JPS5826744B2 - Shinkinapropionsan Ester Yudou Tino Seizou - Google Patents
Shinkinapropionsan Ester Yudou Tino SeizouInfo
- Publication number
- JPS5826744B2 JPS5826744B2 JP50156799A JP15679975A JPS5826744B2 JP S5826744 B2 JPS5826744 B2 JP S5826744B2 JP 50156799 A JP50156799 A JP 50156799A JP 15679975 A JP15679975 A JP 15679975A JP S5826744 B2 JPS5826744 B2 JP S5826744B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- propionic acid
- group
- represented
- compound represented
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
Description
【発明の詳細な説明】
本発明は一般式（Ｉ）
（式中、Ｒは低級アルキルアミノアルキル基、六員環状
アミノアルキル基、ピリジルアルキル基又はハロゲン原
子で置換されたピリジルアルキル基を意味する）で表わ
される新規なプロピオン酸エステル誘導体の製造法に関
するものである。Detailed Description of the Invention The present invention relates to a compound of the general formula (I) (wherein R means a lower alkylaminoalkyl group, a six-membered cyclic aminoalkyl group, a pyridylalkyl group, or a pyridylalkyl group substituted with a halogen atom) ) The present invention relates to a method for producing a novel propionic acid ester derivative represented by:
前記一般式（Ｉ）におけるＲについて更に詳しく説明す
ると、Ｒの低級アルキルアミノアルキル基はジメチルア
ミノエチル、ジメチルアミノプロピル、ジメチルアミノ
ブチル、ジエチルアミノエチル、ジエチルアミノプロピ
ル、ジプロピルアミノエチル、ジプロピルアミノプロビ
ル、ジブチルアミノエチル、ジブチルアミノプロビル等
のジ低級アルキルアミノアルキル基を、六員環状アミノ
アルキル基はモルホリノエチル、Ｎ−低級アルキル−ピ
ペラジノエチル、ピペリジノエチル等の環状アミン基を
、ピリジルアルキル基は２−ピリジルメチル、３−ピリ
ジルメチル、４−ピリジルメチル、２−ピリジルエチル
、３−ピリジルエチル４−ピリジルエチルを、ハロゲン
原子で置換されたピリジルメチル基及びピリジルエチル
基を表わす。To explain R in the general formula (I) in more detail, the lower alkylaminoalkyl group of R is dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminoethyl, diethylaminopropyl, dipropylaminoethyl, dipropylaminopropyl. , di-lower alkylaminoalkyl groups such as dibutylaminoethyl and dibutylaminopropyl, six-membered cyclic aminoalkyl groups are cyclic amine groups such as morpholinoethyl, N-lower alkyl-piperazinoethyl, piperidinoethyl, and pyridylalkyl groups are 2- Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl 4-pyridylethyl represents a pyridylmethyl group and a pyridylethyl group substituted with a halogen atom.
従来、外用消炎剤としては副腎皮質ホルモン製剤が大部
分を占めている。Conventionally, most topical anti-inflammatory agents have been adrenocortical hormone preparations.
しかし、ステロイド製剤は長期間使用すると外用でも重
篤な副作用を発現するため、副作用の少ない局所用の消
炎剤の開発が望まれている現状である。However, steroid preparations, even when used externally, develop serious side effects when used for a long period of time, so there is currently a desire to develop topical anti-inflammatory agents with fewer side effects.
そこで本発明者等は、非ステロイド系消炎剤を外用剤と
して開発することに着目し、新規化合物を求めて種々研
究を重ねた結果、前記一般式（Ｉ）で表わされるプロピ
オン酸エステル誘導体が経口投与及び局所適用において
顕著な鎮痛及び抗炎症作用を有することを見出した。Therefore, the present inventors focused on developing a non-steroidal anti-inflammatory agent as an external preparation, and as a result of conducting various studies in search of new compounds, the propionate ester derivative represented by the above general formula (I) was found to be suitable for oral use. It was found to have significant analgesic and anti-inflammatory effects upon administration and topical application.
本発明の方法で得られる化合物は文献未載の新規化合物
であり、経口投与でも鎮痛及び抗炎症作用が強く且つ胃
腸管における副作用が少なく内服薬として又外用消炎剤
、特にクリール剤、軟膏剤、ゲル剤にすることにより局
所に適用すれば優れた消炎及び鎮痛効果を奏し、副作用
等もほとんどなく非常に安全性の面でも優れていること
を見出し本発明を完成した。The compound obtained by the method of the present invention is a new compound that has not been described in any literature, and it has strong analgesic and anti-inflammatory effects even when administered orally, and has few side effects in the gastrointestinal tract. The present invention was completed based on the discovery that when made into a drug, it exhibits excellent anti-inflammatory and analgesic effects when applied topically, has almost no side effects, and is extremely safe.
本発明はこの様な価値ある化合物の有利な製造法を提供
するものである。The present invention provides an advantageous method for producing such valuable compounds.
即ち本発明によれば、で表わされる化合物又はその反応
性誘導体に一般式（ＩＩ）
（式中、Ｒは前記と同じ意味を有する）で表わされるア
ルコール類を反応させるか、
（２）一般式（Ｉｂ）
（式中、Ｍはアルカリ金属を意味する）で表わされる化
合物に一般式（Ｉｎ）
（式中、Ｘはハロゲン原子又は有機スルホニルオキシ基
を、Ｒは前記と同じ意味を有する）で表わされる化合物
を反応させるか、
（３）一般式（Ｉｃ）
又は
（式中、Ｒ′は低級アルキル基を意味する）で表わされ
る化合物に一般式（ｎ）
（式中、Ｒは前記と同じ意味を有する）で表わされるア
ルコール類を反応させエステル交換反応させることによ
って、前記一般式（Ｉ）で表わされるプロピオン酸エス
テル誘導体を製造することができる。That is, according to the present invention, a compound represented by the formula (II) or a reactive derivative thereof is reacted with an alcohol represented by the general formula (II) (wherein R has the same meaning as above), or (2) a compound represented by the general formula (Ib) (In the formula, M means an alkali metal) A compound represented by the general formula (In) (In the formula, X is a halogen atom or an organic sulfonyloxy group, and R has the same meaning as above) (3) A compound represented by the general formula (Ic) or (in the formula, R' means a lower alkyl group) is reacted with the compound represented by the general formula (n) (in the formula, R is the same as above). The propionic acid ester derivative represented by the general formula (I) can be produced by reacting alcohols represented by the formula (having a meaning) and carrying out a transesterification reaction.
次に、本発明の実施方法を具体的に説明する。Next, a method of implementing the present invention will be specifically explained.
前記（Ｉ）の方法は、２−（ｐ−イソブチルフェニル）
プロピオン酸（Ｉａ）又はその反応性誘導体（例えば、
酸ハライド、酸無水物等）にアルコール類（Ｉ［）を反
応させることによっておこなわれる。In the method (I) above, 2-(p-isobutylphenyl)
Propionic acid (Ia) or its reactive derivatives (e.g.
It is carried out by reacting alcohols (I[) with acid halides, acid anhydrides, etc.).
化合物（Ｉａ）と化合物（ＩＩ）の反応は無溶媒又は不
活性溶媒中、硫酸、ｐ−）ルエンスルホン酸等の脱水剤
の存在下又は存在下におこなわれる。The reaction between compound (Ia) and compound (II) is carried out without a solvent or in an inert solvent, in the presence or in the presence of a dehydrating agent such as sulfuric acid or p-)luenesulfonic acid.
酸無水物を使用する場合は直接アルコール類（ＩＩ）と
加熱すればよい。When using an acid anhydride, it may be heated directly with alcohol (II).
又、酸ハライドを使用する場合は脱酸剤としてピリジン
、トリメチルアミン、トリエチルアミン等の第３級アミ
ンを使用するのが望ましい。Further, when using an acid halide, it is desirable to use a tertiary amine such as pyridine, trimethylamine, or triethylamine as a deoxidizing agent.
以上の反応における反応溶媒は使用するアルコール類（
Ｉ［）を過剰に用い溶媒を兼ねさせてもよく、テトラヒ
ドロンラン、クロロホルム、ベンゼン、トルエン、キシ
レン等の反応に関与しない溶媒を使用してもよい。The reaction solvent in the above reaction is the alcohol used (
I[) may be used in excess to serve as a solvent, or a solvent that does not participate in the reaction, such as tetrahydrone, chloroform, benzene, toluene, or xylene, may be used.
次に（２）の方法は化合物（Ｉａ）をナトリウムアルコ
ラード、ナトリウムアミド、水素化ナトリウム、水素化
カリウム等で化合物（Ｉｂ）とした後、化合物（ｍ）を
２〜１０倍モル加え加温又は還流下に反応させればよい
。Next, in method (2), compound (Ia) is converted into compound (Ib) with sodium alcoholade, sodium amide, sodium hydride, potassium hydride, etc., and then 2 to 10 times the mole of compound (m) is added and heated. Alternatively, the reaction may be carried out under reflux.
（３）の方法は化合物（Ｉｃ）に対してアルコール類（
ＩＩ）を過剰モル使用し直接又は少量のアルカリ金属を
加え５０〜１００℃の温度範囲で加熱すれば速やかにエ
ステル交換がおきる。Method (3) uses alcohols (
If II) is used in molar excess and heated directly or with the addition of a small amount of alkali metal in a temperature range of 50 to 100°C, transesterification can occur quickly.
以下に実施例を示し本発明を具体的に説明するが、勿論
本発明はこれら実施例中の化合物のみに限定されるもの
ではない。The present invention will be specifically explained below with reference to Examples, but of course the present invention is not limited only to the compounds in these Examples.
実施例 １
２−（１）−イソブチルフェニル）プロピオン酸ナトリ
ウム３．３り、ジメチルアミノエチルクロライド２．３
１とベンゼン３ｏＴｒＬｌの混合物を１２時間還流した
。Example 1 Sodium 2-(1)-isobutylphenyl)propionate 3.3%, dimethylaminoethyl chloride 2.3%
A mixture of 1 and benzene 3oTrLl was refluxed for 12 hours.
固形物をｐ別しベンゼンを減圧下留去し残置を減圧下蒸
留して、無色油状の２−（ｐイソブチルフェニル）プロ
ピオン酸ジメチルアミノエチルエステル３．５１を得た
。The solid matter was separated, the benzene was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 3.51 of 2-(p-isobutylphenyl)propionate dimethylaminoethyl ester as a colorless oil.
この物質の沸点、元素分析値、赤外線吸収スペクトル及
びマススペクトルは次の通りであった。The boiling point, elemental analysis values, infrared absorption spectrum, and mass spectrum of this substance were as follows.
マススペクトルは親イオン；２７７を示した。The mass spectrum showed parent ion: 277.
実施例 ２
ナトリウム０．０５Ｐ及び３−ヒドロキシメチルピリジ
ン８ｍｌとの混合物を１０時間６５〜７０℃ニ加熱し、
２−（ｐ−インブチルフェニル）フロピオン酸メチルエ
ステル３．８１を加え８時間９５〜１００℃に加熱した
。Example 2 A mixture of 0.05 P of sodium and 8 ml of 3-hydroxymethylpyridine was heated at 65-70°C for 10 hours,
3.81 g of 2-(p-inbutylphenyl)furopionic acid methyl ester was added and heated at 95-100° C. for 8 hours.
この混合物を再び室温とし水１００ｒｒＬｌを加えエー
テルで抽出した。The mixture was brought to room temperature again, 100 rrLl of water was added, and the mixture was extracted with ether.
エーテルを減圧下留去し残置をシリカゲルを充填したカ
ラムに吸着させクロロホルムにより展開し溶出液を減圧
下留去し、無色油状の２−（ｐ−インブチルフェニル）
プロピオン酸−３−ピリジルメチルエステル２９１を得
た。The ether was distilled off under reduced pressure, the residue was adsorbed on a column packed with silica gel, developed with chloroform, the eluate was distilled off under reduced pressure, and 2-(p-inbutylphenyl) was obtained as a colorless oil.
Propionic acid-3-pyridylmethyl ester 291 was obtained.
この物質の沸点、赤外線吸収スペクトル及びマススペク
トルは次の通りであった。The boiling point, infrared absorption spectrum, and mass spectrum of this substance were as follows.
沸点 １３８〜ｂ 赤外線吸収スペクトルはエステルの吸収 マススペクトルハ親イオン： ２９７を示した。Boiling point 138~b Infrared absorption spectrum shows absorption of ester Mass spectrum parent ion: It showed 297.
実施例 ３
２−（ｐ−イソブチルフェニル）プロピオン酸クロライ
ド４．３１、β−（２−ピリジル）エチルアルコール５
．Ｏ２とテトラヒドロフラン５０ｍ１の混合物を６時間
室温で攪拌した後、テトラヒドロフランを減圧下留去し
残置を減圧下留去して、無色油状の２−（ｐ−インブチ
ルフェニル）プロピオン酸−２−ピリジルエチルエステ
ル５．１１を得た。Example 3 2-(p-isobutylphenyl)propionic acid chloride 4.31, β-(2-pyridyl)ethyl alcohol 5
．． After stirring a mixture of O2 and 50 ml of tetrahydrofuran at room temperature for 6 hours, tetrahydrofuran was distilled off under reduced pressure and the residue was distilled off under reduced pressure to obtain 2-pyridylethyl 2-(p-inbutylphenyl)propionate as a colorless oil. Ester 5.11 was obtained.
この物質の沸点、元素分析値、赤外線吸収スペクトル及
びマススペクトルは次の通りであった。The boiling point, elemental analysis values, infrared absorption spectrum, and mass spectrum of this substance were as follows.
沸点 １１４〜ｂ 元素分析値 Ｃ２ｏＨ２，ＮＯ２ 計算値 Ｃニア７．１３ Ｈ：８．０９Ｎ：４．５０ 実測値 Ｃニア７．０８ Ｈ：８．０３Ｎ：４．４６ 赤外線吸収スペクトルはエステルの吸収 １ｉｑ 。Boiling point 114-b Elemental analysis value C2oH2, NO2 Calculated value C near 7.13 H: 8.09 N: 4.50 Actual value C near 7.08 H: 8.03 N: 4.46 Infrared absorption spectrum shows absorption of ester 1iq.
（ν 、１７３０〜１７３３ｃＩｒＬ−１ ）を示
Ｃ＝０
した。(v, 1730-1733cIrL-1) and C=0.
マススペクトルは親イオン：３１１を示した。The mass spectrum showed parent ion: 311.
実施例 ４〜１０
以下、実施例１〜３の方法に準じて次表の化合物を合成
した。Examples 4 to 10 The compounds shown in the following table were synthesized according to the methods of Examples 1 to 3.
次に本発明の目的化合物の薬理試験及び毒性試験の結果
を示す。Next, the results of pharmacological tests and toxicity tests of the target compound of the present invention are shown.
本発明化合物は全てまず急性毒性について検討し、次に
抗炎症作用や鎮痛作用等の薬理学的作用について検討し
た。All compounds of the present invention were first examined for acute toxicity, and then for pharmacological effects such as anti-inflammatory and analgesic effects.
本発明化合物のあるものは毒性は低くかつ高い薬理作用
を有することが見い出された。It has been found that some of the compounds of the present invention have low toxicity and high pharmacological activity.
特に、本化合物は外用適用により公知化合物２ （ｐ
−イソブチルフェニル）プロピオン酸：（商品名イブプ
ロフェン）より強い抗炎症活性を有することが判明した
。In particular, this compound can be used externally to form a compound known as Compound 2 (p
-isobutylphenyl)propionic acid: It was found to have stronger anti-inflammatory activity than (trade name ibuprofen).
本発明化合物のために用いた試験方法及びその試験結果
を表２に示す。The test methods used for the compounds of the present invention and the test results are shown in Table 2.
試験方法
（１） 急性毒性試験
本試験化合物は０，５％トラガント−生理食塩水溶液に
懸濁化し、ｄｄ系雄性マウス（体重１６〜２４ｉ）に腹
腔内または経口的に投与した。Test method (1) Acute toxicity test The test compound was suspended in 0.5% tragacanth-physiological saline solution and administered intraperitoneally or orally to DD male mice (body weight 16-24I).
その致死濃度は試験化合物投与から７２時間までの動物
の死亡の有無から評価した。The lethal concentration was evaluated from the presence or absence of animal death within 72 hours after administration of the test compound.
結果を表２に表示した。The results are shown in Table 2.
（２）経口投与における抗炎症活性試験
ｗｉｓｔａｒ系雄性ラット（体重１００〜１５０１）を
１群５匹として用いた。(2) Anti-inflammatory activity test in oral administration Male Wistar rats (body weight 100-1501 kg) were used in groups of 5 rats.
０．５％トラガント−生理食塩水溶液に懸濁した本試験
化合物を経口投与し、その３０分後に、注射用蒸留水に
溶解した０、５〜１．０％のカラゲニンを後肢足踵皮下
に注射した。The test compound suspended in 0.5% tragacanth-physiological saline solution was orally administered, and 30 minutes later, 0.5-1.0% carrageenan dissolved in distilled water for injection was injected subcutaneously into the heel of the hind leg. did.
３時間後、定容積を測定して浮腫率を求め、試験化合物
の抑制率は対照群の浮腫率に対する抑制パーセントにて
求めた。After 3 hours, the constant volume was measured to determine the edema rate, and the inhibition rate of the test compound was determined as the percentage of inhibition with respect to the edema rate of the control group.
結果は、試験化合物の抑制率を比較薬イブプロフェンの
抑制率で割り、イブプロフェンの抑制率に対する相対値
として表２に表示した。The results were obtained by dividing the inhibition rate of the test compound by the inhibition rate of the comparative drug ibuprofen, and displayed in Table 2 as a relative value to the inhibition rate of ibuprofen.
なおイブプロフェンの平均抑制率は５０１ｎ９／’Ｋｇ
および１０■／ｋｇの投与にてそれぞれ３７．４％およ
び３３．５％であった。The average inhibition rate of ibuprofen is 501n9/'Kg.
and 37.4% and 33.5% at administration of 10 μ/kg, respectively.
（３）外用適用における抗炎症活性試験
ｗｉｓｔａｒ系雄性ラット（体重的１００ｆ）を用い、
除毛した背部皮膚にカラゲニン溶液２５０γ１０，０５
ｒ／Ｌｌ宛皮肉注射した。(3) Anti-inflammatory activity test for external application using Wistar male rats (weight 100f),
Carrageenin solution 250γ10,05 on the back skin from which hair was removed
I sent a sarcastic injection to r/Ll.
ポリエチレングリコール３００に溶解した１％試験化合
物をしみこませたろ紙（サイズ：径２．３ ｃｒｒｔ
）を注射後直ちに、注射部位に貼布した。Filter paper impregnated with 1% test compound dissolved in polyethylene glycol 300 (size: diameter 2.3 crrt
) was applied to the injection site immediately after injection.
なお、ろ紙にしみ込ませた溶液の重量は１２５．２士１
８゜０即であった。The weight of the solution soaked into the filter paper is 125.2
It was 8°0 immediately.
起炎側処置後３時間に１％ポンタミンスカイフルーを体
重１００１当り０．５ｒＩＬｌとなる様、尾静脈より注
射した。Three hours after treatment on the inflamed side, 1% Pontamine Skyflu was injected into the tail vein at a dose of 0.5 rILl/1001 body weight.
さらに３０分後動物を殺し背部皮膚を剥離し、色素面積
を測定した。After a further 30 minutes, the animals were sacrificed and the dorsal skin was peeled off to measure the pigmented area.
試験化合物の抑制率は対照群に対する抑制パーセントか
ら求め、結果は効力比較のために、各試験化合物の抑制
率を比較薬イブプロフェンの抑制率にて割り、イブプロ
フェンの抑制率に対する相対値として表２に表示した。The inhibition rate of the test compound was determined from the inhibition percentage relative to the control group, and the results are shown in Table 2 as relative values to the inhibition rate of ibuprofen by dividing the inhibition rate of each test compound by the inhibition rate of the comparison drug ibuprofen for efficacy comparison. displayed.
なお、イブプロフェンの平均抑制率は２３．８％であっ
た。Note that the average inhibition rate of ibuprofen was 23.8%.
（４）鎮痛作用試験
本試験化合物は０．５％トラガ゛ントー生理食塩水溶液
に懸濁し、ｄｄ系雄性マウス（体重１８〜２０ｉ）に経
口的に投与した。(4) Analgesic effect test The test compound was suspended in 0.5% traganthate physiological saline solution and orally administered to DD male mice (body weight 18-20I).
１時間後０．６％酢酸溶液を体重１０１当り０．１ ｍ
ｌとなる様腹腔内投与した。After 1 hour, add 0.6% acetic acid solution to 0.1 m/101 body weight.
It was administered intraperitoneally to give a dose of 1.
注射後３０分目から１０分間にわたり苦悶症状を観察し
た。Agony symptoms were observed for 10 minutes starting 30 minutes after the injection.
結果は、リッチフィールドーウイルコクノン法を用いて
５０％の鎮痛効果を示す濃度（Ｅ、Ｄ５ｏ）と９５％信
頼限界（５）カラゲニン皮膚浮腫に対する作用試験試験
方法
体重１００ｆ前後のｗｉｓｔｅｒ系雄ラットを１群８匹
用い、背部皮膚な除毛後−処置いて１％カラゲニン−生
理食塩水溶液及び生理食塩水を背柱対称になるように０
．１ ｍｌｌ ５ｉｔｅ ずつ皮肉注射、２．５ｈｒ後
に１％ポンタミンスカイブルー６Ｂ−生理食塩水溶液０
．５ｒｄ／ １００ ？体重を静脈内注射し、さらに３
０ｍｍ後に放血致死させた。The results are the concentration (E, D5o) showing a 50% analgesic effect using the Litchfield-Wilcochnon method and the 95% confidence limit (5) Carrageenin effect on skin edema Test method Using 8 animals per group, after hair removal on the back skin, treatment with 1% carrageenan-physiological saline solution and physiological saline so that the dorsal column was symmetrical.
．． 1 ml 5ite saline injection, 2.5 hours later 1% Pontamine Sky Blue 6B-Physiological Saline Solution 0
．． 5rd/100? The body weight was injected intravenously, and 3 more
After 0 mm, the animals were killed by exsanguination.
剥離した皮膚の厚みをダイアル式厚み計（ｄｉａｌ ｔ
ｈｉｃｋｎｅｓｓ ｇａｕｇｅ、Ｐｅａｃｏｃｋ−尼崎
製作所）で測り、次式によって浮腫率を求め、皮膚の色
素漏出部の長径と短径を測り、その積として色素漏出面
積、さらにＨａｒａｄａら（１９７１）の方法で漏出色
素量を測定した。Measure the thickness of the exfoliated skin using a dial thickness gauge.
The edema rate was determined using the following formula, the major axis and the minor axis of the pigment leaking part of the skin were measured, and the product was the pigment leakage area, and the leaked pigment was calculated using the method of Harada et al. The amount was measured.
被験薬は外用適用に際して５％になるようにポリエチレ
ングリコール３００に溶解して、その０．１ ｒｕｌを
パッチテスト用絆創膏に吸着させて起炎処理部位に起炎
処置直後から放血致死させるまでの３時間貼付した。For external application, the test drug was dissolved in polyethylene glycol 300 to a concentration of 5%, 0.1 ru of the solution was adsorbed onto a patch test bandage, and applied to the inflammation-treated site for 3 days from immediately after the inflammation treatment until death by exsanguination. I pasted the time.
（経口投与に際しては０．５％トラガント漿−生理食塩
水に懸濁して、その０．１ｍｌ／１００ Ｐを起炎処置
する１時間前に経口ゾンデで５０ ｍｌｌに９投与した
。(For oral administration, tragacanth was suspended in 0.5% serum-physiological saline, and 0.1 ml/100 P of it was administered 9 times in 50 ml with an oral probe 1 hour before treating inflammation.
）以上の薬理試験及び毒性試験から明らかな如く本発明
の目的化合物は公知化合物に比し高い薬理活性を示し、
又、
安全性が高いものである。) As is clear from the above pharmacological and toxicity tests, the target compound of the present invention exhibits higher pharmacological activity than known compounds,
Also, it is highly safe.
Claims (1)
アミノアルキル基、ピリジルアルキル基、又はハロゲン
原子で置換されたピリジルアルキル基を意味する）で表
わされる新規なプロピオン酸エステル誘導体の製造法に
おいて、２−（ｐ−インブチルフェニル）プロピオン酸
（Ｉａ）又はその反応性誘導体に一般式（ｎ） （式中、Ｒは前記と同じ意味を有する）で表わされる化
合物を反応させることを特徴とする前記一般式（Ｉ）で
表わされる新規なプロピオン酸エステル誘導体の製造法
。 ２ 一般式（Ｉｂ） （式中、Ｍはアルカリ金属を意味する）で表わされる化
合物に一般式（ｍ） （式中、Ｘはハロゲン原子又は有機スルホニルオキシ基
を、Ｒは特許請求の範囲第１項におけると同じ意味を有
する）で表わされる化合物を反応させることを特徴とす
る前記一般式（Ｉ）で表わされる新規なプロピオン酸エ
ステル誘導体の製造法。 （式中、Ｒ′は低級アルキル基を意味する）で表わされ
る化合物に一般式（ＩＩ） （式中、Ｒは特許請求の範囲第１項におけると同じ意味
を有する）で表わされる化合物を反応させることを特徴
とする前記一般式（Ｉ）で表わされる新規なプロピオン
酸エステル誘導体の製造法。[Scope of Claims] A novel propionic acid represented by (wherein R means a lower alkylaminoalkyl group, a six-membered cyclic aminoalkyl group, a pyridylalkyl group, or a pyridylalkyl group substituted with a halogen atom) In the method for producing an ester derivative, a compound represented by the general formula (n) (wherein R has the same meaning as above) is added to 2-(p-inbutylphenyl)propionic acid (Ia) or a reactive derivative thereof. A method for producing a novel propionic acid ester derivative represented by the general formula (I), which comprises causing a reaction. 2. A compound represented by the general formula (Ib) (wherein M means an alkali metal) is added to the compound represented by the general formula (m) (wherein, X is a halogen atom or an organic sulfonyloxy group, and R is a A method for producing a novel propionic acid ester derivative represented by the general formula (I), characterized by reacting a compound represented by (having the same meaning as in item 1). (wherein R' means a lower alkyl group) is reacted with a compound represented by general formula (II) (wherein R has the same meaning as in claim 1). A method for producing a novel propionic acid ester derivative represented by the general formula (I), which comprises:
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50156799A JPS5826744B2 (en) | 1975-12-24 | 1975-12-24 | Shinkinapropionsan Ester Yudou Tino Seizou |
| SE7613651A SE433492B (en) | 1975-12-24 | 1976-12-06 | SET TO MAKE PHENYLETIC ACID DERIVATIVES |
| CA267,690A CA1076134A (en) | 1975-12-24 | 1976-12-13 | Process for preparing phenylacetic acid ester derivatives |
| FR7638482A FR2336126A1 (en) | 1975-12-24 | 1976-12-21 | PHENYLACETIC ACID ESTERS DERIVATIVES |
| CH1607276A CH617919A5 (en) | 1975-12-24 | 1976-12-21 | Process for the preparation of new derivatives of esters of phenyl-acetic acid |
| DE2658610A DE2658610C2 (en) | 1975-12-24 | 1976-12-23 | Phenylacetic acid ester derivatives |
| NLAANVRAGE7614308,A NL180381C (en) | 1975-12-24 | 1976-12-23 | METHOD FOR PREPARING A 2- (4-ISOBUTYLPHENYL) PROPIONIC ACID ESTER CONTAINING MEDICINAL PRODUCT AND METHOD FOR PREPARING THE MEDICINAL COMPOUNDS |
| AU20878/76A AU507661B2 (en) | 1975-12-24 | 1976-12-23 | Phenylacetic acid ester derivatives |
| GB51350/76A GB1573322A (en) | 1975-12-24 | 1976-12-24 | Phenylactic acid ester derivatives |
| US05/845,237 US4150137A (en) | 1975-12-24 | 1977-10-25 | Pyridylalkyl esters of 2-(p-isobutylphenyl)acetic acid and propionic acids and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50156799A JPS5826744B2 (en) | 1975-12-24 | 1975-12-24 | Shinkinapropionsan Ester Yudou Tino Seizou |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1176982A Division JPS57206640A (en) | 1982-01-29 | 1982-01-29 | Preparation of novel propionic ester derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5278848A JPS5278848A (en) | 1977-07-02 |
| JPS5826744B2 true JPS5826744B2 (en) | 1983-06-04 |
Family
ID=15635562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50156799A Expired JPS5826744B2 (en) | 1975-12-24 | 1975-12-24 | Shinkinapropionsan Ester Yudou Tino Seizou |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5826744B2 (en) |
| AU (1) | AU507661B2 (en) |
| CA (1) | CA1076134A (en) |
| CH (1) | CH617919A5 (en) |
| DE (1) | DE2658610C2 (en) |
| FR (1) | FR2336126A1 (en) |
| GB (1) | GB1573322A (en) |
| NL (1) | NL180381C (en) |
| SE (1) | SE433492B (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5517358A (en) * | 1978-07-24 | 1980-02-06 | Teikoku Seiyaku Kk | Butyl propionate derivative, its preparation, and antiphlogistic and analgesic comprising it |
| JPS54144336A (en) * | 1978-07-24 | 1979-11-10 | Teikoku Seiyaku Kk | Propionic acid propylester derivative*its manufacture and antiiinflammatory and sedative agent containing it |
| JPS5587770A (en) * | 1978-12-27 | 1980-07-02 | Hisamitsu Pharmaceut Co Inc | Preparation of 2-(p-isobutylphenyl)propionic acid 2-pyridinemethyl ester |
| JPS57203035A (en) * | 1981-06-05 | 1982-12-13 | Taisho Pharmaceut Co Ltd | Carboxylic acid ester |
| DE3225290A1 (en) * | 1982-07-07 | 1984-01-12 | Merck Patent Gmbh | RING CONNECTIONS |
| YU43408B (en) * | 1985-04-26 | 1989-06-30 | Lek Tovarna Farmacevtskih | Process for preparation of 2-(4-isobuthylphenyl)-prophiohydroxamic acid |
| JPH0635378B2 (en) * | 1985-06-27 | 1994-05-11 | ポ−ラ化成工業株式会社 | Cosmetics |
| ES2004447A6 (en) * | 1987-07-06 | 1989-01-01 | Sune Coma Nuria | New 2-(P-isobutylphenyl)-propionic acid ester and process for the preparation thereof. |
| DE3811118C1 (en) * | 1988-03-31 | 1989-10-12 | Merckle Gmbh, 7902 Blaubeuren, De | |
| IT1217589B (en) * | 1988-05-13 | 1990-03-30 | Pulitzer Italiana | ANTI-INFLAMMATORY AGENT FOR THERAPY OF PROSTATIC HYPERTROPHY, ITS PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
| JPH0639449B2 (en) * | 1989-04-10 | 1994-05-25 | エーザイ株式会社 | Polyprenyl compound, method for producing the same, and medicament containing the same |
| US6525214B1 (en) | 1991-05-13 | 2003-02-25 | Bernard John Armitage | Therapeutic agent |
| US6399618B1 (en) * | 1997-07-09 | 2002-06-04 | Cardiome Pharma Corp | Compositions and methods for modulating sexual activity |
| CN103948571A (en) * | 2006-07-18 | 2014-07-30 | 天津昕晨泰飞尔医药科技有限公司 | Water-soluble ibuprofen prodrug with high skin penetration rate and positive charge |
| KR20180049144A (en) | 2007-06-04 | 2018-05-10 | 테크필즈 인크 | Pro-drugs of NSAIAs With Very High Skin and Membranes Penetration Rates and Their New Medicinal Uses |
| US9809557B2 (en) | 2011-10-31 | 2017-11-07 | Claus Selch Larsen | Prodrugs of non-steroid anti-inflammatory agents (NSAIDS) |
| US9500398B2 (en) | 2012-12-13 | 2016-11-22 | Whirlpool Corporation | Twist harvest ice geometry |
| US9470448B2 (en) | 2012-12-13 | 2016-10-18 | Whirlpool Corporation | Apparatus to warm plastic side of mold |
| US9273891B2 (en) | 2012-12-13 | 2016-03-01 | Whirlpool Corporation | Rotational ice maker |
| US9557087B2 (en) | 2012-12-13 | 2017-01-31 | Whirlpool Corporation | Clear ice making apparatus having an oscillation frequency and angle |
| CN105461731B (en) * | 2014-08-07 | 2017-05-24 | 富力 | Phillygenin ibuprofen ester, preparation and applications thereof |
| WO2016065269A2 (en) | 2014-10-23 | 2016-04-28 | Whirlpool Corporation | Method and apparatus for increasing rate of ice production in an automatic ice maker |
| JP6153264B2 (en) * | 2015-01-05 | 2017-06-28 | テックフィールズ インコーポレイテッド | NSAIA prodrug with very fast skin and membrane permeation rate and novel pharmaceutical use thereof |
| CN109134262A (en) * | 2017-06-15 | 2019-01-04 | 北京蓝丹医药科技有限公司 | A kind of loxoprofen derivative |
| CN109134261A (en) * | 2017-06-15 | 2019-01-04 | 北京蓝丹医药科技有限公司 | A kind of loxoprofen derivative |
| US10907874B2 (en) | 2018-10-22 | 2021-02-02 | Whirlpool Corporation | Ice maker downspout |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB971700A (en) * | 1961-02-02 | 1964-09-30 | Boots Pure Drug Co Ltd | Anti-Inflammatory Agents |
-
1975
- 1975-12-24 JP JP50156799A patent/JPS5826744B2/en not_active Expired
-
1976
- 1976-12-06 SE SE7613651A patent/SE433492B/en not_active IP Right Cessation
- 1976-12-13 CA CA267,690A patent/CA1076134A/en not_active Expired
- 1976-12-21 FR FR7638482A patent/FR2336126A1/en active Granted
- 1976-12-21 CH CH1607276A patent/CH617919A5/en not_active IP Right Cessation
- 1976-12-23 AU AU20878/76A patent/AU507661B2/en not_active Expired
- 1976-12-23 NL NLAANVRAGE7614308,A patent/NL180381C/en not_active IP Right Cessation
- 1976-12-23 DE DE2658610A patent/DE2658610C2/en not_active Expired
- 1976-12-24 GB GB51350/76A patent/GB1573322A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NL180381C (en) | 1987-02-16 |
| NL7614308A (en) | 1977-06-28 |
| DE2658610C2 (en) | 1982-12-23 |
| AU2087876A (en) | 1978-06-29 |
| SE433492B (en) | 1984-05-28 |
| GB1573322A (en) | 1980-08-20 |
| DE2658610A1 (en) | 1977-07-07 |
| NL180381B (en) | 1986-09-16 |
| FR2336126A1 (en) | 1977-07-22 |
| AU507661B2 (en) | 1980-02-21 |
| FR2336126B1 (en) | 1979-03-09 |
| CH617919A5 (en) | 1980-06-30 |
| SE7613651L (en) | 1977-06-25 |
| JPS5278848A (en) | 1977-07-02 |
| CA1076134A (en) | 1980-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS5826744B2 (en) | Shinkinapropionsan Ester Yudou Tino Seizou | |
| FI105155B (en) | Process for the preparation of therapeutically useful bile acid derivatives | |
| JPH08283238A (en) | Retinoid-like heterocyclic compound | |
| CA1154755A (en) | Cholesterol derivatives | |
| CN102001916A (en) | Indene derivatives as pharmaceutical agents | |
| JPH0127044B2 (en) | ||
| JPS58113142A (en) | Manufacture of novel naphthalene derivative | |
| JPH059424B2 (en) | ||
| JPS6058209B2 (en) | β,γ-dihydropolyprenyl alcohol and antihypertensive agents consisting of it | |
| US3886278A (en) | Ammonium carboxylate sebum inhibition process | |
| JPS6254106B2 (en) | ||
| US4251543A (en) | 2-(p-Prenylphenyl)propionic acid | |
| JPS5877849A (en) | Biphenylalkylcarboxylic acid ester derivative, manufacture and medicine containing same | |
| JPS6056130B2 (en) | Novel salicylic acid derivatives | |
| CN108191944B (en) | Sesquiterpenes aspertepinol B derivative from marine microorganisms, synthetic method and carbohydrase application | |
| CA1161445A (en) | Methyl 3-acetamido-2-(5-methoxy-indol-3-yl) propanoate | |
| KR800001260B1 (en) | Method for the preparation of phenyl acetic acid ester derivatives | |
| JPS6345295A (en) | Novel derivative of androstane | |
| US4335251A (en) | Phenyl-i-propionic acid esters and pharmaceutical use thereof | |
| JPH11228535A (en) | New compound and anti-dermatitis agent | |
| JPH045664B2 (en) | ||
| JPS6315275B2 (en) | ||
| JPS6058904B2 (en) | Novel cyclohexanecarboxylic acid amide derivative | |
| JPS6023672B2 (en) | Triazolyl acetic acid derivative | |
| JPS61148120A (en) | Analgesic agent |