JPH01216984A - Novel benzofuran derivative, uric acid eccritic agent and production thereof - Google Patents
Novel benzofuran derivative, uric acid eccritic agent and production thereofInfo
- Publication number
- JPH01216984A JPH01216984A JP4259288A JP4259288A JPH01216984A JP H01216984 A JPH01216984 A JP H01216984A JP 4259288 A JP4259288 A JP 4259288A JP 4259288 A JP4259288 A JP 4259288A JP H01216984 A JPH01216984 A JP H01216984A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- methyl
- tables
- formulas
- general formula
- 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.)
- Granted
Links
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title claims description 9
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 229940116269 uric acid Drugs 0.000 title claims description 9
- 150000001907 coumarones Chemical class 0.000 title claims description 4
- 239000003795 chemical substances by application Substances 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 13
- 230000029142 excretion Effects 0.000 claims description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract description 4
- 201000001431 Hyperuricemia Diseases 0.000 abstract description 4
- QMOGZHOXLCWJIX-UHFFFAOYSA-N COC(COC1=C(C=C(C=C1)C(=O)C1=C(OC2=C1C=CC=C2)C(C)OC(C)=O)C)=O Chemical compound COC(COC1=C(C=C(C=C1)C(=O)C1=C(OC2=C1C=CC=C2)C(C)OC(C)=O)C)=O QMOGZHOXLCWJIX-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- -1 [2-methyl-4-(2-(1-hydroxyethyl) -3-Benzofuroyl)phenoxy]acetic acid Chemical compound 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、新規なベンゾフラン誘導体及びその製法並び
に高尿酸血症治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel benzofuran derivative, a method for producing the same, and a therapeutic agent for hyperuricemia.
（従来技術）
高尿酸血症は、痛風、心血管病の誘因をなすもので、近
年ますます増加する傾向にあり、その治療剤として尿酸
排泄作用を有する、医薬上有用な活性を示す新規化合物
の創製と、それに基づくより優れた尿酸排泄剤の実用化
が強く望まれている。この種の物質として先に本出願人
によって特開昭５９−７３５７９号公報において優れた
尿酸排泄作用を示す一連の新規化合物が開示されている
。(Prior art) Hyperuricemia is a trigger for gout and cardiovascular disease, and the number of cases has been increasing in recent years.As a therapeutic agent for hyperuricemia, a new compound that exhibits a uric acid excretion effect and a pharmaceutically useful activity has been proposed. There is a strong desire for the creation of uric acid and the practical application of better uric acid excretion agents based on it. As a substance of this type, a series of new compounds which exhibit excellent uric acid excretion activity have been previously disclosed by the present applicant in Japanese Patent Application Laid-open No. 73579/1983.
（発明の構成）
本発明は、このような背景のもとになされたもので、前
記公開公報において本願発明者が開示した化合物の生体
内における活性代謝物を探求している際に見出された新
規化合物である。(Structure of the Invention) The present invention was made against this background, and was discovered while searching for in vivo active metabolites of the compound disclosed by the inventor in the above-mentioned publication. It is a new compound.
本発明に係る化合物は、一般式（１）：［但し、式中、
Ａは、−ＣＨ−ＣＨｓ又は−ＣＨ＊ＣＨａＯＨを、ＯＨ
Ｂは、低級アルキル基を、夫々表わす。以下同じ］で示
されるベンゾフラン誘導体、又はその医薬として許容さ
れる塩である。The compound according to the present invention has the general formula (1): [wherein,
A represents -CH-CHs or -CH*CHaOH, and OH B represents a lower alkyl group, respectively. The same applies hereinafter] or a pharmaceutically acceptable salt thereof.
上記一般式（１）における低級アルキル基Ｂは、炭素数
が１〜４の低級アルキル基を、又、医薬として許容され
る塩としては、一般式（１）の化合物と水酸化ナトリウ
ム、水酸化カリウム等のアルカリとの反応によって得ら
れる塩で、前記の他、カルシウム塩、アルミニウム塩な
どを例示することができる。一般式（１）の化合物のう
ち、Ａが−ＣＨ−ＣＨ。The lower alkyl group B in the above general formula (1) is a lower alkyl group having 1 to 4 carbon atoms, and as a pharmaceutically acceptable salt, the compound of the general formula (1) and sodium hydroxide, hydroxide, etc. Salts obtained by reaction with alkalis such as potassium include, in addition to the above, calcium salts, aluminum salts, and the like. In the compound of general formula (1), A is -CH-CH.
ＯＨ
の場合の化合物は、前述の特開昭５９−７３５７９号公
報においてその製造方法と共に開示されている化合物：
の製法に準じた方法により得られる一般式（２）：・・
・・・・・・・・−・・・−・・−・・・・・−・・（
２）［但し、Ｂは前記に同じ。Ｒは低級アルキル基を表
わす。以下同じ］
の化合物を、二酸化セレン（Ｓｅａｓ）存在下で、氷酢
酸−無水酢酸と加熱して反応許せて得られる、一般式（
３）：
％式％（３）
［式中、Ｂ、 Ｒは前記に同じ。］
の化合物を常法に基づいて加水分解することにより得ら
れる。In the case of OH, the compound is a compound of the general formula (2) obtained by a method similar to the method for producing the compound disclosed in the above-mentioned JP-A-59-73579 together with its production method.
・・・・・・・・・−・・・−・・−・・・・・−・・(
2) [However, B is the same as above. R represents a lower alkyl group. The same applies hereinafter] A compound of the general formula (
3): %Formula %(3) [In the formula, B and R are the same as above. ] can be obtained by hydrolyzing the compound according to a conventional method.
又、一般式（１）の化合物のうち、Ａが−ＣＨ！ −Ｃ
Ｈ１−ＯＨである場合の化合物は、２−アシルオキシエ
チルベンゾフラン（４）と、４−アシルオキシカルボニ
ルメチルオキシ−３−イ氏級アルキルベンゾイルハライ
ド（５）とのフリーデルクラフッ反応により得られる、
一般式（６）の化合物を加水分屏することにより得られ
る。これを反応式で示すと以下の通りである（但し、下
記反応式中、Ｒ１Ｒ゛は、夫々低級アルキル基、Ｘは、
ハロゲン基、Ｂは前記と同じ）。Furthermore, in the compound of general formula (1), A is -CH! -C
The compound in the case of H1-OH is obtained by a Friedel-Crach reaction between 2-acyloxyethylbenzofuran (4) and 4-acyloxycarbonylmethyloxy-3-y-class alkylbenzoyl halide (5).
It is obtained by hydrolyzing the compound of general formula (6). This is shown in the following reaction formula (in the following reaction formula, R1R' is a lower alkyl group, respectively, and X is
halogen group, B is the same as above).
上記フリーゾルタラフッ反応の触媒として用いるルイス
酸としては、塩化アルミニウム、塩化第二錫、塩化亜鉛
等が挙げられる。溶媒は、ジクロルエタン、クロロホル
ム、四塩化炭素、ベンゼン等が用いられる。Examples of the Lewis acid used as a catalyst for the free-sol fluoride reaction include aluminum chloride, stannic chloride, and zinc chloride. As the solvent, dichloroethane, chloroform, carbon tetrachloride, benzene, etc. are used.
上述の如くにして得られる本願化合物は、顕著な尿酸排
泄作用を有し、生体内に投与きれた親化合物である［２
−メチル−４−（２−エチル−３−ベンゾフロイル）フ
ェノキシ］アセチックアシドと同等ないしはそれ以上の
薬理活性と持続性を有している。The compound of the present application obtained as described above has a remarkable uric acid excretion effect and is a parent compound that can be administered in vivo [2]
-Methyl-4-(2-ethyl-3-benzofuroyl)phenoxy]acetic acid has pharmacological activity and persistence equivalent to or longer than that of methyl-4-(2-ethyl-3-benzofuroyl)phenoxy]acetic acid.
また、本願化合物の毒性は、前記親化合物よりも低く、
低毒性の化合物である。Furthermore, the toxicity of the compound of the present invention is lower than that of the parent compound,
It is a compound of low toxicity.
さらに、分配係数（ｌｏｇ Ｐ）を測定するとその値が
小きく、水溶性の高いことを示しているので尿酸排泄剤
として腎臓に到達しやすいことを示すものである。Furthermore, when the distribution coefficient (log P) is measured, the value is small, indicating high water solubility, which indicates that it can easily reach the kidneys as a uric acid excretor.
本願物質は、製剤上許容きれる溶剤に溶屏後注射剤とし
て、或いは、製剤上許容される賦形剤を使用して、錠剤
、顆粒剤、細粒剤、カプセル剤等の経口剤として用いる
ことができる。投与量は、成人１回当り５０ｍｇ〜３０
０ｍｇを１日３回投与することにより、所期の効果が得
られるものと期待される。The substance of this application can be used as an injection after dissolving in a pharmaceutically acceptable solvent, or as an oral preparation such as a tablet, granule, fine granule, or capsule using a pharmaceutically acceptable excipient. Can be done. The dosage is 50mg to 30mg per adult.
It is expected that the desired effect will be obtained by administering 0 mg three times a day.
以下に薬理試験例及び製造実施例を掲げるが、本発明が
、実施例に限定きれるものでないことは、勿論のことで
ある。Although pharmacological test examples and manufacturing examples are listed below, it goes without saying that the present invention is not limited to these examples.
［尿酸排泄作用（フェノール・レッド法）コ（試験例）
ウィスター系雄性ラット（体重：１００〜１４０ｇ）を
用い、ジャーナル 才ブ メディシナル ケミストリー
（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅ
ｍｉｓｔｒｙ（１９７２）５゜Ｐ、 １７５）に記ｔＩ
ｃキれている方法に準じて行なった。この方法は、被検
物質をラットに前投与し、尾静脈より注入したフェノー
ルレッドの貯留を見るものであり、Ｒｅ排泄促進作用が
強いもの程フェノールレッドの血中からの消失が遅くな
る。[Uric acid excretion effect (phenol red method) (test example) Using Wistar male rats (body weight: 100-140 g), the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry)
Mistry (1972) 5゜P, 175)
It was carried out according to the method described in C. In this method, a test substance is pre-administered to rats, and the accumulation of phenol red injected through the tail vein is observed, and the stronger the Re excretion promoting effect, the slower the disappearance of phenol red from the blood.
本試験例においては、本願物質１００ｍｇ／ｋｇを経口
投与し、夫々の場合について３０分後、３時間後、６時
間後に、フェノールレッド７５ｍｇ／ｋｇを尾静脈より
注入し、更に６０分後に眼窩叢より血液を採取し、その
中に含まれるフェノールレッドを常法により測定し、薬
物非投与の比較対照群の血中フェノールレッド濃度に対
する本願物質投与群のそれの百分率を求めた。比較時点
は上記したようにフェノールレッド注入後６０分である
。結果を表１［対照薬＝［２−メチル−４−（２−エチ
ル−３−ベンゾフロイル）フェノキシコアセチックアシ
ド、 ＊ｐ ＜０．０５． ＊＊ｐ ＜０．０１ （１
）’危険率）コ（化合物１及び化合物２は夫々後記実施
例１及び２の目的化合物を示す。以下同じ。）
［毒性試験コ
本化合物の急性毒性をマウス（雄性、ｄｄｙ 、体重２
０〜３０ｇ）を用い、Ｕｐ ＆ Ｄｏｗｎ法で２４時間
での観察より求めると次の如くである。下表における薬
剤の夫々は、１％メチルセルロース液に懸濁して経口投
与した。In this test example, 100 mg/kg of the claimed substance was orally administered, 75 mg/kg of phenol red was injected through the tail vein after 30 minutes, 3 hours, and 6 hours in each case, and after another 60 minutes, the orbital plexus was injected. Blood was collected from each patient, and the phenol red contained therein was measured by a conventional method, and the percentage of the blood phenol red concentration in the group administered with the substance of the present invention relative to that in the control group to which no drug was administered was determined. The comparison time point is 60 minutes after phenol red injection as described above. The results are shown in Table 1 [Control drug=[2-methyl-4-(2-ethyl-3-benzofuroyl)phenoxycoacetic acid, *p<0.05. **p <0.01 (1
)'Risk Rating) (Compound 1 and Compound 2 refer to the target compounds of Examples 1 and 2 below, respectively. The same applies hereinafter.)
0 to 30 g), and was determined by observation over 24 hours using the Up & Down method, as follows. Each of the drugs in the table below was suspended in a 1% methylcellulose solution and administered orally.
対照薬＝床酸排泄作用試験の対照薬に同じ［分配係数（
ｌｏｇＰ）］
水−オクタンの分配係数を定量薬物設計法（Ｙ、 Ｃ。Control drug = Same as the control drug in the floor acid excretion test [partition coefficient (
logP)] Determination of water-octane partition coefficient Drug design method (Y, C.
マーチン著、地大書館）より求めると次のようである。According to the author Martin, Chidaishokan), it is as follows.
対照薬−ズ酸排泄作用試験の対照薬に同じ［実施例１コ
［２−メチル−４−（２−（１−ハイドロキシエチル）
−３−ベンゾフロイル）フェノキシ］アセチックアシド
（化合物１）の製造
第１工程
メチル［２−メチル−４−（２−エチル−３−ベンゾフ
ロイル）フェノキシ］アセテート ３．４ｇ及び氷酢酸
：無水酢酸＜２０：１）混液５０ｍ１の溶液に二酸化セ
レンを加え、９０〜１００°Ｃで１２時間過熱攪拌し、
終了後、反応液は濾過し、濾液を減圧濃縮する。濃縮物
はエーテルに溶解後、水洗、乾燥、減圧濃縮し、メチル
［２−メチル−４−（２−（１−アセトキシエチル）−
３−ベンゾフロイル）フェノキシ］アセテート ３．１
ｇを得る。Control drug - Same as the control drug for the zuronic acid excretion test [Example 1 [2-methyl-4-(2-(1-hydroxyethyl)
-3-Benzofuroyl)phenoxy]acetic acid (Compound 1) Production 1st step Methyl[2-methyl-4-(2-ethyl-3-benzofuroyl)phenoxy]acetate 3.4g and glacial acetic acid:acetic anhydride<20:1 ) Add selenium dioxide to 50 ml of mixed solution and stir at 90 to 100 °C for 12 hours.
After completion, the reaction solution is filtered and the filtrate is concentrated under reduced pressure. The concentrate was dissolved in ether, washed with water, dried, and concentrated under reduced pressure to obtain methyl[2-methyl-4-(2-(1-acetoxyethyl)-
3-Benzofuroyl)phenoxy]acetate 3.1
get g.
ｉ、ｒ、＝３０１０．１７４０．１６００．１２１５．
７５０（Ｃｍ−’）Ｍ、Ｓ、（＋ｎ／ｚ）：４１１（Ｍ
”＋１）、 ３６７、２７７、１８８第２工程
メチル［２−メチル−４−（２−（１−アセトキシエチ
ル）−３−ベンゾフロイル）フエノキシコアセテート
４．１ｇ及びメタノール８０ｍ１の溶液に炭酸カリウム
１．４ｇを加え、室温で３０分攪拌し、終了後、反応液
は濾過し、濾液を減圧濃縮する。濃縮物はエーテルに溶
解後、水洗、乾燥、減圧濃縮し、エーテル：ヘキサン（
３０：１）混液より再結晶してメチル［２−メチル−４
−（２−（１−ハイドロキシエチル）−３−ベンゾフロ
イル）フェノキシ］アセテート３，３ｇを得る。i, r, = 3010.1740.1600.1215.
750 (Cm-') M, S, (+n/z): 411 (M
"+1), 367, 277, 188 2nd step methyl[2-methyl-4-(2-(1-acetoxyethyl)-3-benzofuroyl)phenoxycoacetate
1.4 g of potassium carbonate was added to a solution of 4.1 g and 80 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. After completion, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ether, washed with water, dried, concentrated under reduced pressure, and diluted with ether:hexane (
30:1) Recrystallize from the mixture to obtain methyl [2-methyl-4
3.3 g of -(2-(1-hydroxyethyl)-3-benzofuroyl)phenoxy]acetate are obtained.
ｉ、ｒ、：３４１０．１７５０．１２１０．７６０（Ｃ
ｍ−’）Ｍ、Ｓ、（ｍ／ｚ）：３６８（Ｍ”）、 ３３
６．１９３第３工程
メチル［２−メチル−４−（２−（１−ハイドロキシエ
チル）−３−ベンゾフロイル）フェノキシ］アセテート
３．３ｇ及びメタノール２５ｍ１の溶液に、水１０ｍ１
に溶解した水酸化ナトリウム０．４ｇを加え、室温で１
２時間攪拌する。終了後、反応液は水冷下ｌＮＨＣｌで
中性とし、酢酸エチルを加えて抽出する。抽出液は水洗
、乾燥、減圧濃縮し、得られた粗結晶をシリカゲルカラ
ムクロマトグラフィー（溶離液、クロロホルム：メタノ
ール＝２０：１）により精製して目的化合物を得る。i, r, :3410.1750.1210.760(C
m-') M, S, (m/z): 368 (M"), 33
6.193 Third step Add 10 ml of water to a solution of 3.3 g of methyl [2-methyl-4-(2-(1-hydroxyethyl)-3-benzofuroyl)phenoxy] acetate and 25 ml of methanol.
Add 0.4 g of sodium hydroxide dissolved in
Stir for 2 hours. After completion, the reaction solution was made neutral with 1N HCl under water cooling, and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure, and the resulting crude crystals are purified by silica gel column chromatography (eluent: chloroform:methanol = 20:1) to obtain the target compound.
Ｍ、Ｐ、：４１〜４２℃
ｉ、ｒ、：３４２０．１７４０．１６００，１２５０．
７５０（ｃｍ−’）Ｍ、Ｓ、（ｍ／ｚ）：３５４（Ｍ”
）、３１１，２７７．１４５［実施例２コ
［２−メチル−４−（２−（２−ハイドロキシエチル）
−３−ベンゾフロイル）フエノキシコアセチックアシド
（化合物２）の製造
第１工程
２−アセトキシエチルベンゾフラン３．１ｇ及び４−メ
トキシカルボニルメチルオキシ−ルベンゾイルクロライ
ド４．１ｇをジクロルメタン８０ｍｌに溶解し、−２０
°Ｃ冷却下無水塩化第二錫を徐々に滴下し、終了後、室
温で１２時間攪拌する。M, P,: 41-42°C i, r,: 3420.1740.1600, 1250.
750 (cm-') M, S, (m/z): 354 (M"
), 311,277.145 [Example 2 [2-methyl-4-(2-(2-hydroxyethyl)
-Production of 3-benzofuroyl) phenoxycoacetic acid (compound 2) First step 3.1 g of 2-acetoxyethylbenzofuran and 4.1 g of 4-methoxycarbonylmethyloxy-rubenzoyl chloride were dissolved in 80 ml of dichloromethane, - 20
While cooling at °C, anhydrous stannic chloride was gradually added dropwise, and after completion, the mixture was stirred at room temperature for 12 hours.
攪拌後、反応液は氷−濃塩酸混液中にあけエーテルを加
えて抽出する。抽出液は水洗、乾燥、減圧濃縮し、得ら
れた粗生成物をシリカゲルカラムクロマトグラフィー（
溶離液、ヘキサン：エーテル＝１＝１）により精製して
メチル［２−メチル−４−（２−＜２−アセトキシエチ
ル）−３−ベンゾフロイル）フェノキシ］アセテート２
．６ｇを得る。After stirring, the reaction solution is poured into an ice-concentrated hydrochloric acid mixture and extracted with ether. The extract was washed with water, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (
Methyl[2-methyl-4-(2-<2-acetoxyethyl)-3-benzofuroyl)phenoxy]acetate 2 was purified by eluent, hexane:ether=1=1)
．． Obtain 6g.
ｉ．ｒ．：１７６０． １７４０． １２４０． ７５
０（Ｃｍ−’）Ｍ． Ｓ． （ｍ／ｚ）：４１１（Ｍ”
−１ ＞、 ３５０． ２７７第２工程
メチル［２−メチル−４−（２−（２−アセトキシエチ
ル）−３−ベンゾフロイル）フェノキシコアセテート２
．６ｇ及びメタノール５０ｍｌの溶液に、−１０°Ｃ冷
却下炭酸カリウム１．４ｇを加え３０分間攪拌する。終
了後反応液は濾過し、濾液をｇｆＥｉ！縮する。濃縮物
はエーテルに溶Ｍ後水洗、乾燥、減圧濃縮する。得られ
た粗生成物をシリカゲルカラムクロマトグラフィー（溶
離液、エーテル：ヘキサン＝３ ： ２）により精製し
てメチル［２−メチル−４−（２−（２−ハイドロキシ
エチル）−３−ベンゾフロイル）フェノキシ］アセテー
ト１．６ｇを４０ ”６。i. r. :1760. 1740. 1240. 75
0(Cm-')M. S. (m/z):411(M”
−1 >, 350. 277 Second step Methyl [2-methyl-4-(2-(2-acetoxyethyl)-3-benzofuroyl)phenoxycoacetate 2
．． To a solution of 6 g and 50 ml of methanol, 1.4 g of potassium carbonate was added while cooling at -10°C, and the mixture was stirred for 30 minutes. After completion, the reaction solution was filtered and the filtrate was gfEi! Shrink. The concentrate was dissolved in ether, washed with water, dried, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent, ether:hexane = 3:2) to obtain methyl[2-methyl-4-(2-(2-hydroxyethyl)-3-benzofuroyl)phenoxy] ] 1.6 g of acetate in 40 ”6.
ｉ．ｒ．＝３０００． １７６０． １６００． １２
１０． ７５０（ｃｍ−’）Ｍ．Ｓ．（ｍ／ｚ）”３６
９（Ｍ”）、 ３２４， ２６１． ２１９第３工程
メチル［２−メチル−４−（２−（２−ハイドロキシエ
チル）−３−ベンゾフロイル）フエノキシコアセテート
１．５ｇ及びメタノール５０ｍｌの溶液に、水１０ｍｌ
に溶解した水酸化ナトリウム０．２ｇを加え、室温で１
２時間攪拌する。終了後反応液は水冷下ＩＮ）ＩＣＩで
中性とし、酢酸エチルを加えて抽出する。抽出液は水洗
、乾燥、減圧濃縮し、得られた粗結晶は酢酸エチル：エ
ーテル（２：１）混液より再結晶して目的化合物を得る
。i. r. =3000. 1760. 1600. 12
10. 750 (cm-')M. S. (m/z)"36
9(M”), 324, 261. 219 Third step: In a solution of 1.5 g of methyl [2-methyl-4-(2-(2-hydroxyethyl)-3-benzofuroyl)phenoxycoacetate and 50 ml of methanol, 10ml of water
Add 0.2 g of sodium hydroxide dissolved in
Stir for 2 hours. After completion of the reaction, the reaction solution was made neutral with IN) ICI under water cooling, and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure, and the obtained crude crystals are recrystallized from a mixture of ethyl acetate and ether (2:1) to obtain the target compound.
ｍ．ｐ．７１３８〜１４０℃m. p. 7138~140℃
Claims (1)
▼又は−ＣＨ＿２ＣＨ＿２ＯＨを、Ｂは、低級アルキル
基を、夫々表わす。］ で示されるベンゾフラン誘導体、又は薬理学的に許容さ
れるその塩。 （２）特許請求の範囲第１項記載の化合物を有効成分と
して含有する尿酸排泄剤。 ▲数式、化学式、表等があります▼ ［但し、式中、Ｂ、Ｒは夫々低級アルキル基を表わす。 ］ で示される化合物と酢酸とを反応させて得られる一般式
： ▲数式、化学式、表等があります▼ ［式中、Ｂ、Ｒは前記に同じ］ で示される化合物を加水分解することを特徴とする、 一般式： ▲数式、化学式、表等があります▼ ［式中、Ｂは前記に同じ］ で示されるベンゾフラン誘導体の製造方法。 （４）一般式： ▲数式、化学式、表等があります▼ ［式中、Ｒ′は低級アルキル基を表わす］ で示される化合物と、一般式： ▲数式、化学式、表等があります▼ ［式中、Ｘはハロゲン基を、Ｂ、Ｒは夫々低級アルキル
基を、表わす］ で示される化合物とを反応させて得られる、一般式： ▲数式、化学式、表等があります▼ ［式中、Ｂ、Ｒ、Ｒ′は前記に同じ］ で示される化合物を加水分解することを特徴とする、 一般式： ▲数式、化学式、表等があります▼ ［但し、Ｂは前記に同じ］ で示されるベンゾフラン誘導体の製造方法。[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or -CH_2CH_2OH, and B is a lower Each represents an alkyl group. ] A benzofuran derivative represented by these or a pharmacologically acceptable salt thereof. (2) A uric acid excretion agent containing the compound according to claim 1 as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, B and R each represent a lower alkyl group. ] General formula obtained by reacting the compound represented by and acetic acid: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, B and R are the same as above] Characterized by hydrolyzing the compound represented by General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, B is the same as above] A method for producing a benzofuran derivative represented by the following. (4) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R' represents a lower alkyl group] Compounds represented by and general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [Formula [In the formula, B represents a halogen group, and B and R each represent a lower alkyl group]. , R, R' are the same as above] General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, B is the same as above] Benzofuran Method for producing derivatives.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63042592A JP2566153B2 (en) | 1988-02-24 | 1988-02-24 | Novel benzofuran derivative, uric acid excretion agent and process for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63042592A JP2566153B2 (en) | 1988-02-24 | 1988-02-24 | Novel benzofuran derivative, uric acid excretion agent and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01216984A true JPH01216984A (en) | 1989-08-30 |
| JP2566153B2 JP2566153B2 (en) | 1996-12-25 |
Family
ID=12640335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63042592A Expired - Lifetime JP2566153B2 (en) | 1988-02-24 | 1988-02-24 | Novel benzofuran derivative, uric acid excretion agent and process for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2566153B2 (en) |
-
1988
- 1988-02-24 JP JP63042592A patent/JP2566153B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2566153B2 (en) | 1996-12-25 |
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