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 ingredientsInfo
- 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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- formula
- group
- general formula
- benzoic acid
- tables
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Classifications
-
- 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)
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.
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 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57144244A JPS57144244A (en) | 1982-09-06 |
JPS6045866B2 true JPS6045866B2 (en) | 1985-10-12 |
Family
ID=11159081
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP57012523A Expired JPS6045866B2 (en) | 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 |
Country Status (7)
Country | Link |
---|---|
JP (1) | JPS6045866B2 (en) |
AT (1) | AT375635B (en) |
DE (1) | DE3148424C2 (en) |
ES (1) | ES8207115A1 (en) |
FR (1) | FR2499559B1 (en) |
IT (1) | IT1194790B (en) |
ZA (1) | ZA818149B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2953832B1 (en) * | 2009-12-10 | 2012-01-13 | Galderma Res & Dev | DERIVATIVES OF NEW PEROXIDES, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS FOR THE TREATMENT OR PREVENTION OF ACNE |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3681445A (en) * | 1968-01-19 | 1972-08-01 | Merck & Co Inc | Substituted phenyl benzoic acid compounds |
US4216340A (en) * | 1979-05-02 | 1980-08-05 | Merck & Co., Inc. | Preparation of 5-(2,4-difluorophenyl)salicylic acid and derivatives |
-
1981
- 1981-02-06 IT IT19562/81A patent/IT1194790B/en active
- 1981-11-24 ZA ZA818149A patent/ZA818149B/en unknown
- 1981-12-02 ES ES507643A patent/ES8207115A1/en not_active Expired
- 1981-12-08 DE DE3148424A patent/DE3148424C2/en not_active Expired
- 1981-12-10 AT AT0529081A patent/AT375635B/en not_active IP Right Cessation
-
1982
- 1982-01-27 FR FR8201267A patent/FR2499559B1/en not_active Expired
- 1982-01-27 JP JP57012523A patent/JPS6045866B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
DE3148424A1 (en) | 1982-09-09 |
ZA818149B (en) | 1982-10-27 |
ES507643A0 (en) | 1982-09-01 |
ES8207115A1 (en) | 1982-09-01 |
IT8119562A0 (en) | 1981-02-06 |
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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