JPS6045866B2 - Benzoic acid derivatives, their production methods, and antipyretic analgesics, anti-inflammatory agents, and expectorants containing them as active ingredients - Google Patents

Benzoic acid derivatives, their production methods, and antipyretic analgesics, anti-inflammatory agents, and expectorants containing them as active ingredients

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Publication number
JPS6045866B2
JPS6045866B2 JP57012523A JP1252382A JPS6045866B2 JP S6045866 B2 JPS6045866 B2 JP S6045866B2 JP 57012523 A JP57012523 A JP 57012523A JP 1252382 A JP1252382 A JP 1252382A JP S6045866 B2 JPS6045866 B2 JP S6045866B2
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JP
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Prior art keywords
formula
group
general formula
benzoic acid
tables
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Expired
Application number
JP57012523A
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JPS57144244A (en
Inventor
カルロ・ミラニ
ギオバンニ・マリア・カルミナチ
アツチリオ・ソベ−ラ
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SERUBI E CO SpA
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SERUBI E CO SpA
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Publication of JPS57144244A publication Critical patent/JPS57144244A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/12—Preparation of carboxylic acid esters from asymmetrical anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

【発明の詳細な説明】 本発明は新規な安息香酸誘導体、その製造法およびそれ
を有効成分とする解熱鎮痛剤、消炎剤および去痰剤に関
する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel benzoic acid derivative, a method for producing the same, and an antipyretic analgesic, an antiinflammatory agent, and an expectorant containing the same as an active ingredient.

さらに詳しくは、本発明は一般式（１）（式中、Ｒは水
素原子または一般式（■）（式中、Ｘは炭素数１〜６の
直鎖もしくは分枝鎖のアルキル基、ベンジル基または２
，２，２−トリクロロエチル基で表わされるオキシカル
ボニル基）で表わされる安息香酸誘導体、その製造法お
よびそれを有効成分とする解熱鎮痛剤、消炎剤および去
痰剤に関する。More specifically, the present invention relates to the general formula (1) (wherein R is a hydrogen atom or the general formula (■) (wherein, X is a straight or branched alkyl group having 1 to 6 carbon atoms, a benzyl group or 2
The present invention relates to benzoic acid derivatives represented by oxycarbonyl groups represented by , 2,2-trichloroethyl groups), a method for producing the same, and an antipyretic analgesic, an antiinflammatory agent, and an expectorant containing the same as an active ingredient.

前記Ｘにおいてアルキル基の具体例としてはメチル基、
エチル基、プロピル基、イソプロピル基、ｎ−ブチル基
、イソブチル基、ｔ−ブチル基、ｎ−ペンチル基、イソ
ペンチル基、ネオペンチル基、ｎ−ヘキシル基、２，３
−ジメチルーブチル基、２−メチルーペンチル基、３−
メチルーペンチル基などがあげられる。Specific examples of the alkyl group in the above X include a methyl group,
Ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, 2,3
-dimethyl-butyl group, 2-methyl-pentyl group, 3-
Examples include methyl-pentyl group.

なかんづく本発明において好ましい化合物は、前記一般
式（１）においてＲが水素原子であるかまたはＸが炭素
数１〜４の直鎖もしくは分枝鎖アルキル基あるいはベン
ジル基である化合物である。Particularly preferred compounds in the present invention are those in the general formula (1) in which R is a hydrogen atom or X is a straight or branched alkyl group having 1 to 4 carbon atoms or a benzyl group.

従来より、式（■） で表わされる安息香酸誘導体は公知の化合物である（英
国特許第１，１７５，２１鏝、南アフリカ共和国特許第
６７０１，０２１号、フランス特許第１，５２２，５ｍ
号、西独特許第１，６１８，６６３号、米国特許第３，
６７４，８ｍ号、米国特許第３，６８１，４４５号の各
明細書および西独特許公告第２，５３２，５関号公報参
照）。Conventionally, the benzoic acid derivative represented by the formula (■) is a known compound (British Patent No. 1,175,21, South African Patent No. 6701,021, French Patent No. 1,522,5m).
No. 1,618,663, U.S. Patent No. 3,
No. 674,8m, U.S. Pat. No. 3,681,445 and West German Patent Publication No. 2,532,5).

またその生物学的性質はジエイ・ハンナー（Ｊ．Ｈａｎ
ｎａｈ）らの論文（Ｂｒｉｑ．ＪＯＬｌｒ．Ｃｌｉｎ．
ＰｈａｒｍａｃＯｌ．、↓、７５〜１３５（１９７７）
参照）やピー●ダブリユー・マジユワース（Ｐ．Ｗ．Ｍ
ａｊｅｕｒｓ）らの論文（Ｂｒｉｔ．ＪＯｕｒ．Ｃｌｌ
ｎ．ＰｈａｒｍａｃＯｌ．、±、１５５〜１８５（１９
７７）参照）などによつて報告されている。しかし、式
（■）で表わされる化合物の誘導体である一般式（１）
で表わされる化合物は未知の新規化合物である。一般式
（１）で表わされる化合物は、その種類によつて種々の
製造法がある。その一例としては、つぎの２工程反応が
あげられる。すなわち、 （ａ）前記式（■）で表わされる化合物に一般式（■）
・（式中、Ｙはハロゲン原子、ｘは前記と同じ）で表わ
される炭酸誘導体を反応させて一般式（■） Ｊ（式中、Ｘは前記と同じ）で表わされる化合物をうる
工程、および（ｂ）前記（ａ）の工程でえられた一般式
（Ｖ）で表わされる化合物に式（■）で表わされる２−
メトキシフェノールを反応させる工程また叙上の２工程
反応でえられる化合物のうち、Ｘが２，２，２−トリク
ロロエチル基であるものは、さらに還元することによつ
て、一般式（１）で表わされる化合物のうちＲが水素原
子である化合物とすることができる。Its biological properties were also explained by J. Hanner.
nah) et al. (Briq. JOLlr. Clin.
PharmaOl. , ↓, 75-135 (1977)
) and P.W.M.
ajeurs et al. (Brit.Jour.Cll
n. PharmaOl. , ±, 155-185 (19
77)) and others. However, general formula (1) which is a derivative of the compound represented by formula (■)
The compound represented by is an unknown new compound. There are various manufacturing methods for the compound represented by the general formula (1) depending on its type. An example of this is the following two-step reaction. That is, (a) the compound represented by the above formula (■) has the general formula (■)
・A step of reacting a carbonic acid derivative represented by (wherein, Y is a halogen atom and x is the same as above) to obtain a compound represented by general formula (■) J (wherein, X is the same as above), and (b) The compound represented by the general formula (V) obtained in the step (a) is added to
Among the compounds obtained by the step of reacting methoxyphenol or the two-step reaction described above, those in which X is a 2,2,2-trichloroethyl group can be further reduced to form the compound of general formula (1). Among the compounds represented, R may be a hydrogen atom.

つぎに好ましい反応条件について述べる。（ａ）の工程
では、式（■）で表わされる化合物に対して約２〜４倍
モルの一般式（■）て表わされる化合物を用いるのが好
ましい。Next, preferred reaction conditions will be described. In the step (a), it is preferable to use about 2 to 4 times the molar amount of the compound represented by the general formula (■) relative to the compound represented by the formula (■).

また一般式（■）で表わされる化合物はＹが塩素原子の
ものが好ましい。反応温度は約−１０℃ないし室温の範
囲が好ましく、反応時間は約１０〜旬分間、好ましくは
約１５〜３紛間が適当である。反応は、好ましくは乾燥
した有機溶媒中で行なう。かかる有機溶媒としてはアセ
トン、メチルエチルケトン、ジエチルケトンなどの低級
脂肪族ケトン類が好ましい。また反応進行の過程で生ず
るハロゲン化水素による反応液の酸性化を防ぐために、
トリメチルアミン、トリエチルアミン、ピリジン、ピコ
リンなどを加えておくのが好ましい。この工程でえられ
る生成物は単離して確認しうるが、未精製のま８からな
る製造法であり、それによつて前記一般式（１）におい
てＲが一般式（■）で表わされるオキシカルボニル基で
ある化合物をうることができる。この２工程反応を反応
式で示すとつぎのとおりである。まつぎの工程に供して
もよい。（ｂ）の工程では、一般式（Ｖ）で表わされる
化合物に対して（未精製のばあいには式（■）で表わさ
れる化合物に対して）わずかに過剰モル量の式（■）で
表わされる２−メトキシフェノールを用いるのが好まし
い。Further, in the compound represented by the general formula (■), it is preferable that Y is a chlorine atom. The reaction temperature is preferably in the range of about -10°C to room temperature, and the reaction time is about 10 to 10 minutes, preferably about 15 to 3 minutes. The reaction is preferably carried out in a dry organic solvent. As such an organic solvent, lower aliphatic ketones such as acetone, methyl ethyl ketone, and diethyl ketone are preferred. In addition, in order to prevent acidification of the reaction solution due to hydrogen halide generated during the reaction process,
Preferably, trimethylamine, triethylamine, pyridine, picoline, etc. are added. Although the product obtained in this step can be isolated and confirmed, it is an unpurified production method consisting of 8, whereby in the general formula (1), R is oxycarbonyl represented by the general formula (■). A compound that is a group can be obtained. The reaction formula for this two-step reaction is as follows. It may also be used in the process of making pine nuts. In step (b), a slightly excess molar amount of formula (■) is added to the compound represented by general formula (V) (in the unpurified case, to the compound represented by formula (■)). Preference is given to using 2-methoxyphenol as shown.

反応温度は約−１０℃ないし室温が好ましく、反応時間
は約３〜８時間が好ましい。かくしてえられる生成物（
一般式（■）で表わされる化合物）は通常の方法によつ
て単離され、ついで構造を確認する。The reaction temperature is preferably about -10°C to room temperature, and the reaction time is preferably about 3 to 8 hours. The product thus obtained (
The compound represented by the general formula (■)) is isolated by a conventional method, and then its structure is confirmed.

前述したように、一般式（１）で表わされる化合物のう
ちＲが水素原子であるものは、Ｒが２，２，２−トリク
ロロエチルオキシカルボニル基であるものを還元するこ
とによつてうることができる。As mentioned above, compounds represented by general formula (1) in which R is a hydrogen atom can be obtained by reducing a compound in which R is a 2,2,2-trichloroethyloxycarbonyl group. I can do it.

かかる還元反応は、たとえばジエチルエーテル中て亜鉛
と酢酸を作用させる方法や酸化白金（ＰｔＯ２）もしく
はパラジウムー炭素（Ｐｄ／Ｃ）を触媒として用いる接
触還元法などの通常の方法によつて行ないうる。前記一
般式（１）においてＲが水素原子であるもののもう一つ
の製造法として、式（■）で表わされる化合物と式（■
）で表わされる化合物とを反応させる方法がある。Such a reduction reaction can be carried out by a conventional method such as a method in which zinc and acetic acid are reacted in diethyl ether or a catalytic reduction method using platinum oxide (PtO2) or palladium-carbon (Pd/C) as a catalyst. As another method for producing the general formula (1) in which R is a hydrogen atom, a compound represented by the formula (■) and a compound represented by the formula (■
) There is a method of reacting with a compound represented by

この方法において好ましい反応条件は、（１）式（■）
で表わされる化合物に対して約３〜７倍モルの式（■）
で表わされる化合物を用い、（Ｉｉ）触媒量の強酸、好
ましくは硫酸またはｐ−トルエンスルホン酸の存在下、
（Ｉｉｉ）不活性気体の雰囲気中、 （Ｉｖ）反応混合物の融点の温度で （■）無溶媒 の条件である。Preferred reaction conditions in this method are (1) formula (■)
Approximately 3 to 7 times the molar amount of the formula (■) relative to the compound represented by
using a compound represented by (Ii) in the presence of a catalytic amount of a strong acid, preferably sulfuric acid or p-toluenesulfonic acid,
(Iii) in an inert gas atmosphere, (Iv) at a temperature of the melting point of the reaction mixture (■) in the absence of a solvent.

反応は、その進行を薄層クロマトグラフィー（以下、Ｌ
℃という）によつてチェックし、原料（式（■）で表わ
される化合物）のスポットが認められなくなるまで行な
う。つぎに実施例をあげて本発明の安息香酸誘導体およ
びその製造法についてより詳細に説明するが、本発明は
それらの実施例のみに限定されるものではない。The progress of the reaction was monitored by thin layer chromatography (hereinafter referred to as L
℃), and the process is continued until spots of the raw material (compound represented by formula (■)) are no longer observed. EXAMPLES Next, the benzoic acid derivative of the present invention and the method for producing the same will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

実施例１ （２−ヒドロキシー５−（２″，４″−ジフルオロフェ
ニル）一安息香酸と２−メトキシーフェノールのエステ
ル（一般式（１）においてＲが水素原子である化合物）
の製造）２−ヒドロキシー５−（２″，４″−ジフルオ
ロフェニル）一安息香酸２５ｙ（０．１モル）、２−メ
トキシーフェノール６２ｙ（０．５モル）およびｐ−ト
ルエンスルホン酸０．５〜１ｙからなる混合物を不活性
気体雰囲気下で加熱溶融させて均一な液状とした。Example 1 (Ester of 2-hydroxy-5-(2″,4″-difluorophenyl)monobenzoic acid and 2-methoxyphenol (compound in which R is a hydrogen atom in general formula (1))
2-hydroxy-5-(2″,4″-difluorophenyl)monobenzoic acid 25y (0.1 mol), 2-methoxyphenol 62y (0.5 mol) and p-toluenesulfonic acid 0.5 A mixture consisting of ~1y was heated and melted under an inert gas atmosphere to form a uniform liquid.

反応の進行はＴＬＣ（プレートニＭｅｒｃｋＦ２５４シ
リカゲルプレート；展開溶媒：無水ベンゼン；発色法：
紫外線光（２５４ｎｍ）発色）を用いて追跡した。反応
終了が認められたのち、溶融物を冷却し、ついでシリカ
ゲルカラム（Ｍｅｒｃｋ６Ｏシリカゲル（平均粒径：２
３０〜４００メッシュ））中に無水ベンゼンを展開溶媒
として通過させた。Ｒｆ値０．７０を有する単一スポッ
トのフラクシヨンを集め、ついでベンゼンを減圧下で留
去して油状残渣をえた。この油状残渣は数時間放置して
おくと結晶化した。このものをさらにジイソプロピルエ
ーテルから再結晶して目的化合物をえた。融点：１０２
〜１０３物Ｃ 元素分析値：Ｃ２ＯＨｌ４Ｆ２Ｏ４（分子量３５６．３
３として）理論値（％）：Ｃ６７．４ｌＨ３．９７ 実測値（％）：Ｃ６７．４２Ｈ４．Ｏ４ 赤外線吸収スペクトル分析値（クロロホルム溶媒中）特
性吸収帯の周波数（Ｃｍ−リニ３２３０、１７００、１
６００〜１６２０ＮＭＲスペクトル分析値（測定溶媒：
ＣＤＣ′３内部標準：テトラメチルシラン）：δ３．７
７（Ｓ，．３Ｈ）、６．６７〜７．７７（Ｍ．．９Ｈ）
、８．１７〜８．２７（ＭｌｌＨ）、１０．５７ （ＳｌｌＨ）Ｐｐｍ 実施例２ （２−ヒドロキシー５−（７，４″−ジフルオロフェニ
ル）一安息香酸と２−メトキシーフェノールのエステル
（一般式（１）においてＲが水素原子である化合物）の
製造）２−ヒドロキシー５−（２″，４″−ジフルオロ
フェニル）一安息香酸５ｙ（０．０２０モル）および無
水トリエチルアミン４ｆ（０．０３９モル）を無水メチ
ルエチルケトン５８ｍＬに溶かした。The progress of the reaction was monitored by TLC (Merck F254 silica gel plate; developing solvent: anhydrous benzene; color development method:
Tracking was performed using ultraviolet light (254 nm). After the completion of the reaction was confirmed, the melt was cooled and then transferred to a silica gel column (Merck 6O silica gel (average particle size: 2
Anhydrous benzene was passed through the solution (30 to 400 mesh) as a developing solvent. A single spot fraction with an Rf value of 0.70 was collected and the benzene was then distilled off under reduced pressure to yield an oily residue. This oily residue crystallized upon standing for several hours. This product was further recrystallized from diisopropyl ether to obtain the target compound. Melting point: 102
～103 substance C Elemental analysis value: C2OHl4F2O4 (molecular weight 356.3
3) Theoretical value (%): C67.4lH3.97 Actual value (%): C67.42H4. O4 Infrared absorption spectrum analysis value (in chloroform solvent) Frequency of characteristic absorption band (Cm-Lini 3230, 1700, 1
600-1620 NMR spectrum analysis value (measurement solvent:
CDC'3 internal standard: tetramethylsilane): δ3.7
7 (S, .3H), 6.67-7.77 (M..9H)
, 8.17-8.27 (MllH), 10.57 (SllH)Ppm 2-hydroxy-5-(2″,4″-difluorophenyl)monobenzoic acid 5y (0.020 mol) and triethylamine anhydride 4f (0.039 mol) ) was dissolved in 58 mL of anhydrous methyl ethyl ketone.

その溶液を０℃に冷却したのち、２，２，２−トリクロ
ロエチルークロロカーボネート８．４ｆ（０．０３９モ
ル）を滴下し、さらに温度を０℃以下に保つたまま１５
〜３０分間反応させるとトリエチルアミン塩酸塩の沈殿
が生じた。つぎに２−メトキシフェノール３．６ｙ（イ
）．０２９モル）を無水メチルエチルケトン４０ｍ１に
溶かした溶液を加え、反応液温度を室温にまで上昇させ
たのち、反応液を数時間攪拌し、ついで不溶物を？過し
て除いた。戸液を減圧下で濃縮し、えられた油状残渣を
塩化メチレン中に溶かした。この塩化メチレ溶液はまず
５％塩酸水溶液で洗浄し、ついで５％ＮａＯＨ水溶液で
洗浄し、最後に水で洗浄した。つぎに無水硫酸ナトリウ
ム上で乾燥し、枦過し、炉液を減圧下で濃縮して油状残
渣をえた。この油状残渣はＬ℃（プレートニＭｅｒｃｋ
Ｆ２５４シリカゲルプレート；展開溶媒：無水酢酸エチ
ルニ発色法：紫外線光（２５４ｎｍ）発色）において反
応生成物によるものと考えられる主スポットと原料カル
ボン酸の痕跡量スポットを示した。この油状残渣を冷却
下に放置して結晶化させ、さらに低級脂肪族アルコール
、好ましくはエタノールから数回再結晶を行ない、一般
式（１）においてＲが２，２，２−トリクロロエトキシ
カルボニル基である化合物、すなわち２−（２，２，２
ートリクロロエトキシカルボニルオキシ）−５一（２″
，４″−ジフルオロフェニル）安息香酸と２一メトキシ
フェノールのエステルをえた。融点：１２１〜１２４℃ 元素分析値：Ｃ２３Ｈｌ５Ｆ２ｃｅ３Ｏ６（分子量５３
０．７１として）理論値（％）：Ｃ５ｌ．９５Ｈ２．８
４ 実測値（％）：Ｃ５２．ｌ６Ｈ２．８４ 叙上の方法によりえられた生成物をつぎに示す公知の方
法（ａ）または（ｂ）にしたがつて還元した。After cooling the solution to 0°C, 8.4f (0.039 mol) of 2,2,2-trichloroethyl-chlorocarbonate was added dropwise, and the temperature was kept below 0°C for 15 minutes.
Triethylamine hydrochloride precipitated after reacting for ~30 minutes. Next, 2-methoxyphenol 3.6y (a). A solution of 029 mol) dissolved in 40 ml of anhydrous methyl ethyl ketone was added, the temperature of the reaction solution was raised to room temperature, the reaction solution was stirred for several hours, and then the insoluble matter was removed. I removed it after a while. The solution was concentrated under reduced pressure and the resulting oily residue was dissolved in methylene chloride. This methylene chloride solution was first washed with 5% aqueous hydrochloric acid, then with 5% aqueous NaOH, and finally with water. It was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give an oily residue. This oily residue is produced at L°C (Plate Ni Merck).
F254 silica gel plate; developing solvent: ethyl acetate anhydride; color development method: ultraviolet light (254 nm) color development) showed main spots thought to be caused by reaction products and trace spots of raw material carboxylic acid. This oily residue is allowed to stand under cooling to crystallize, and is further recrystallized several times from a lower aliphatic alcohol, preferably ethanol. A certain compound, namely 2-(2,2,2
-trichloroethoxycarbonyloxy)-5-(2″
, 4''-difluorophenyl) benzoic acid and 2-methoxyphenol. Melting point: 121-124°C Elemental analysis: C23Hl5F2ce3O6 (molecular weight 53
0.71) Theoretical value (%): C5l. 95H2.8
4 Actual value (%): C52. 16H2.84 The product obtained by the above method was reduced according to the following known methods (a) or (b).

（ａ）生成物を氷酢酸を含有するジエチルエーテルに溶
かし、ついで亜塩粉末を加えて反応させた。（ｂ）生成
物を酸化白金またはパラジウム炭素の存在下で接触還元
した。えられた還元生成物（油状残渣）は固形化するま
で放置し、ついでジイソプロピルエーテルまたはジエチ
ルエーテルー軽油混合溶媒から再結晶した。(a) The product was dissolved in diethyl ether containing glacial acetic acid, then subsalt powder was added and reacted. (b) The product was catalytically reduced in the presence of platinum oxide or palladium on carbon. The obtained reduction product (oily residue) was allowed to stand until solidified, and then recrystallized from diisopropyl ether or diethyl ether/gas oil mixed solvent.

融点：１０５〜１０６軽Ｃ 赤外線吸収スペクトル分析値およびＮＭＲスペクトル分
析値は前記実施例１でえられたものと一致した。Melting point: 105-106 light C Infrared absorption spectrum analysis values and NMR spectrum analysis values were consistent with those obtained in Example 1 above.

実施例３ （２−（ベンジルオキシ−カルボニルオキシ）−５−（
２″，４″−ジフルオロフェニル）一安息香酸と２−メ
トキシフェノールのエステル（一般式（１）においてＲ
がベンジルオキシカルボニル基である化合物）の製造）
２−ヒドロキシー５−（２″，４″−ジフルオロフーエ
ニル）一安息香酸８ダ（イ）．０３２モル）および無水
トリエチルアミン８ｆ（０．０７９モル）をメチルエチ
ルケトン（またはそのほかの低級脂肪族ケトン）１１２
ｍ１に溶かした溶液をＯ℃以下に冷却し、ついでベンジ
ル−クロロカーボネート２６．９ｆ．（イ）．０７９モ
ル）を５唾量％含有するメチルエチルケトン溶液を１紛
間かけて滴下した。Example 3 (2-(benzyloxy-carbonyloxy)-5-(
Ester of 2″,4″-difluorophenyl)monobenzoic acid and 2-methoxyphenol (R in general formula (1)
is a benzyloxycarbonyl group)
2-Hydroxy-5-(2″,4″-difluorophenyl)monobenzoic acid 8d(a). 032 mol) and anhydrous triethylamine 8f (0.079 mol) to methyl ethyl ketone (or other lower aliphatic ketone) 112
The solution in ml was cooled to below 0°C and then the benzyl-chlorocarbonate 26.9f. (stomach). One drop of a methyl ethyl ketone solution containing 5% by volume of 079 mol) was added dropwise.

滴下終了後、さらに反応液を０℃以下に保ちながら攪拌
し、ついで２−メトキシフェノール４ｇ（０．０３２モ
ル）をメチルエチルケトン１６ｍ１に溶かした溶液を速
や，かに加えた。反応をＴＣＬ（前記実施例２のばあい
と同じ条件、目的物のＲｆ値は０．８２）で追跡しなが
ら室温で数時間攪拌したのち、溶媒を減圧下で留去して
油状残渣をえた。この油状残渣はシリカゲルカラムクロ
マトグラフィー（Ｍｅｒｃｋ６Ｏシリカゲル（平均粒径
：２３０〜４００メシユ）、展開溶媒：クロロホルム／
ｎ−ヘキサン（容量比１／１）混合液）に供し、単一ス
ポットのフラクシヨンを集め、ついで溶媒を留去して目
的物を無色の油状物としてえた。元素分析値：Ｃ２８Ｈ
２ＯＦ２Ｏ６（分子量４９０．４７として）理論値（％
）：Ｃ６８．５７Ｈ４．ｌｌＦ７．７５ｌ実測値（％）
：Ｃ６８．３６Ｈ３．９９Ｆ７．９Ｏ赤外線吸収スペク
トル分析値（無溶媒）：１７６５、１７００ｃｍ−１Ｎ
ＭＲスペクトル分析値（測定溶媒：ＣＤＣ′３、内部標
準：ーテトラメチルシラン）：３．７０（Ｓ，．３Ｈ）
、５．１７（Ｓ．ｓ２ｌｌ）、６．５５〜８．３３（Ｍ
ｌｌ５ｌｌ）Ｐｐｍ 実施例４ （２−（メトキシ−カルボニルオキシ）−５−”（２″
，４″−ジフルオロフェニル）一安息香酸と２ーメトキ
シフェノールのエステル（一般式（１）においてＲがメ
トキシカルボニル基である化合物）の製造）ベンジルク
ロロカーボネートに代えてメチルクロロカーボネートを
用いたほかは実施例３と同様にして実験を行ない油状残
渣をえた。After the dropwise addition was completed, the reaction solution was further stirred while being kept at 0° C. or lower, and then a solution of 4 g (0.032 mol) of 2-methoxyphenol dissolved in 16 ml of methyl ethyl ketone was immediately added. After stirring the reaction for several hours at room temperature while monitoring the reaction with TCL (same conditions as in Example 2, Rf value of the target product was 0.82), the solvent was distilled off under reduced pressure to obtain an oily residue. . This oily residue was purified by silica gel column chromatography (Merck 6O silica gel (average particle size: 230-400 mesh), developing solvent: chloroform/
n-hexane (volume ratio 1/1 mixture)), a single spot fraction was collected, and then the solvent was distilled off to obtain the desired product as a colorless oil. Elemental analysis value: C28H
2OF2O6 (as molecular weight 490.47) theoretical value (%
): C68.57H4. llF7.75l actual value (%)
:C68.36H3.99F7.9O Infrared absorption spectrum analysis value (without solvent): 1765, 1700cm-1N
MR spectrum analysis value (measurement solvent: CDC'3, internal standard: -tetramethylsilane): 3.70 (S, .3H)
, 5.17 (S.s2ll), 6.55-8.33 (M
ll5ll) Ppm Example 4 (2-(methoxy-carbonyloxy)-5-"(2"
, 4''-difluorophenyl) monobenzoic acid and 2-methoxyphenol ester (a compound in which R is a methoxycarbonyl group in the general formula (1))) except that methyl chlorocarbonate was used in place of benzyl chlorocarbonate. The experiment was carried out in the same manner as in Example 3 and an oily residue was obtained.

この油状残渣は粘稠てあり、放置しておくと結晶化した
のでカラムクロマトグラフィーに供する必要がなかつた
。結晶化物はジイソプロピルエーテルから再結晶して目
的化合物をえた。融点：１０２〜１０６℃ ＴＣＬ（実施例３のばあいと同じ条件（のＲｆ値：０．
８５元素分析値：Ｃ２２Ｈｌ６Ｆ２Ｏ６（分子量４１４
．３７として）理論値（％）：Ｃ６３．７７Ｈ３．８９
Ｆ９．ｌ４実測値（％）：Ｃ６３．８９Ｈ４．ＯｌＦ９
．ｌ４赤外線吸収スペクトル分析値（ヌジヨール）１７
６へ１７４０ｃｍ−１ＮＭＲスペクトル分析値（測定溶
媒：ＣＤｃｅ３内部標準：テトラメチルシラン）：δ３
．７７（Ｓ，．３）１）、３．８３（Ｓ，．３Ｈ）、６
．５〜８．４（ＭｌｌＯＨ）Ｐｐｍ 実施例５ （２−（イソブチルオキシーカルボニルオキシ）一５−
（２″，４″−ジフルオロフェニル）一安息香酸と２−
メトキシフェノールのエステル（一般式（１）において
Ｒがイソブチルオキシカルボニル基である化合物）の製
造）ベンジルクロロカーボネートに代えてイソブチルク
ロロカーボネートを用いたほかは実施例３と同様にして
実験を行ない、粗生成物をえた。This oily residue was viscous and crystallized on standing, so there was no need to subject it to column chromatography. The crystallized product was recrystallized from diisopropyl ether to obtain the target compound. Melting point: 102-106°C Rf value of TCL (same conditions as in Example 3): 0.
85 element analysis value: C22Hl6F2O6 (molecular weight 414
．． 37) Theoretical value (%): C63.77H3.89
F9. l4 actual value (%): C63.89H4. OlF9
．． l4 infrared absorption spectrum analysis value (nujiol) 17
6 to 1740 cm-1 NMR spectrum analysis value (measurement solvent: CDce3 internal standard: tetramethylsilane): δ3
．． 77 (S, .3) 1), 3.83 (S, .3H), 6
．． 5-8.4 (MllOH)Ppm Example 5 (2-(isobutyloxy-carbonyloxy)-5-
(2″,4″-difluorophenyl)monobenzoic acid and 2-
Production of ester of methoxyphenol (compound in which R is an isobutyloxycarbonyl group in general formula (1))) An experiment was conducted in the same manner as in Example 3 except that isobutyl chlorocarbonate was used in place of benzyl chlorocarbonate. I got the product.

この粗生成物は実施例３と同様にしてカラムクロマトグ
ラフィーに供し、Ｒｆ値０．８４を有する単一スポット
のフラクシヨンを集め、ついで溶媒を留去した。生成物
は放置しておくと結晶化した。このものは無水エタノー
ルから再結晶した。融点：７６〜７８ルＣ 元素分析値：Ｃ２５Ｈ２２Ｆ２Ｏ，（分子量４５６．４
６として）理論値（％）：Ｃ６５。This crude product was subjected to column chromatography as in Example 3, a single spot fraction having an Rf value of 0.84 was collected, and then the solvent was distilled off. The product crystallized on standing. This product was recrystallized from absolute ethanol. Melting point: 76~78lC Elemental analysis value: C25H22F2O, (molecular weight 456.4
6) Theoretical value (%): C65.

７８Ｈ４．８５Ｆ８．３２実測値（％）：Ｃ６５．６２
Ｈ５．Ｏ６Ｆ８．３４赤外線スペクトル分析値（ヌジヨ
ール）：１７７０、１７５０ｃｍ−１ＮＭＲスペクトル
分析値（測定溶媒：ＣＤｃｅ３、内部標準：テトラメチ
ルシラン）゜δ０．８８（Ｄ，．６Ｈ）、１．５０〜２
．３０（ＭｌｌＨ）、３．７７（Ｓ．ｓ３Ｈ）、３．９
８（Ｄｌ ２Ｈ）、６．６７〜７．９０（Ｍｌ ９Ｈ）、８．２７〜８．４３（Ｍｌ ＩＨ）Ｐｐｍ 実施例６ （２−（エトキシ−カルボニルオキシ）−５一（２″，
４−ジフルオロフェニル）一安息香酸と２−メトキシフ
ェノールのエステル（一般式（１）においてＲがエトキ
シカルボニル基である化合物）の製造）ベンジルクロロ
カーボネートに代えてエチルクロロカーボネートを用い
たほかは実施例３と同様にして実験を行ない粗生成物を
えた。78H4.85F8.32 Actual value (%): C65.62
H5. O6F8.34 Infrared spectrum analysis value (Nujiol): 1770, 1750cm-1 NMR spectrum analysis value (measurement solvent: CDce3, internal standard: tetramethylsilane) °δ0.88 (D, .6H), 1.50-2
．． 30 (MllH), 3.77 (S.s3H), 3.9
8 (Dl 2H), 6.67-7.90 (Ml 9H), 8.27-8.43 (Ml IH) Ppm Example 6 (2-(ethoxy-carbonyloxy)-5-(2'',
Production of ester of monobenzoic acid (4-difluorophenyl) and 2-methoxyphenol (compound in which R is an ethoxycarbonyl group in general formula (1))) Example except that ethyl chlorocarbonate was used in place of benzyl chlorocarbonate. The experiment was carried out in the same manner as in 3 to obtain a crude product.

えられた粗生成物は常法にしたがつて有機溶媒で洗うと
結晶化した。このものをジイソプロピルエーテルから再
結晶して目的物をえた。融点：９０〜９７Ｃ ＴＬＣ（実施例３のばあいと同じ条件）のＲｆ値：０．
８７赤外線吸収スペクトル分析値（ヌジヨール）１７６
０、１７４０ｃ！ＲＬ−１ＮＭＲスペクトル分析値（測
定溶媒：ＣＤｃｅ３内部標準：テトラメチルシラン）：
δ１．２５（Ｔ．．３Ｈ）、３．７５（Ｓ．ｓ３Ｈ）、
４．２０（Ｑｌ２ｌｌ）、６．５３〜７。The obtained crude product was washed with an organic solvent in a conventional manner and crystallized. This product was recrystallized from diisopropyl ether to obtain the desired product. Melting point: 90-97C Rf value by TLC (same conditions as in Example 3): 0.
87 Infrared absorption spectrum analysis value (nujiol) 176
0,1740c! RL-1 NMR spectrum analysis value (measurement solvent: CDce3 internal standard: tetramethylsilane):
δ1.25 (T..3H), 3.75 (S.s3H),
4.20 (Ql2ll), 6.53-7.

７７（Ｍｌ ９Ｈ）、８．１３〜８．２３（Ｍｌ ｌＨ）Ｐｐｍ 以上で説明した本発明の一般式（１）で表わされる化合
物は薬理学的に活性である。77(Ml 9H), 8.13-8.23(Ml 1H)Ppm The compound represented by the general formula (1) of the present invention described above is pharmacologically active.

すなわち、本発明の化合物は顕著な解熱活性、鎮痛活性
、消炎活性および去痰活性活性を有している。本発明の
化合物は、解熱活性、鎮痛活性および消炎活性について
は、投与量をＭ９／Ｋ９体重で表示したばあい、比較例
とされる２−ヒドロキシー５−（２″，４″−ジフルオ
ロフェニル）一安息香酸（以下、ＨＢＡという）よりも
多く投与しなければ同程度の活性は認められないが、投
与量をミリモル／Ｋｇ体重で表示したばあい、当量程度
またはそれよりも少ない投与量で同程度の活性が認めら
れる。一方、本発明の化合物はＨＢＡにはまつたく認め
られなかつた去痰活性を有している。しかも本発明の化
合物は毒性が非常に低く、それゆえ治療指数（Ｔｈｅｒ
ａｐｅｕｔｉｃａｌｌｎｄｅｘ）、すなわちＬＤ５Ｏ値
の最低有効投与量に対する比はすでに高い値を有してい
るＨＢＡにくらべてもより好ましい値である。なお治療
指数が高いものであるほど医薬としての信頼性にすぐれ
ている。つぎに毒性試験および薬理活性試験について述
べる。That is, the compounds of the present invention have significant antipyretic, analgesic, antiinflammatory and expectorant activities. Regarding the antipyretic activity, analgesic activity and anti-inflammatory activity, the compound of the present invention has the following properties: The same level of activity is not observed unless the dose is higher than that of monobenzoic acid (hereinafter referred to as HBA), but when the dose is expressed in mmol/Kg body weight, the same level of activity can be obtained by administering an equivalent or smaller dose. Some degree of activity is observed. On the other hand, the compounds of the present invention have expectorant activity that was not found in HBA. Moreover, the compounds of the present invention have very low toxicity and therefore have a therapeutic index (Thermal
apeutical index), ie, the ratio of LD5O value to the lowest effective dose, is a more favorable value than that of HBA, which already has a high value. Note that the higher the therapeutic index, the more reliable it is as a medicine. Next, toxicity tests and pharmacological activity tests will be described.

それらの試験には、前記実施例１〜６でえた化合物およ
び１１ＢＡ（比較例）を用いた。（急性毒性試験）急性
毒性試験はマウスに供試化合物を経口投与する方法にし
たがつて行ない、ＬＤ５Ｏ値はリッチフイールドーウイ
ルコクソン法（ＪＯｕｒ．Ｐｈａｒｍ．Ｅｘｐｔ．Ｔｈ
ｅｒ．、？、９９（１９４９）参照）によつて算出した
。The compounds obtained in Examples 1 to 6 and 11BA (comparative example) were used in these tests. (Acute toxicity test) The acute toxicity test was conducted by orally administering the test compound to mice, and the LD5O value was determined by the Richfield-Wilcoxon method (JOur.Pharm.Expt.Th
er. ,? , 99 (1949)).

えられた結果および以下の消炎活性試・験、解熱活性試
験、鎮痛活性試験および去痰活性試験によつて調べた最
低有効投与量を第１表に示す。第１表に示した最低有効
投与量では生体に顕著な変化はみられなかつた（ｐ＜０
．０１）。Table 1 shows the results obtained and the lowest effective doses determined by the following anti-inflammatory activity test, antipyretic activity test, analgesic activity test and expectorant activity test. No significant changes were observed in the body at the lowest effective dose shown in Table 1 (p<0
．． 01).

なおＬＤ５Ｏ値において１以上ョで示した数値はその投
与量においてもマウスの死亡が認められなかつたばあい
であり、最低有効投与量において１以上ョで示した数値
はその投与量では顕著な効果が認められなかつたばあい
を示す。（消炎活性試験） 消炎活性はラットを用い、カラゲエニン （Ｃａｒｒａ？Ｅｎｊｎ）で誘発された浮腫の抑制を測
定する試験によつて調べた。Note that a value of 1 or more for the LD5O value indicates that no mouse death was observed at that dose, and a value of 1 or more for the lowest effective dose indicates a significant effect at that dose. Indicates a case where this is not recognized. (Anti-inflammatory activity test) The anti-inflammatory activity was examined in rats by a test measuring the inhibition of edema induced by carrageenin (Carra-Enjn).

ラットとしてはオスの７３０ＳＤ−ラット（平均体重１
５０ｙ）を用い、試験方法はシー・エイ・ウインター（
Ｃ．Ａ．Ｗｉｎｔｅｒ）らの論文（ＰｒＯｃ．ＳＯｃ．
ＥｘｐｔＩ．ＢｉＯｌ．Ｍｅｄ．、川．、５４４（１９
６２）参照）に述べられている方法にしたがつた。また
供試化合物は実施例３でえたものとＦＩＢＡ（比較例）
を用いた。供誌化合物の各投与量（経口投与）における
浮腫の抑制率（対照投与に対して）および統計的信頼性
（Ｓｔａｔｉｓｔｉｃｓｉｇｒｌｊｆｊｃａｎｃｅ）を
第２表に示す。（鎮痛活性試験）鎮痛活性はビール酵母
を注射してあらかじめ炎症を生ぜしめておいたラットの
後足を圧迫し、痛みを知覚する閾値を記録するランドー
ル（Ｒａｎｄａｌりおよびセリツト（ＳｅｌｉｔｔＯ）
の方法によつて調べた。The rats are male 730SD-rats (average weight 1
50y), and the test method was C.A. Winter (
C. A. Winter) et al. (PrOc.SOc.
ExptI. BiOl. Med. ,river. , 544 (19
The method described in 62) was followed. In addition, the test compounds were those obtained in Example 3 and FIBA (comparative example).
was used. Table 2 shows the edema inhibition rate (relative to control administration) and statistical reliability at each dose (oral administration) of the sample compound. (Analgesic activity test) Analgesic activity was measured by Randall and Selitt, who pressured the hind paws of rats that had been injected with brewer's yeast to cause inflammation in advance, and recorded the pain perception threshold.
This was investigated using the following method.

供試化合物としては実施例６でえた化合物およびＨＢＡ
を用い、また対照投与例のためにピーナツツ油１０ｍ９
／Ｋ９体重を投与した。各投与量における経口投与１時
間後と２時間後の閾値の平均と対照投与に対するそれぞ
れの閾値の増加率を第３表に示す。（解熱活性試験） ラット（１６５ＳＤ−ラット、オス、平均体重２００ｇ
）にビール酵母を筋肉内注射して誘発せしめた高熱症（
Ｈｙｐｅｒｐｙｒｅｘｉａ）に対する本発明の化合、÷
第４表に示した結果から明らかなように、本発明の化合
物、とくに実施例３，５および６でえた化合物は上呼吸
器における水分含量を増加せしめる効果があり、したが
つて該呼吸器の分泌能を刺激する活性を有することが実
証された。The test compounds were the compound obtained in Example 6 and HBA.
and peanut oil 10 m9 for the control example.
/K9 body weight was administered. Table 3 shows the average threshold value for each dose 1 hour and 2 hours after oral administration and the increase rate of each threshold value relative to control administration. (Antipyretic activity test) Rat (165SD-rat, male, average weight 200g
) induced hyperthermia by intramuscular injection of brewer's yeast (
The compound of the present invention against Hyperpyrexia), ÷
As is clear from the results shown in Table 4, the compounds of the present invention, particularly the compounds obtained in Examples 3, 5 and 6, have the effect of increasing the water content in the upper respiratory tract, and therefore It was demonstrated that it has the activity of stimulating secretion ability.

一方、ＨＢＡを投与したばあいは対照投与にくらべて殆
んど変化がなく、また実施例１および４でえた化合物は
同様な活性を有しているが、低い値であつた。ゝ物の活
性を調べた。On the other hand, when HBA was administered, there was almost no change compared to control administration, and the compounds obtained in Examples 1 and 4 had similar activities, but at lower values. We investigated the activity of things.

その結果、実施例３、５および６でえた化合物がとくに
すぐれた解熱活性を示した。実際前記第１表に示した投
与量では、経口投与から１時間、２時間および４時間後
にそれぞれ１℃ずつ体温を下げることができた。（去痰
活性試験） 去痰活性試験はＳＤ−ラットを用い、イー・エム・ボイ
ド（Ｅ．Ｍ．ＢＯｙｄ）およびジー・エム・ジヨンスト
ン（Ｇ．Ｍ．ＪＯｈｎｓｔＯｎ）の方法（Ａｍ．ＪＯｕ
ｒ．Ｍｅｄ．Ｓｃｉ．、埋、２４４（９４０）およびＩ
ｂｉｄ，．狐、８１０（１９４１）参照）にしたがつて
調べた。As a result, the compounds obtained in Examples 3, 5 and 6 showed particularly excellent antipyretic activity. In fact, at the doses shown in Table 1 above, the body temperature was able to be lowered by 1° C. 1 hour, 2 hours, and 4 hours after oral administration. (Expectant activity test) The expectorant activity test was performed using SD rats using the method of E.M. Boyd and G.M. JOhnstOn (Am. Jou).
r. Med. Sci. , Buri, 244 (940) and I
bid,. (see Kitsune, 810 (1941)).

供試化合物は前記実施例１〜６でえた化合物および１（
ＢＡを用い、それぞれを生理溶液を用いて経口投与した
。また生理溶液のみを投与したばあにを対照投与とした
。それぞれの投与のばあいの上呼吸器（Ｕｐｐｅｒｒｅ
ｓｐｉｒａｔＯｒｙｔｒａｃｔ）における水の含量（平
均値）および対照値に対する増加率を第４表に示す。The test compounds were the compounds obtained in Examples 1 to 6 and 1(
BA was used and each was orally administered using a physiological solution. In addition, the control animals were treated with only physiological solution. Upper respiratory (upper respiratory)
Table 4 shows the water content (average value) and the percentage increase relative to the control value.

本発明の化合物は叙上のことき薬理活性を有し、毒性が
低いので、それを有効成分とする医薬（解熱鎮痛剤、消
炎剤および去痰剤）として用いうる。そのばあい、経口
投与、非経口投与、直腸）内投与などに好適な形態に製
剤して用いてもよいし、そのままで用いてもよい。経口
投与に好適な製剤形態としては、たとえば錠剤、カプセ
ル、糖衣錠、分散性散剤、トローチ、ロゼンジ、シロツ
プ、エリキシルなどがあげられる。Since the compound of the present invention has the above-mentioned pharmacological activity and low toxicity, it can be used as a medicine (antipyretic analgesic, antiinflammatory agent, and expectorant) containing it as an active ingredient. In that case, it may be used after being formulated into a form suitable for oral administration, parenteral administration, rectal administration, etc., or it may be used as it is. Pharmaceutical forms suitable for oral administration include, for example, tablets, capsules, sugar-coated tablets, dispersible powders, troches, lozenges, syrups, and elixirs.

それらの製剤に際しては香り、見ばえ、味覚などをよく
するために、種々の通常用いられている補助剤を１種ま
たは２種以上加えることができる。かかる補助剤として
は、たとえば甘味剤、香料、着色剤、コーティング剤、
防腐剤などがあげられる。非経口投与、すなわち静脈内
注射や筋肉内注射に好適な製剤形態としては、たとえば
小ピンまたはアンプルなどがあげられる。When preparing these preparations, one or more of various commonly used adjuvants can be added to improve the aroma, appearance, taste, etc. Such adjuvants include, for example, sweeteners, flavoring agents, coloring agents, coating agents,
Preservatives etc. Preparation forms suitable for parenteral administration, ie, intravenous injection or intramuscular injection, include, for example, small pins or ampoules.

それらの注射液への製剤は当業者によく知られた方法に
したがつて行なわれ、その際適当な分散剤、温潤剤、懸
濁剤、緩衝剤などが添加されうる。また直腸内投与に好
適な製剤形態としては座薬などがあげられる。Their preparation into injection solutions is carried out according to methods well known to those skilled in the art, and appropriate dispersants, wetting agents, suspending agents, buffers, etc. may be added at this time. In addition, suppositories and the like are examples of formulations suitable for rectal administration.

座薬への製剤も同様に当業者によく知られた方法にした
がつて行なわれ、その際適当な賦形剤が用いられる。か
かる賦形剤としては、たとえばワックス、鯨蝋、胡麻油
、ゼラチン、ピーナツツ油またはそれらの化合物などが
あげられる。本発明の解熱鎮痛剤、消炎剤および去痰剤
は１日あたりその有効成分の約５〜２５ｍ９／Ｋｇ体重
を投与するのが好ましい。The formulation into suppositories is likewise carried out according to methods well known to those skilled in the art, using suitable excipients. Such excipients include, for example, wax, spermaceti, sesame oil, gelatin, peanut oil or compounds thereof. The antipyretic analgesic, antiinflammatory agent and expectorant of the present invention is preferably administered in an amount of about 5 to 25 m9/Kg body weight of its active ingredient per day.

したがつて本発明の解熱鎮痛剤、消炎剤および去痰剤は
その有効成分が１日あたり１回または２回以上で約３５
０〜１７００ｍ９投与されるように製剤されているもの
が好ましい。つぎに製剤例を示すが、本発明の解熱鎮痛
剤、消炎剤および去痰剤はそれらの製剤例のみに限定さ
れるものではない。製剤例１ 有効成分を約４００〜１０００ｍ９含有する錠剤。Therefore, the antipyretic analgesic, antiinflammatory agent, and expectorant of the present invention has an active ingredient of about 35% when administered once or twice or more per day.
Those formulated to be administered at 0 to 1700 m9 are preferred. Next, formulation examples will be shown, but the antipyretic analgesic, antiinflammatory agent, and expectorant of the present invention are not limited to these formulation examples. Formulation Example 1 Tablet containing about 400 to 1000 m9 of active ingredient.

製剤例２有効成分を約７００〜１５００ｍ９含有する座
薬。Formulation Example 2 A suppository containing about 700 to 1500 m9 of the active ingredient.

Claims (1)

【特許請求の範囲】 １ 一般式（ I ）： ▲数式、化学式、表等があります▼（ I ）（式中、Ｒ
は水素原子または一般式（II）：▲数式、化学式、表等
があります▼（II）（式中、Ｘは炭素数１〜６の直鎖も
しくは分枝鎖のアルキル基、ベンジル基または２，２，
２−トリクロロエチル基）で表わされるオキシカルボニ
ル基）で表わされる安息香酸誘導体。 ２ 前記Ｒが、前記一般式（II）においてＸが炭素数１
〜４の直鎖もしくは分枝鎖のアルキル基またはベンジル
基であるオキシカルボニル基または水素原子である特許
請求の範囲第１項記載の安息香酸誘導体。 ３ 前記Ｒが水素原子である特許請求の範囲第１項記載
の安息香酸誘導体。 ４ 前記Ｒがベンジルオキシカルボニル基である特許請
求の範囲第１項記載の安息香酸誘導体。 ５ 前記Ｒがメトキシカルボニル基である特許請求の範
囲第１項記載の安息香酸誘導体。 ６ 前記Ｒがイソブチルオキシカルボニル基である特許
請求の範囲第１項記載の安息香酸誘導体。 ７ 前記Ｒがエトキシカルボニル基である特許請求の範
囲第１項記載の安息香酸誘導体。 ８（ａ）式（III）： ▲数式、化学式、表等があります▼（III）で表わされ
る化合物に一般式（IV）： ▲数式、化学式、表等があります▼（IV）（式中、Ｘは
炭素数１〜６の直鎖もしくは分枝鎖のアルキル基、ベン
ジル基または２，２，２−トリクロロエチル基、Ｙはハ
ロゲン原子）で表わされる化合物を反応させて一般式（
Ｖ）：▲数式、化学式、表等があります▼（Ｖ）（式中
、Ｘは前記と同じ）で表わされる化合物をうる工程、お
よび（ｂ）前記（ａ）の工程でえられた一般式（Ｖ）で
表わされる化合物に式（VI）：▲数式、化学式、表等が
あります▼（VI）で表わされる２−メトキシフェノール
を反応させる工程からなることを特徴とする一般式（
I ）：▲数式、化学式、表等があります▼（ I ）（式
中、Ｒは水素原子または一般式（II）：▲数式、化学式
、表等があります▼（II）（式中、Ｘは前記と同じ）で
表わされるオキシカルボニル基）で表わされる安息香酸
誘導体の製造法。 ９ 前記（ａ）および（ｂ）の工程に加えて、（ｃ）前
記一般式（ I ）においてＸが２，２，２−トリクロロ
エチル基であるものを還元してＸが水素原子であるもの
に変換する工程を有することを特徴とする特許請求の範
囲第８項記載の製造法。 １０ 前記（ａ）の工程が （イ）一般式（III）で表わされる化合物に対して約２
〜４倍モルの一般式（IV）で表わされる化合物を用い、
（ロ）約−１０℃ないし室温で、 （ハ）約１０〜４０分間、 （ニ）乾燥有機溶媒中、 （ホ）第３級アミンの存在下 の条件下で行なわれることを特徴とする特許請求の範囲
第８項または第９項記載の製造法。 １１ 前記（ｂ）の工程が （ヘ）一般式（Ｖ）で表わされる化合物に対してわずか
に過剰モル量の式（VI）で表わされる化合物を用い、（
ト）約−１０℃ないし室温で、 （チ）約３〜８時間 の条件下で行なわれることを特徴とする特許請求の範囲
第８項、第９項または第１０項記載の製造法。 １２ 式（III）： ▲数式、化学式、表等があります▼（III）で表わされ
る化合物と式（VI）： ▲数式、化学式、表等があります▼（VI）で表わされる
化合物とを反応させることを特徴とする式（ I ′）：
▲数式、化学式、表等があります▼（ I ′）で表わさ
れる安息香酸誘導体の製造法。 １３ 前記反応が （ｉ）式（III）で表わされる化合物に対して約３〜７
倍モルの式（VI）で表わされる化合物を用い、（ｉｉ）
触媒量の強酸の存在下、（ｉｉｉ）不活性気体雰囲気中
、 （ｉｖ）反応混合物の融点の温度で （ｖ）無溶媒 の条件下で行なわれることを特徴とする特許請求の範囲
第１２項記載の製造法。 １４ 一般式（ I ）： ▲数式、化学式、表等があります▼（ I ）（式中、Ｒ
は水素原子または一般式（II）：▲数式、化学式、表等
があります▼（II）（式中、Ｘは炭素数１〜６の直鎖も
しくは分枝鎖のアルキル基、ベンジル基または２，２，
２−トリクロロエチル基）で表わされるオキシカルボニ
ル基）で表わされる安息香酸誘導体を有効成分とする解
熱鎮痛剤。 １５ 前記Ｒが、前記一般式（II）においてＸが炭素数
１〜４の直鎖もしくは分枝鎖のアルキル基またはベンジ
ル基であるオキシカルボニル基または水素原子である特
許請求の範囲第１４項記載の解熱鎮痛剤。 １６ 前記有効成分を約３５０〜１７００ｍｇ含有し、
薬理学的に許容しうる賦形剤を用いてなる特許請求の範
囲第１５項記載の解熱鎮痛剤。 １７ 一般式（ I ）： ▲数式、化学式、表等があります▼（ I ）（式中、Ｒ
は水素原子または一般式（II）：▲数式、化学式、表等
があります▼（II）（式中、Ｘは炭素数１〜６の直鎖も
しくは分枝鎖のアルキル基、ベンジル基または２，２，
２−トリクロロエチル基）で表わされるオキシカルボニ
ル基）で表わされる安息香酸誘導体を有効成分とする消
炎剤。 １８ 前記Ｒが、前記一般式（II）においてＸが炭素数
１〜４の直鎖もしくは分枝鎖のアルキル基またはベンジ
ル基であるオキシカルボニル基または水素原子である特
許請求の範囲第１７項記載の消炎剤。 １９ 前記有効成分を約３５０〜１７００ｍｇ含有し、
薬理学的に許容しうる賦形剤を用いてなる特許請求の範
囲第１８項記載の消炎剤。 ２０ 一般式（ I ）： ▲数式、化学式、表等があります▼（ I ）（式中、Ｒ
は水素原子または一般式（II）：▲数式、化学式、表等
があります▼（II）（式中、Ｘは炭素数１〜６の直鎖も
しくは分枝鎖のアルキル基、ベンジル基または２，２，
２−トリクロロエチル基）で表わされるオキシカルボニ
ル基）で表わされる安息香酸誘導体を有効成分とする去
痰剤。 ２１ 前記Ｒが、前記一般式（II）においてＸが炭素数
１〜４の直鎖もしくは分枝鎖のアルキル基またはベンジ
ル基であるオキシカルボニル基または水素原子である特
許請求の範囲第２０項記載の去痰剤。 ２２ 前記有効成分を約３５０〜１７００ｍｇ含有し、
薬理学的に許容しうる賦形剤を用いてなる特許請求の範
囲第２１項載の去痰剤。[Claims] 1. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (in the formula, R
is a hydrogen atom or general formula (II): ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (wherein, X is a straight or branched alkyl group having 1 to 6 carbon atoms, a benzyl group, or 2,
A benzoic acid derivative represented by an oxycarbonyl group) represented by a 2-trichloroethyl group). 2 The above R is the general formula (II) where X has 1 carbon number
The benzoic acid derivative according to claim 1, which is an oxycarbonyl group or a hydrogen atom which is a linear or branched alkyl group or a benzyl group of -4. 3. The benzoic acid derivative according to claim 1, wherein R is a hydrogen atom. 4. The benzoic acid derivative according to claim 1, wherein R is a benzyloxycarbonyl group. 5. The benzoic acid derivative according to claim 1, wherein R is a methoxycarbonyl group. 6. The benzoic acid derivative according to claim 1, wherein R is an isobutyloxycarbonyl group. 7. The benzoic acid derivative according to claim 1, wherein the R is an ethoxycarbonyl group. 8(a) Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼The compound represented by (III) has general formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (in the formula, X is a linear or branched alkyl group having 1 to 6 carbon atoms, a benzyl group or a 2,2,2-trichloroethyl group, and Y is a halogen atom) by reacting a compound represented by the general formula (
V): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Step of obtaining the compound represented by (V) (in the formula, X is the same as above), and (b) the general formula obtained in the step of (a) above. The compound represented by (V) has the formula (VI): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The general formula (
I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is a hydrogen atom or general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, X is A method for producing a benzoic acid derivative represented by an oxycarbonyl group (same as above). 9 In addition to the steps (a) and (b) above, (c) those in which X is a 2,2,2-trichloroethyl group in the general formula (I) are reduced and X is a hydrogen atom. 9. The manufacturing method according to claim 8, characterized by comprising a step of converting into . 10 The step (a) is performed in a manner that is approximately 2
Using ~4 times the molar amount of the compound represented by general formula (IV),
(b) at about -10°C to room temperature; (c) for about 10 to 40 minutes; (d) in a dry organic solvent; and (e) in the presence of a tertiary amine. The manufacturing method according to claim 8 or 9. 11 In step (b), (f) using a compound represented by formula (VI) in a slightly excess molar amount with respect to the compound represented by general formula (V), (
The manufacturing method according to claim 8, 9 or 10, characterized in that the process is carried out under the following conditions: g) at about -10°C to room temperature; and (h) for about 3 to 8 hours. 12 Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Reacting the compound represented by (III) with the compound represented by formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The formula (I ′) is characterized by:
▲Mathematical formulas, chemical formulas, tables, etc. are available▼Production method of benzoic acid derivative represented by (I′). 13 The reaction is about 3 to 7 for the compound represented by (i) formula (III)
(ii) using twice the molar amount of the compound represented by formula (VI);
(iii) in an inert gas atmosphere; (iv) at a temperature of the melting point of the reaction mixture; and (v) in the absence of a solvent. Manufacturing method described. 14 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
is a hydrogen atom or general formula (II): ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (wherein, X is a straight or branched alkyl group having 1 to 6 carbon atoms, a benzyl group, or 2,
An antipyretic analgesic agent containing a benzoic acid derivative represented by an oxycarbonyl group (2-trichloroethyl group) as an active ingredient. 15. Claim 14, wherein R is an oxycarbonyl group or a hydrogen atom in which X is a linear or branched alkyl group having 1 to 4 carbon atoms or a benzyl group in the general formula (II). antipyretic analgesic. 16 Contains about 350 to 1700 mg of the above active ingredient,
The antipyretic analgesic agent according to claim 15, which comprises a pharmacologically acceptable excipient. 17 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
is a hydrogen atom or general formula (II): ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (wherein, X is a straight or branched alkyl group having 1 to 6 carbon atoms, a benzyl group, or 2, 2,
An anti-inflammatory agent containing a benzoic acid derivative represented by an oxycarbonyl group (2-trichloroethyl group) as an active ingredient. 18. Claim 17, wherein R is an oxycarbonyl group or a hydrogen atom in which X is a linear or branched alkyl group having 1 to 4 carbon atoms or a benzyl group in the general formula (II). anti-inflammatory agent. 19 Contains about 350 to 1700 mg of the above active ingredient,
The anti-inflammatory agent according to claim 18, which comprises a pharmacologically acceptable excipient. 20 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
is a hydrogen atom or general formula (II): ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (wherein, X is a straight or branched alkyl group having 1 to 6 carbon atoms, a benzyl group, or 2, 2,
An expectorant containing a benzoic acid derivative represented by an oxycarbonyl group (2-trichloroethyl group) as an active ingredient. 21. Claim 20, wherein R is an oxycarbonyl group or a hydrogen atom in which X is a linear or branched alkyl group having 1 to 4 carbon atoms or a benzyl group in the general formula (II). expectorant. 22 Contains about 350 to 1700 mg of the above active ingredient,
22. The expectorant according to claim 21, which comprises a pharmacologically acceptable excipient.
JP57012523A 1981-02-06 1982-01-27 Benzoic acid derivatives, their production methods, and antipyretic analgesics, anti-inflammatory agents, and expectorants containing them as active ingredients Expired JPS6045866B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT19562A/81 1981-02-06
IT19562/81A IT1194790B (en) 1981-02-06 1981-02-06 SALICYLIC ACID DERIVATIVES

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JPS6045866B2 true JPS6045866B2 (en) 1985-10-12

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DE (1) DE3148424C2 (en)
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FR (1) FR2499559B1 (en)
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ATA529081A (en) 1984-01-15
DE3148424C2 (en) 1985-12-05
FR2499559B1 (en) 1986-04-25
AT375635B (en) 1984-08-27
IT1194790B (en) 1988-09-28
FR2499559A1 (en) 1982-08-13
JPS57144244A (en) 1982-09-06

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