JP2001354627A - Allenecarboxylic acid derivative - Google Patents
Allenecarboxylic acid derivativeInfo
- Publication number
- JP2001354627A JP2001354627A JP2000178213A JP2000178213A JP2001354627A JP 2001354627 A JP2001354627 A JP 2001354627A JP 2000178213 A JP2000178213 A JP 2000178213A JP 2000178213 A JP2000178213 A JP 2000178213A JP 2001354627 A JP2001354627 A JP 2001354627A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- acid derivative
- salt
- allenecarboxylic
- ulcer
- 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.)
- Pending
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は強力なウレアーゼ阻
害作用及び抗潰瘍作用を有するアレンカルボン酸誘導体
又はその塩、並びにこれを含有する医薬に関する。TECHNICAL FIELD The present invention relates to an allenecarboxylic acid derivative or a salt thereof having a potent urease inhibitory activity and an antiulcer activity, and a medicament containing the same.
【0002】[0002]
【従来の技術】近年、ヘリコバクターピロリの感染が、
胃潰瘍、胃癌その他胃疾患の発生に関与していることが
解明されつつあり、消化性潰瘍では、ヘリコバクターピ
ロリ菌を除菌することにより再発が抑制されることが報
告されている[J.Gastroenterol,30(suppl 210),70(199
5)]。ピロリ菌は菌体の6重量%にも及ぶウレアーゼを
有しており、これがピロリ菌の胃内での棲息を可能にし
ている。従って、消化性潰瘍を治癒させ、再発を起こさ
せないためにはウレアーゼ活性を強力に阻害し、ピロリ
菌の棲息を不可能にすることが必要である。現在ウレア
ーゼ阻害活性を有する抗潰瘍剤としては、プロトンポン
プ阻害剤であるオメプラゾールや本発明者等が先に提案
したアレンカルボン酸誘導体等が知られている(特開平
10−182451号公報)。BACKGROUND OF THE INVENTION In recent years, the infection of Helicobacter pylori has
It is being elucidated that it is involved in the development of gastric ulcer, gastric cancer and other gastric diseases, and it has been reported that in peptic ulcer, recurrence is suppressed by eliminating Helicobacter pylori [J. Gastroenterol, 30 (suppl 210), 70 (199
Five)]. H. pylori has urease, which accounts for as much as 6% by weight of the cells, which allows H. pylori to inhabit the stomach. Therefore, in order to heal peptic ulcer and prevent recurrence, it is necessary to strongly inhibit urease activity and to make it impossible for H. pylori to inhabit. At present, as antiulcer agents having urease inhibitory activity, omeprazole, which is a proton pump inhibitor, and an allenecarboxylic acid derivative previously proposed by the present inventors have been known (Japanese Patent Application Laid-Open No. 10-182451).
【0003】[0003]
【発明が解決しようとする課題】しかしながら、前記既
知のアレンカルボン酸誘導体のウレアーゼ阻害活性及び
抗潰瘍作用はいずれも充分満足すべきものではなく、更
に優れた作用を有する化合物の創製が望まれていた。However, the urease-inhibiting activity and the anti-ulcer activity of the above-mentioned known allenecarboxylic acid derivatives are not sufficiently satisfactory, and it has been desired to create a compound having a more excellent action. .
【0004】[0004]
【課題を解決するための手段】そこで本発明者らは、ア
レンカルボン酸誘導体を更に数多く合成し、その薬理作
用を検討してきたところ、全く意外にもベンゼン環上に
フッ素原子を導入したアレンカルボン酸誘導体が、フッ
素原子を有さない場合に比べて10倍以上強力なウレア
ーゼ阻害活性及び抗潰瘍作用を有し、抗潰瘍剤として有
用であることを見出し、本発明を完成するに至った。The present inventors have synthesized a greater number of allene carboxylic acid derivatives and studied their pharmacological actions. As a result, surprisingly, the allene carboxylic acid derivative having a fluorine atom introduced on the benzene ring has been obtained. The present inventors have found that an acid derivative has a urease inhibitory activity and an anti-ulcer effect that are at least 10 times stronger than those having no fluorine atom, and is useful as an anti-ulcer agent, thereby completing the present invention.
【0005】すなわち、本発明は、一般式(1)That is, the present invention provides a compound represented by the general formula (1)
【0006】[0006]
【化2】 Embedded image
【0007】(式中、R1は低級アルキル基を示し、R2
は水素原子又はカルボキシル基の保護基を示す)で表さ
れるアレンカルボン酸誘導体又はその塩を提供するもの
である。また本発明は上記アレンカルボン酸誘導体
(1)又はその塩(以下、本発明化合物ということがあ
る)を含有する医薬及びウレアーゼ阻害剤を提供するも
のである。[0007] (In the formula, R 1 represents a lower alkyl group, R 2
Represents a protecting group for a hydrogen atom or a carboxyl group) or a salt thereof. The present invention also provides a medicament and a urease inhibitor containing the above allenecarboxylic acid derivative (1) or a salt thereof (hereinafter, sometimes referred to as the compound of the present invention).
【0008】[0008]
【発明の実施の形態】一般式(1)中、R1で示される
低級アルキル基としては、炭素数1〜5の直鎖又は分枝
状のアルキル基が挙げられ、具体的にはメチル基、エチ
ル基、n−プロピル基、イソプロピル基、n−ブチル基
等が挙げられる。このうち、R1としてはメチル基が特
に好ましい。BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), examples of the lower alkyl group represented by R 1 include a linear or branched alkyl group having 1 to 5 carbon atoms, and specifically, a methyl group , Ethyl group, n-propyl group, isopropyl group, n-butyl group and the like. Of these, a methyl group is particularly preferred as R 1 .
【0009】R2で示されるカルボキシル基の保護基と
しては、メチル、エチル、n−プロピル、n−ブチル、
第3級ブチル、n−ペンチル、1−シクロプロピルエチ
ル等の直鎖、分枝状又は環状のアルキル基;ビニル、ア
リル等の低級アルケニル基;エチニル、プロピニル等の
低級アルキニル基;メトキシメチル、1−メトキシエチ
ル等の低級アルコキシ低級アルキル基;2−ヨードエチ
ル、2,2,2−トリクロロエチル等のハロ低級アルキ
ル基;メシルメチル、メシルエチル等の低級アルカンス
ルホニル低級アルキル基;フェニル、トリル、第3級ブ
チルフェニル、サリチル、3,4−ジメトキシフェニル
等の置換されていてもよいアリール基;ベンジル、トリ
チル、ベンズヒドリル等のアリール低級アルキル基;ト
リメチルシリル、トリエチルシリル基等のトリ低級アル
キルシリル基;ジメチルメトキシシリル、ジエチルメト
キシシリル等のジ低級アルキル低級アルコキシシリル基
等を例示することができる。このうち、R2としては、
アルキル基が好ましく、炭素数1〜5のアルキル基がよ
り好ましく、メチル基、エチル基、n−プロピル基が更
に好ましく、エチル基が特に好ましい。なお、ここで
「低級」の語は炭素数1〜5であることを意味する。The carboxyl-protecting group represented by R 2 includes methyl, ethyl, n-propyl, n-butyl,
Linear, branched or cyclic alkyl groups such as tertiary butyl, n-pentyl and 1-cyclopropylethyl; lower alkenyl groups such as vinyl and allyl; lower alkynyl groups such as ethynyl and propynyl; -Lower alkoxy lower alkyl groups such as -methoxyethyl; halo lower alkyl groups such as 2-iodoethyl and 2,2,2-trichloroethyl; lower alkanesulfonyl lower alkyl groups such as mesylmethyl and mesylethyl; phenyl, tolyl and tertiary butyl Optionally substituted aryl groups such as phenyl, salicyl and 3,4-dimethoxyphenyl; aryl lower alkyl groups such as benzyl, trityl and benzhydryl; tri-lower alkylsilyl groups such as trimethylsilyl and triethylsilyl groups; dimethylmethoxysilyl; Dimethoxymethoxysilyl Can be exemplified grade alkyl lower alkoxysilyl group. Among them, as R 2 ,
An alkyl group is preferable, an alkyl group having 1 to 5 carbon atoms is more preferable, a methyl group, an ethyl group, and an n-propyl group are further preferable, and an ethyl group is particularly preferable. Here, the term “lower” means having 1 to 5 carbon atoms.
【0010】また、一般式(1)中のベンゼン環上のフ
ッ素原子はアレンカルボン酸に対して、オルト、メタ、
パラのいずれの位置に置換していてもよいが、パラ位
(4位)に置換しているのが特に好ましい。In the general formula (1), the fluorine atom on the benzene ring is ortho, meta,
The substituent may be substituted at any position of para, but it is particularly preferable that the substituent is substituted at para position (position 4).
【0011】本発明化合物のうち、α−メチル−γ−
(4−フルオロフェニル−γ−フェニルアレンカルボン
酸エチルエステル(一般式(1)において、R1=メチ
ル基、R2=エチル基、フッ素がパラ位に置換)が特に
好ましい。Among the compounds of the present invention, α-methyl-γ-
(4-fluorophenyl-γ-phenylarenecarboxylic acid ethyl ester (in the general formula (1), R 1 = methyl group, R 2 = ethyl group, fluorine is substituted at the para-position)) is particularly preferred.
【0012】一般式(1)においてR2が水素原子であ
る場合には、本発明化合物は塩を形成し得る。当該塩と
しては、薬学的に許容される塩であれば特に制限されな
いが、ナトリウム塩、カリウム塩などのアルカリ金属
塩;カルシウム塩などのアルカリ土類金属塩;トリエチ
ルアミン塩などのアミン塩等が挙げられる。When R 2 is a hydrogen atom in the general formula (1), the compound of the present invention can form a salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; and amine salts such as triethylamine salt. Can be
【0013】また、本発明化合物は、水和物、溶媒和物
の形態であってもよい。更に本発明化合物には立体異性
体が存在し、本発明には光学活性体及びラセミ体のいず
れも含まれる。なお、光学分割は、光学分割剤を用いて
行ってもよいが、ブタ肝臓由来エステラーゼ等の酵素処
理により行ってもよい。The compound of the present invention may be in the form of a hydrate or a solvate. Further, the compounds of the present invention have stereoisomers, and the present invention includes both optically active forms and racemic forms. In addition, optical resolution may be performed using an optical resolution agent, or may be performed by enzymatic treatment such as porcine liver-derived esterase.
【0014】本発明化合物は、例えば次式に従って製造
することができる。The compound of the present invention can be produced, for example, according to the following scheme.
【0015】[0015]
【化3】 Embedded image
【0016】(式中、Xはハロゲン原子を示し、R1及
びR2は前記と同じ)(Wherein X represents a halogen atom, and R 1 and R 2 are the same as described above)
【0017】すなわち、一般式(2)で表されるα−
(フルオロフェニル)フェニル酢酸ハライドと一般式
(3)で表されるトリフェニルホスホラン誘導体とを反
応させることにより、本発明化合物(1)を製造するこ
とができる。That is, α- represented by the general formula (2)
The compound (1) of the present invention can be produced by reacting a (fluorophenyl) phenylacetic halide with a triphenylphosphorane derivative represented by the general formula (3).
【0018】α−(フルオロフェニル)フェニル酢酸ハ
ライド(2)は、例えばα−(フルオロフェニル)フェ
ニル酢酸に塩化チオニル、オキシ塩化リン等のハロゲン
化剤を反応させることによって得られる。また、トリフ
ェニルホスホラン誘導体(3)は、トリフェニルホスフ
ィンとα−ブロモ脂肪酸エステルとを反応させることに
より得られる。The α- (fluorophenyl) phenylacetic acid halide (2) can be obtained, for example, by reacting α- (fluorophenyl) phenylacetic acid with a halogenating agent such as thionyl chloride or phosphorus oxychloride. Further, the triphenylphosphorane derivative (3) is obtained by reacting triphenylphosphine with an α-bromo fatty acid ester.
【0019】α−(フルオロフェニル)フェニル酢酸ハ
ライド(2)とトリフェニルホスホラン誘導体(3)と
の反応は、例えばトリエチルアミン、ピリジン等の塩基
の存在下に行うのが好ましい。反応は、ジクロロメタ
ン、クロロホルム等の不活性有機溶媒中、0〜60℃、
1〜48時間行うのが好ましい。The reaction between α- (fluorophenyl) phenylacetic acid halide (2) and triphenylphosphorane derivative (3) is preferably carried out in the presence of a base such as triethylamine, pyridine or the like. The reaction is carried out in an inert organic solvent such as dichloromethane and chloroform at 0 to 60 ° C.
It is preferably performed for 1 to 48 hours.
【0020】反応混合物から目的物を単離するには、再
結晶、抽出、各種クロマトグラフィー等により行うのが
好ましい。The isolation of the desired product from the reaction mixture is preferably carried out by recrystallization, extraction, various types of chromatography and the like.
【0021】かくして得られた本発明化合物は、フッ素
原子を有さないジフェニルアレンカルボン酸エステルに
比べて10倍以上強いウレアーゼ阻害活性及び抗潰瘍作
用を有することから、胃潰瘍、十二指腸潰瘍等の消化性
潰瘍の予防治療薬、胃癌治療薬として有用である。The compound of the present invention thus obtained has a urease inhibitory activity and anti-ulcer activity which is at least 10 times stronger than that of diphenylarene carboxylate having no fluorine atom, and therefore has a peptic property such as gastric ulcer and duodenal ulcer. It is useful as a prophylactic or therapeutic drug for ulcers and a therapeutic drug for gastric cancer.
【0022】本発明の医薬の投与剤型としては、散剤、
細粒剤、顆粒剤、錠剤、被覆錠剤、カプセル剤等の経口
用固形剤やシロップ剤等の経口用液体剤を挙げることが
でき、製剤化の際には通常の製剤担体を用いて常法によ
り製造することができる。The dosage form of the medicament of the present invention includes powder,
Oral solids such as fine granules, granules, tablets, coated tablets and capsules and oral liquids such as syrups can be mentioned. Can be manufactured.
【0023】すなわち、経口用固形剤を調製する場合
は、上記有効成分に賦形剤を添加し、更に必要に応じて
結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤を加えた
後、常法により散剤、細粒剤、顆粒剤、錠剤、被覆錠
剤、カプセル剤等とする。That is, when an oral solid preparation is prepared, an excipient is added to the above-mentioned active ingredient, and a binder, a disintegrant, a lubricant, a coloring agent, and a flavoring agent are further added as necessary. Thereafter, powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared in a usual manner.
【0024】賦形剤としては、乳糖、コーンスターチ、
白糖、ブドウ糖、ソルビット、結晶セルロース、二酸化
ケイ素等を用いることができ、結合剤としては、ポリビ
ニルアルコール、ポリビニルエーテル、エチルセルロー
ス、メチルセルロース、アラビヤゴム、トラガント、ゼ
ラチン、シェラック、ヒドロキシプロピルセルロース、
ヒドキシプロピルスターチ、ポリビニルピロリドン等を
用いることができる。また崩壊剤としては、デンプン、
寒天、ゼラチン末、結晶セルロース、炭酸カルシウム、
炭酸水素ナトリウム、クエン酸カルシウム、デキストリ
ン、ペクチン等を用いることができ、滑沢剤としては、
ステアリン酸マグネシウム、タルク、ポリエチレングリ
コール、シリカ、硬化植物油等を用いることができる。
着色剤としては医薬品に添加することが許容されている
物質を用い、矯味矯臭剤としては、ココア末、ハッカ
脳、芳香酸、ハッカ油、竜脳、桂皮末等を用いることが
できる。As excipients, lactose, corn starch,
Sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide and the like can be used.As the binder, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl starch, polyvinylpyrrolidone and the like can be used. As disintegrants, starch,
Agar, gelatin powder, crystalline cellulose, calcium carbonate,
Sodium bicarbonate, calcium citrate, dextrin, pectin, etc. can be used.
Magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like can be used.
As the coloring agent, a substance which is allowed to be added to a medicine is used, and as the flavoring agent, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like can be used.
【0025】なお、経口用固形剤とするにあたっては、
糖衣、ゼラチン衣等によりコーティングしてもさしつか
えないことはもちろんである。[0025] In preparing an oral solid preparation,
It goes without saying that coating with sugar coating, gelatin coating or the like is not a problem.
【0026】経口用液体剤とする場合には、例えば通常
のシロップ剤(溶液)では、甘味料として白糖、ソルビ
トール等を添加し、溶解補助剤としてソルビタン脂肪酸
エステル、ポリソルベート、ポリビニルピロリドン、エ
チレンジアミン、グリセリン等を添加し、必要に応じて
パラオキシ安息香酸エステル類、安息香酸ナトリウム、
ベンジルアルコール、デヒドロ酢酸ナトリウム等の防腐
剤を添加する。また、懸濁シロップ剤とする場合には、
上記製剤原料の他に、懸濁剤としてアラビヤゴム、トラ
ガント、ナトリウムカルボキシメチルセルロース、メチ
ルセルロース等を添加する。In the case of a liquid preparation for oral use, for example, in a usual syrup (solution), sucrose, sorbitol, etc. are added as a sweetener, and sorbitan fatty acid ester, polysorbate, polyvinylpyrrolidone, ethylenediamine, glycerin are added as solubilizers. Etc., and if necessary, paraoxybenzoates, sodium benzoate,
Preservatives such as benzyl alcohol and sodium dehydroacetate are added. When used as a suspension syrup,
In addition to the above-mentioned raw materials for the preparation, Arabic gum, tragacanth, sodium carboxymethylcellulose, methylcellulose and the like are added as suspending agents.
【0027】本発明の医薬を消化性潰瘍患者に投与する
場合、その投与量は潰瘍の発生部位、病状の程度、患者
の年齢、健康状態、併用する薬剤の有無等により異なる
ため特定することはできないが、本発明化合物を概ね1
〜1000mg/日の割合で投与することにより、所望の
効果を得ることができる。When the medicament of the present invention is administered to a patient with peptic ulcer, the dosage depends on the site of ulcer occurrence, degree of medical condition, age of the patient, health condition, presence or absence of concomitant drug, and the like. Although it is not possible, the compound of the present invention
The desired effect can be obtained by administering at a rate of 10001000 mg / day.
【0028】[0028]
【実施例】次に実施例を挙げて本発明を更に詳細に説明
するが、本発明はこれに何ら限定されるものではない。Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
【0029】実施例1 (1)α−(4−フルオロフェニル)フェニル酢酸に塩
化チオニルを溶媒兼反応剤として滴下し、2時間加熱還
流した。その後、溶媒を減圧下留去し、真空ポンプで1
0分間程放置し、α−(4−フルオロフェニル)フェニ
ル酢酸クロリドを得た。Example 1 (1) Thionyl chloride was added dropwise to α- (4-fluorophenyl) phenylacetic acid as a solvent and a reactant, and the mixture was heated under reflux for 2 hours. Thereafter, the solvent was distilled off under reduced pressure, and 1
The mixture was left for about 0 minutes to obtain α- (4-fluorophenyl) phenylacetic acid chloride.
【0030】(2)トリフェニルホスフィン(25g,95mmo
l)を無水ベンゼン(15mL)に溶解し、攪拌下α−ブロモプ
ロピオン酸エチルエステル(12mL,95mmol)を室温で滴下
し、60℃で48時間攪拌した。反応液を室温まで戻し
析出したホスホニウム塩を濾過し冷却したベンゼンで洗
浄した後、蒸留水に溶解してエーテルで洗浄した。水層
を冷却しながら2N NaOHをpH8〜10になるまで
滴下し析出した結晶を濾過した後、乾燥させ無水酢酸エ
チルで再結晶し、(エトキシカルボニルエチレン)トリ
フェニルホスホラン(28.0g,81%)を得た。 黄色プリズム晶、mp157-159℃.1 H-NMR(200MHz,CDCl3)δ:0.66(3H,t,J=7.0Hz),1.58(3H,
s),3.81(2H,q,J=7.0Hz),7.40-7.66(15H,m). EI-MS:362(M+)(C23H23O2P).(2) Triphenylphosphine (25 g, 95 mmo
l) was dissolved in anhydrous benzene (15 mL), and α-bromopropionic acid ethyl ester (12 mL, 95 mmol) was added dropwise at room temperature with stirring, followed by stirring at 60 ° C for 48 hours. The reaction solution was returned to room temperature, and the precipitated phosphonium salt was filtered and washed with cooled benzene, then dissolved in distilled water and washed with ether. While cooling the aqueous layer, 2N NaOH was added dropwise until the pH became 8 to 10, and the precipitated crystals were filtered, dried, recrystallized from anhydrous ethyl acetate, and (ethoxycarbonylethylene) triphenylphosphorane (28.0 g, 81%). ). Yellow prism crystals, mp 157-159 ° C. 1 H-NMR (200 MHz, CDCl 3 ) δ: 0.66 (3H, t, J = 7.0 Hz), 1.58 (3H,
s), 3.81 (2H, q , J = 7.0Hz), 7.40-7.66 (15H, m) EI-MS:. 362 (M +) (C 23 H 23 O 2 P).
【0031】(3)(エトキシカルボニルエチレン)ト
リフェニルホスホラン(1.15g,3.2mmol)を無水ジクロロ
メタン(10mL)に溶解し、室温でトリエチルアミン(0.32m
L,2.3mmol)を滴下し、窒素雰囲気下で攪拌した。10分
後、α−(4−フルオロフェニル)フェニル酢酸クロリ
ド(794mg,3.2mmol)を無水ジクロロメタン(5mL)に溶解し
たものを反応溶液に室温で滴下し、24時間攪拌した。
次いで、溶媒を減圧留去後、シリカゲルカラムクロマト
グラフィー(n−ヘキサン:酢酸エチル=20:1)を
行い、α−メチル−γ−(4−フルオロフェニル)−γ
−フェニルアレンカルボン酸エチルエステル(以下、化
合物aという)(824mg,87%)を得た。 黄色油状物 IR(cm-1):1941,1721.1 H-NMR(300MHz,CDCl3)δ:1.28(3H,t,J=7.2Hz),2.05(3H,
s),4.22(2H,q,J=7.2Hz),7.02-7.08(2H,m),7.29-7.37(7
H,m).13 C-NMR(75MHz,CDCl3)δ:14.3(q),15.2(q),61.2(t),98.
4(s),111.6(s),115.5(d,J=22Hz),128.0(d),128.5(d),12
8.6(d),130.3(d,J=8Hz),131.5(s,J=3Hz),135.4(s),162.
5(s,J=246Hz),167.1(s),212.2(s). HR-EI-MS:296.1209(M+)(CalcdforC19H17O2F:296.1213).(3) (Ethoxycarbonylethylene) triphenylphosphorane (1.15 g, 3.2 mmol) was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (0.32 m
L, 2.3 mmol) was added dropwise, and the mixture was stirred under a nitrogen atmosphere. After 10 minutes, a solution of α- (4-fluorophenyl) phenylacetic acid chloride (794 mg, 3.2 mmol) dissolved in anhydrous dichloromethane (5 mL) was added dropwise to the reaction solution at room temperature, and the mixture was stirred for 24 hours.
Then, after the solvent was distilled off under reduced pressure, silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) was performed to obtain α-methyl-γ- (4-fluorophenyl) -γ.
-Ethyl phenylarenecarboxylic acid ester (hereinafter, referred to as compound a) (824 mg, 87%) was obtained. Yellow oil IR (cm -1):. 1941,1721 1 H-NMR (300MHz, CDCl 3) δ: 1.28 (3H, t, J = 7.2Hz), 2.05 (3H,
s), 4.22 (2H, q, J = 7.2Hz), 7.02-7.08 (2H, m), 7.29-7.37 (7
. H, m) 13 C- NMR (75MHz, CDCl 3) δ: 14.3 (q), 15.2 (q), 61.2 (t), 98.
4 (s), 111.6 (s), 115.5 (d, J = 22Hz), 128.0 (d), 128.5 (d), 12
8.6 (d), 130.3 (d, J = 8Hz), 131.5 (s, J = 3Hz), 135.4 (s), 162.
5 (s, J = 246Hz) , 167.1 (s), 212.2 (s) HR-EI-MS:. 296.1209 (M +) (CalcdforC 19 H 17 O 2 F: 296.1213).
【0032】実施例2 (1)化合物a(500mg,1.69mmol)をt−ブタノール(5m
L)に溶解し、0.1Mリン酸バッファー(42.875mL)加え
た後、ブタ肝臓エステラーゼ(シグマ社)(2.215mL,250
0units)を加え、37℃で24時間攪拌した。反応液を
減圧下留去し、1N NaOH(100mL)とクロロホルム
(100mL)を加え攪拌し、3000×gで10分間遠心分
離を行いエステラーゼを取り除いた。その後、抽出操作
を行いクロロホルム層を分取し溶媒を減圧下留去し、再
度上記の操作を行い、(−)−α−メチル−γ−(4−
フルオロフェニル)−γ−フェニルアレンカルボン酸エ
チルエステル(196mg,39%)を得た。 黄色油状物 IR(cm-1):1942,1713.1 H-NMR(300MHz,CDCl3)δ:1.29(3H,t,J=7.1Hz),2.05(3H,
s),4.22(2H,q,J=7.1Hz),7.00-7.16(2H,m),7.25-7.40(7
H,m).13 C-NMR(75MHz,CDCl3)δ:1.43(q),15.3(q),61.2(t),98.
4(s),111.6(s),115.5(d,J=22Hz),128.0(d),128.4(d),12
8.6(d),130.3(d,J=8Hz),131.5(s,J=3Hz),135.4(s),162.
5(s,J=246Hz),167.1(s),210.5(s). HR-EI-MS:296.1198(M+)(CalcdforC19H17O2F:296.1212). [α]D 20−4°(c=1.03,CHCl3).Example 2 (1) Compound a (500 mg, 1.69 mmol) was added to t-butanol (5 m
L) and added 0.1 M phosphate buffer (42.875 mL), and then swine liver esterase (Sigma) (2.215 mL, 250
0 units) and stirred at 37 ° C. for 24 hours. The reaction solution was evaporated under reduced pressure, and 1N NaOH (100 mL) and chloroform
(100 mL), and the mixture was stirred and centrifuged at 3000 × g for 10 minutes to remove esterase. Thereafter, an extraction operation was performed to separate the chloroform layer, the solvent was distilled off under reduced pressure, and the above operation was performed again to obtain (-)-α-methyl-γ- (4-
Fluorophenyl) -γ-phenylarenecarboxylic acid ethyl ester (196 mg, 39%) was obtained. Yellow oil IR (cm -1):. 1942,1713 1 H-NMR (300MHz, CDCl 3) δ: 1.29 (3H, t, J = 7.1Hz), 2.05 (3H,
s), 4.22 (2H, q, J = 7.1Hz), 7.00-7.16 (2H, m), 7.25-7.40 (7
. H, m) 13 C- NMR (75MHz, CDCl 3) δ: 1.43 (q), 15.3 (q), 61.2 (t), 98.
4 (s), 111.6 (s), 115.5 (d, J = 22Hz), 128.0 (d), 128.4 (d), 12
8.6 (d), 130.3 (d, J = 8Hz), 131.5 (s, J = 3Hz), 135.4 (s), 162.
5 (s, J = 246Hz), 167.1 (s), 210.5 (s) .HR-EI-MS: 296.1198 (M + ) (CalcdforC 19 H 17 O 2 F: 296.1212). [Α] D 20 -4 ° (c = 1.03, CHCl 3 ).
【0033】(2)上記(1)において、遠心分離によ
りエステラーゼを除いた液について抽出操作を行って水
層を分取し、1N HCl(150mL)を加え酸性にしクロ
ロホルムで抽出した。溶媒を減圧下留去し得られたもの
176mgを無水エタノール3mLに溶解しトリエチルアミ
ン(407μL,2.97mmol)とクロロギ酸エチル(417μL,4.3
8mmol)を加え室温で攪拌した。36時間後反応液を減圧
下留去し、シリカゲルカラムクロマトグラフィー(n−
ヘキサン:クロロホルム=1:1)を行い、(+)−α
−メチル−γ−(4−フルオロフェニル)−γ−フェニ
ルアレンカルボン酸エチルエステル(130mg,30%)を得
た。 黄色油状物 IRcm-1:1942,1713.1 H-NMR(400MHz,CDCl3)δ:1.29(3H,t,J=7.0Hz),2.05(3H,
s),4.23(2H,q,J=7.0Hz),6.96-7.10(2H,m),7.25-7.37(7
H,m).13 C-NMR(100MHz,CDCl3)δ:1.43(q),15.2(q),61.2(t),9
8.4(s),111.6(s),115.5(d,J=22Hz),128.1(d),128.5(d),
128.7(d),130.3(d,J=8Hz),130.8(s,J=3Hz),135.4(s),16
2.5(s,J=246Hz),167.1(s),212.2(s). HR-EI-MS:296.1196(M+)(CalcdforC19H17O2F:296.1212). [α]D 20+3°(c=1.14,CHCl3).(2) In the above (1), an aqueous layer was separated by extracting the solution from which the esterase had been removed by centrifugation, and the mixture was acidified with 1N HCl (150 mL) and extracted with chloroform. The solvent was distilled off under reduced pressure, and 176 mg obtained was dissolved in 3 mL of absolute ethanol, and triethylamine (407 µL, 2.97 mmol) and ethyl chloroformate (417 µL, 4.3
8 mmol) and stirred at room temperature. After 36 hours, the reaction solution was distilled off under reduced pressure, and silica gel column chromatography (n-
Hexane: chloroform = 1: 1), and (+)-α
-Methyl-γ- (4-fluorophenyl) -γ-phenylarenecarboxylic acid ethyl ester (130 mg, 30%) was obtained. Yellow oil IRcm -1:. 1942,1713 1 H- NMR (400MHz, CDCl 3) δ: 1.29 (3H, t, J = 7.0Hz), 2.05 (3H,
s), 4.23 (2H, q, J = 7.0Hz), 6.96-7.10 (2H, m), 7.25-7.37 (7
. H, m) 13 C- NMR (100MHz, CDCl 3) δ: 1.43 (q), 15.2 (q), 61.2 (t), 9
8.4 (s), 111.6 (s), 115.5 (d, J = 22Hz), 128.1 (d), 128.5 (d),
128.7 (d), 130.3 (d, J = 8Hz), 130.8 (s, J = 3Hz), 135.4 (s), 16
2.5 (s, J = 246Hz), 167.1 (s), 212.2 (s). HR-EI-MS: 296.1196 (M + ) (CalcdforC 19 H 17 O 2 F: 296.1212). [Α] D 20 + 3 ° ( c = 1.14, CHCl 3 ).
【0034】実施例3(ウレアーゼ阻害活性) ジメチルスルホキシド(DMSO)の濃度を1%以下に
調製した検体50μLにウレアーゼ(終濃度0.12Units/
mL、東洋紡社製)100μL、0.1M リン酸バッフ
ァー(pH7.0)650μLを加え、37℃で10分間保温
した。その後、尿素(終濃度0.1mg/mL)100μLを加
え、37℃で15分間保温した。次いで、10%K2C
O3500μL、0.5%ダンシルクロリド(アセトン溶
液)600μLを加え、55℃で90分間保温した後、
5%グリシン3mLを加え、更に55℃で30分間保温し
た。その後、注射用水5mLを加え室温になるまで放置し
た。これに、クロロホルム2mLを加え攪拌し、液相分離
濾紙により濾過し、クロロホルム層を得た。次に、窒素
ガスにて溶媒を留去し、内部標準物質(ダンシルジメチ
ルアミド1×10-6M)を含むアセトニトリル1mLを加
え、YMCデュオーフィルターを用いて濾過した濾液を
下記の条件でHPLCにより、10μL中のダンシルア
ミド量を測定し、コントロールに対する阻害率を求め
た。陽性対照には、オメプラゾール、アセトヒドロキサ
ム酸及びα−メチル−γ,γ−ジフェニルアレンカルボ
ン酸エチルエステル(特開平10−182451号公報
の化合物II、以下化合物IIという)を用いた。Example 3 (Urease Inhibitory Activity) Urease (final concentration: 0.12 Units / well) was added to 50 μL of a sample prepared by adjusting the concentration of dimethyl sulfoxide (DMSO) to 1% or less.
mL, Toyobo Co., Ltd.) (100 µL) and 0.1 M phosphate buffer (pH 7.0) (650 µL) were added, and the mixture was kept at 37 ° C for 10 minutes. Thereafter, 100 μL of urea (final concentration 0.1 mg / mL) was added, and the mixture was kept at 37 ° C. for 15 minutes. Then, 10% K 2 C
After adding 500 μL of O 3 and 600 μL of 0.5% dansyl chloride (acetone solution) and keeping the temperature at 55 ° C. for 90 minutes,
3 mL of 5% glycine was added, and the mixture was further kept at 55 ° C. for 30 minutes. Thereafter, 5 mL of water for injection was added, and the mixture was left to reach room temperature. To this, 2 mL of chloroform was added and stirred, and the mixture was filtered with a liquid phase separation filter paper to obtain a chloroform layer. Next, the solvent was distilled off with nitrogen gas, 1 mL of acetonitrile containing an internal standard substance (dansyl dimethylamide 1 × 10 −6 M) was added, and the filtrate filtered using a YMC Duo filter was subjected to HPLC under the following conditions. As a result, the amount of dansylamide in 10 μL was measured, and the inhibition ratio with respect to the control was determined. As a positive control, omeprazole, acetohydroxamic acid and α-methyl-γ, γ-diphenylarenecarboxylic acid ethyl ester (compound II of JP-A-10-182451, hereinafter referred to as compound II) were used.
【0035】HPLCの条件 カラム;YMC-PackODS-A,S-5mm,120Å150×6.0mmI.D. 液相;アセトニトリル:17.2mMリン酸バッファー(pH7.
2)(1:1) 流速;1mL/min 蛍光光度検出器;EX340nm,EM530nm カラム温度;30℃HPLC conditions Column; YMC-PackODS-A, S-5 mm, 120Å150 × 6.0 mm I.D. Liquid phase; acetonitrile: 17.2 mM phosphate buffer (pH 7.
2) (1: 1) Flow rate; 1mL / min Fluorescence detector; EX340nm, EM530nm Column temperature; 30 ℃
【0036】その結果、表1に示すように化合物aは特
開平10−182451号公報記載の化合物IIの10倍
以上強力なウレアーゼ阻害活性を有していた。As a result, as shown in Table 1, Compound a had urease inhibitory activity which was at least 10 times stronger than Compound II described in JP-A-10-182451.
【0037】[0037]
【表1】 [Table 1]
【0038】実施例4(ストレス潰瘍治療作用) Wistar/ST系雄性ラット(260g前後)を24時間絶食
後、東大薬作型ストレスゲージに入れ、22℃の水槽内
に剣状突起の高さまで浸し、ストレス負荷した。7時間
後、ストレスケージから出し、エーテル致死させた後、
胃内に生理食塩水10mLを入れ、そのあと胃を切り離し
て摘出し、1%ホルマリン溶液に10分間浸した。その
後、生理食塩水で置換し、大弯部に沿って切開し、腺胃
部に発生している潰瘍の面積(mm2)を測定し、一匹当
たりの潰瘍の総和を潰瘍係数とした。検体は0.5%ア
ラビアガムに懸濁し、ストレス負荷10分前に経口投与
した。コントロールには検体の代わりに0.5%アラビ
アガムを投与し、各検体のコントロールに対する阻害率
を求めた。Example 4 (Effect of treating stress ulcer) Wistar / ST male rats (around 260 g) were fasted for 24 hours, then placed in a Tokyo University drug-type stress gauge, and immersed in a water tank at 22 ° C to the level of the xiphoid process. , Stressed. After 7 hours, take out of the stress cage, let it die with ether,
10 mL of physiological saline was put into the stomach, and then the stomach was cut off and removed, and immersed in a 1% formalin solution for 10 minutes. Thereafter, the ulcer was replaced with physiological saline, and incised along the greater curvature, the area (mm 2 ) of the ulcer occurring in the glandular stomach was measured, and the total ulcer per animal was defined as the ulcer index. The sample was suspended in 0.5% gum arabic and orally administered 10 minutes before stress loading. For the control, 0.5% gum arabic was administered instead of the sample, and the inhibition rate of each sample with respect to the control was determined.
【0039】その結果、図1に示すように、化合物aは
特開平10−182451号公報記載の化合物II及びシ
メチジンの約10倍強い抗潰瘍作用を有していた。As a result, as shown in FIG. 1, Compound a had about 10 times stronger antiulcer activity than Compound II and cimetidine described in JP-A-10-182451.
【0040】[0040]
【発明の効果】本発明化合物は強力なウレアーゼ阻害活
性及び抗潰瘍作用を有することから、これを含有する本
発明の抗潰瘍剤はピロリ菌の増殖を抑制または除菌し、
消化性潰瘍の治療作用及び再発抑制作用に優れた医薬と
して有用である。Since the compound of the present invention has a potent urease inhibitory activity and an anti-ulcer effect, the anti-ulcer agent of the present invention containing the compound inhibits or eliminates the growth of H. pylori,
It is useful as a medicament excellent in treating peptic ulcer and suppressing recurrence.
【図1】本発明化合物の水浸ストレス潰瘍に対する治療
作用を示す図である。FIG. 1 is a graph showing the therapeutic effect of the compound of the present invention on water immersion stress ulcer.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61P 43/00 111 A61P 43/00 111 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 111 A61P 43/00 111
Claims (5)
はカルボキシル基の保護基を示す)で表されるアレンカ
ルボン酸誘導体又はその塩。1. A compound of the general formula (1) (Wherein, R 1 represents a lower alkyl group, R 2 represents a hydrogen atom or a carboxyl-protecting group) or a salt thereof.
ル)−γ−フェニルアレンカルボン酸エチルエステルで
ある請求項1記載の化合物。2. The compound according to claim 1, which is α-methyl-γ- (4-fluorophenyl) -γ-phenylarenecarboxylic acid ethyl ester.
誘導体又はその塩を含有する医薬。3. A medicament comprising the allene carboxylic acid derivative according to claim 1 or 2 or a salt thereof.
誘導体又はその塩を含有するウレアーゼ阻害剤。5. A urease inhibitor comprising the allene carboxylic acid derivative according to claim 1 or 2 or a salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000178213A JP2001354627A (en) | 2000-06-14 | 2000-06-14 | Allenecarboxylic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000178213A JP2001354627A (en) | 2000-06-14 | 2000-06-14 | Allenecarboxylic acid derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2001354627A true JP2001354627A (en) | 2001-12-25 |
Family
ID=18679674
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000178213A Pending JP2001354627A (en) | 2000-06-14 | 2000-06-14 | Allenecarboxylic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2001354627A (en) |
-
2000
- 2000-06-14 JP JP2000178213A patent/JP2001354627A/en active Pending
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