1-benzyl-2-aminobenzimidazole and 318 mg of sodium methoxide were suspended in 48 ml of diethyl n-propylmalonate and heated at 150 ° C for 9 hours. It was stirred. After completion of the reaction, the mixture was allowed to cool, the precipitated crude crystals were taken and the ether was washed. The crude crystals were once dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate and concentrated, and the obtained crystals were further washed with ether to give the target compound 3.95.
got g.
得られた化合物の構造及び物性（融点及び1H−NMR
値）を第１表に化合物No.1として示す。Structure and physical properties of the obtained compound (melting point and 1 H-NMR
The values are shown in Table 1 as Compound No. 1.
実施例 ２〜10 実施例１と同様にして、第１表に示す各化合物（化合
物No.2〜化合物No.10）を製造した。Examples 2 to 10 In the same manner as in Example 1, each compound shown in Table 1 (Compound No. 2 to Compound No. 10) was produced.
得られた各化合物の構造及び物性を第１表し併記す
る。The structure and physical properties of each of the obtained compounds are shown in Table 1.
実施例11 ３−ニトロ−４−ヒドロキシ−10−ベンジル−２−オキ
ソ−2H−ピリミド［2,1−ｂ］ベンズイミダゾールの製
造 実施例２で得られた化合物650mgを酢酸9.3mlと水2.3m
lに懸濁させ、これに氷冷下亜硝酸ナトリウム175mgを加
えた後、室温にて2.5時間撹拌した。反応終了後、析出
した粗結晶を取してエーテルで洗浄した。この粗結晶
を一旦クロロホルムに溶かし、水で洗浄後、無水硫酸マ
グネシウムで乾燥させ、濃縮し、得られる結晶を更にエ
ーテルで洗浄して、目的化合物470mgを得た。Example 11 Preparation of 3-nitro-4-hydroxy-10-benzyl-2-oxo-2H-pyrimido [2,1-b] benzimidazole 650 mg of the compound obtained in Example 2 was added to 9.3 ml of acetic acid and 2.3 m of water.
The mixture was suspended in 1 l, 175 mg of sodium nitrite was added to the suspension under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the precipitated crude crystals were collected and washed with ether. The crude crystals were once dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate and concentrated, and the obtained crystals were further washed with ether to obtain 470 mg of the target compound.
得られた化合物の構造及び物性を第１表に化合物No.1
1として示す。The structure and physical properties of the obtained compound are shown in Table 1 as compound No. 1
Shown as 1.
実施例12 ナトリウム・３−ｎ−プロピル−10−ベンジル−２−オ
キソ−2H−ピリミド［2,1−ｂ］ベンズイミダゾール−
４−オレートの製造 実施例１で得られた化合物1.7gを、水素化ナトリウム
（60％）266mgの1,2−ジメトキシエタン205ml懸濁液中
に加え、室温で30分撹拌した。反応終了後、析出粗結晶
を取し、これをエーテルで洗浄した後、エタノール・
1,2−ジメトキシエタンにて再結晶を行ない、目的化合
物1.5gを得た。Example 12 Sodium 3-n-propyl-10-benzyl-2-oxo-2H-pyrimido [2,1-b] benzimidazole-
Preparation of 4-oleate 1.7 g of the compound obtained in Example 1 was added to a suspension of 266 mg of sodium hydride (60%) in 205 ml of 1,2-dimethoxyethane, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the precipitated crude crystals were collected and washed with ether, and then ethanol.
Recrystallization from 1,2-dimethoxyethane gave 1.5 g of the target compound.
得られた化合物の構造及び物性を第２表に化合物No.1
8として示す。The structure and physical properties of the obtained compound are shown in Table 2 as compound No. 1
Shown as 8.
実施例19及び20 実施例18と同様にして、第２表に示す化合物No.19及
び20を製造した。Examples 19 and 20 In the same manner as in Example 18, compounds Nos. 19 and 20 shown in Table 2 were produced.
各化合物の構造及び物性を第２表に示す。 Table 2 shows the structure and physical properties of each compound.
Claims (1)
基、低級アルコキシ基及びヒドロキシ基から選ばれる基
を１〜３個有することのあるフェニル基を、R2は水素原
子、ニトロ基、低級アルキル基、低級アルケニル基、低
級アルコキシカルボニル基又はベンジル基をそれぞれ示
し、ｎは０又は１を示す。〕 で表わされるピリミドベンズイミダゾール誘導体及びそ
の塩。1. A general formula [Wherein R 1 is a phenyl group which may have 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group as a substituent, and R 2 is a hydrogen atom, a nitro group or a lower alkyl group. Group, lower alkenyl group, lower alkoxycarbonyl group or benzyl group, respectively, and n represents 0 or 1. ] The pyrimidobenzimidazole derivative represented by these, and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005913A JP2549931B2 (en) | 1990-01-12 | 1990-01-12 | Pyrimidobenzimidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005913A JP2549931B2 (en) | 1990-01-12 | 1990-01-12 | Pyrimidobenzimidazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03215488A JPH03215488A (en) | 1991-09-20 |
| JP2549931B2 true JP2549931B2 (en) | 1996-10-30 |
Family
ID=11624138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005913A Expired - Fee Related JP2549931B2 (en) | 1990-01-12 | 1990-01-12 | Pyrimidobenzimidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2549931B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102712657A (en) | 2009-10-16 | 2012-10-03 | Rib-X制药公司 | Antimicrobial compounds and methods of making and using the same |
| SG10201406635QA (en) * | 2009-10-16 | 2014-11-27 | Melinta Therapeutics Inc | Antimicrobial compounds and methods of making and using the same |
| CA2979342A1 (en) | 2015-03-11 | 2016-09-15 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
| CA3023317A1 (en) | 2016-05-06 | 2017-11-09 | Melinta Therapeutics, Inc. | Antimicrobials and methods of making and using same |
-
1990
- 1990-01-12 JP JP2005913A patent/JP2549931B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03215488A (en) | 1991-09-20 |
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