JPS63313750A - 2-(2-fluoro-4-biphenylyl)propionic acid ester and anti-inflammatory agent containing said ester as active component - Google Patents

Abstract

NEW MATERIAL:The 2-(2-fluoro-4-biphenylyl)propionic acid ester of formula I (n is 1-3). EXAMPLE:3,7,11-Trimethyl-2,6,10-dodecatrien-1-yl 2-(2-fluoro-4-biphenylyl)propio nate. USE:Useful as an anti-inflammatory agent. It is effective for the remedy of inflam mation caused by various factors and has no side effects such as gastrointestinal injury. It can be administered by oral or parenteral administration. PREPARATION:The compound of formula I can be produced by reacting a terpene alcohol of formula II or its reactive derivative with flurbiprofen (prefer ably 0.8-1.0 equivalent of an acid chloride of flurbiprofen based on the com pound of formula II) in the presence of a tertiary organic base (e.g. triethylamine) at about 0 deg.C- room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-(2-fluoro-4-biphenylyl)propionic acid ester and an anti-inflammatory agent containing it as an active ingredient.

Two lids of rice! 2-(2-fluoro-4-?l''phenylyl)flopionic acid [generic name: flurbiprofen] is already commercially available as a drug with anti-inflammatory, analgesic and antipyretic effects.

It has also been reported that flurbiprofen, its alkyl esters having 1 to 8 carbon atoms, and pharmacologically acceptable salts are useful for the treatment of adult respiratory distress syndrome, and for the prophylactic and therapeutic treatment of herpes virus. (Unexamined Japanese Patent Publication No. 1983)
-24517 and JP-A-59-110646).

Problems to be Solved by the Invention Flurbiprofen is known to cause gastrointestinal disorders, like many other non-steroidal anti-inflammatory drugs, when continuously administered in large doses.

Therefore, one object of the present invention is to provide a flurbiprofen derivative that has an anti-inflammatory effect comparable to or superior to flurbiprofen and exhibits fewer side effects. Another object of the present invention is to provide an anti-inflammatory agent containing the flurbiprofen derivative.

According to the present invention, the above object is achieved by the general formula (where n is 1
2-(2-fluoro-
This is achieved by providing a 4-biphenylyl) furopionic acid ester, and 2 of the general formula (1).
This is achieved by providing an anti-inflammatory agent containing -(2-fluoro-4-biphenylyl)propionate as an active ingredient.

2-(2-fluoro-4=biphenylyl)propionic acid ester a represented by general formula (1), terpene alcohol n represented by general formula (wherein n is as defined above) [hereinafter referred to as this] Terpene alcohol (n
)] or its reactive derivative and flurbiprofen or its reactive derivative. Here, reactive derivatives of terpene alcohol (If) include halides, alkanesulfonates, arenesulfonates, carboxylates, etc., and reactive derivatives of flurbiprofen include lower alkyl esters, acidolides, mixed acid anhydride,
Examples include alkali metal salts, silver salts, and salts of organic tertiary or quaternary bases. Terpene alcohol (I[)
The reaction between flurbiprofen or its reactive derivative and flurbiprofen or its reactive derivative can be carried out under conventionally known general ester synthesis reaction conditions. Representative examples of the ester synthesis reaction are shown below. show.

(Reaction example () Terpene alcohol (II), !: Reaction of flurbiprofen with acid halide Terpene alcohol (■) About 0.5 to 1 for this n
．． 2 equivalents, preferably 0.8 to 1.0 equivalents, of flurbiprofen with an acid halide, preferably an acid chloride, in the presence or absence of an inert solvent, at a concentration of about 1.0 equivalents relative to the acid halide. 2-(2-
Fluoro-4-biphenylyl)propionic acid ester can be obtained. Examples of inert solvents include hydrocarbon solvents such as toluene, benzene, and hexane; carbon tetrachloride, chloroform, dichloromethane, dichloroethane,
Halogenated hydrocarbon solvents such as trichlene; ether solvents such as diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofine, and dimethoxyethane; ketone solvents such as acetone and ethyl methyl ketone; dimethyl sulfoxide , aprotic polar solvents such as dimethylformamide are used (reaction side inlet), terpene alcohol (II), reaction of toflurbiprofen and other acids with mixed acid anhydrides, terpene alcohol (If), Approximately 0.5 for the eave
~1.2 equivalents, preferably 0.8 to 1.0 equivalents of flurbiprofen and a mixed acid anhydride such as pivalin &% p-)luenesulfonic acid are mixed with the inert solvent used in Reaction Example A. in the presence or absence of a similar solvent, preferably in the presence of a catalytic to solvent amount of sulfuric acid sp), an acid such as luenesulfonic acid, or a tertiary amine such as pyridine, triethylamine, at about By the reaction, 2-(2-fluoro-4-biphenylyl)propionic acid ester represented by general formula (1) can be obtained.

(Reaction example C) Terpene alcohol (It),! : Reaction with terpene alcohol (n) and tulurbiprofen, active solvents such as benzene, toluene, xylene, etc., e.g. synchhexylcarbodiimide, or 2-chloro-1-methyl iodide 2-(2- Fluoro-4-biphenylyl)propionic acid ester can be obtained.

(Anti-r6 Example 2) Reaction of terpene alcohol (II) with lower alkyl ester of toflurbiprofen Terpene alcohol (II) and lower alkyl ester of flurbiprofen are transesterified using a suitable transesterification catalyst, such as p-toluenesulfonic acid, Alternatively, the general formula (
2-(2-fluoro-4-biphenylyl)furopionic acid ester represented by 1) can be obtained.

(Reaction example E) Terpene alcohol” (II) (7)
/N Ride, alkanesulfonate or haarenesulfonate reaction with alkali metal salt, silver salt or salt of organic tertiary or quaternary base of flurbiprofen Halide of terpene alcohol (U), alkanesulfone) In addition, U arenes sulfonate and an alkali metal salt, silver salt, or salt of a tertiary or quaternary base of flurbiprofen are mixed in a solvent such as dimethylformamide, benzene, acetone, etc. at about θ° C. or under heating. 2-(2-fluoro-4-biphenylyl)furopionic acid ester represented by general formula (1) can be obtained by reacting at a temperature of .

The separation and purification of the 2-(2-fluoro-4-biphenylyl)propionic acid ester represented by the general formula (1) obtained by the above ester synthesis reaction can usually be carried out by the method -8=. For example, water is added to the reaction mixture, then extracted with ethyl acetate etc., the extract is washed with water and dried, the solvent is distilled off, and the residue is subjected to column chromatography, for example, to obtain the general formula (1).
) 2-(2-fluoro-4-biphenylyl)
Propionate ester can be separated and obtained.

Next, 2-(2-fluoro-4
-biphenylyl)furopionic acid ester, 3,7
．． 11-) Limethyl-2,6,10-dodecatriene-
Anti-inflammatory effects of 1-yl=2-(2-fluoro-4-biphenylyl)propionate (hereinafter sometimes referred to as fL1 flurhyflofene farnesyl nistert) and flurbiprofen used as a control system. The test and results are shown below.

Carrageenin-induced edema suppression test Test method Male Wistar rats (5 weeks old, weight 150f) it
A group of 5 animals was used for the test. 0.11 L of a suspension obtained by suspending lambda type carrageenan in physiological saline to a concentration of 1% was administered subcutaneously to the right hind limb of the rat. Measure the rat's paw volume in advance before administering carrageenin. Two hours after administration, a predetermined amount of flurbiprofen soarnesyl ester dissolved in Nicoma oil was administered intravenously.

After administration, the paw volume was measured over time, and the edema rate was calculated according to the following formula.

In the flurbipro 7-treated group and the control group, the same procedures as above were performed except that for flurbiprofen dissolved in sesame oil, only sesame oil was administered intravenously.

Test Results The edema rate in the flurbiflofen 9-furnesyl ester administration group is shown in Figure 1, and the edema rate in the flurbiprofen administration group is shown in Figure 2. In the figure, 0.03+1v administration group, 0.1!
The edema rate of each of the administration group and the 111v administration group is indicated by a mark, a △ mark, and a mu mark, and the edema rate of the control group is indicated by an O mark. In addition, in the diagram, the middle mark, the *mark, and the mark** have the following meanings, respectively.
- have.

*...Significant difference compared to the control group (1)<0.
05. (Tested) Medium Medium...Significant difference compared to the control group (1) <0.01. (tested)***...Significant difference compared to control group (tested p<0.001) As is clear from Figures 1 and 2, flurbiprofen/farnesilnisterha control drug Compared to flurbiprofen, it has an inhibitory effect on carrageenin-induced edema that is equal to or greater than that of flurbiprofen.

In 2-(2-fluoro-4-biphenylyl)flopionic acid ester represented by general formula (I), represented by flurbiprofen-farnesyl ester, side effects such as gastrointestinal disorders associated with flurbiprofen are significantly reduced. Sanru.

2-(2-fluoro-4-biphenylyl)propionate represented by general formula (I) is an excellent anti-inflammatory agent.
It has several characteristics. Furthermore, the 2-(2-fluoro-4-biphenylyl)propionic acid ester was confirmed to have low toxicity in toxicity tests.

As clarified above, 2- represented by general formula (1)
(2-Fluoro-4-biphenylyl) fropionate is useful as a precautionary drug for the treatment of inflammation caused by various factors.

According to the present invention, a pharmaceutical composition containing a 2-(2-fluoro-4-biphenylyl)propionic acid ester represented by general formula (I) is provided.

Administration of the pharmaceutical composition may be either oral or parenteral. Oral dosage forms include powders, tablets, emulsions, capsules, granules, and liquids (including tinctures, liquid extracts, spirits, suspensions, limonases, syrups, etc.). Ushita parenteral dosage forms include injections, drops, ointments, plasters, liquids (including alcoholic agents, tinctures, lotions, etc.), poultices, liniments, sprays, dusting agents, and liniments. , creams, emulsions, solvents, etc.

The dosage varies depending on the symptoms, but in the case of oral preparations, injections, and infusions, it is 1 dose per day for adults as 2-(2-fluoro-4-biphenylyl)propionate represented by general formula (1). ~500η, preferably 5~ioow
g, and this dosage can be administered once a day or in divided doses. In the case of external use for parenteral use, the 2-(2-fluoro-4-bife=IJA/)propionate represented by the general formula (1) may be blended at a concentration of 0.01 to 10%, preferably It is best to use it as a preparation of 0.1 to 3 inches.

The 2-(2-fluoro-4-biphenyly/I/)propionic acid ester represented by the general formula (1) can be prepared by various methods described above using a suitable pharmacologically acceptable diluent (or carrier). The pharmaceutical composition may be adapted for formulation into a dosage form. Examples of diluents used in pharmaceutical compositions (eg granules) suitable for forming into tablets and capsules include the following: (a)
Fillers and extenders, such as starch, sugar, mannitol, silicic acid, etc.; (b) Binders, such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, etc.; (C) Wetting agents. (d) Disintegrants, such as agar, calcium carbonate, sodium bicarbonate, etc.; (e) Dissolution slowing agents, such as paraffin; (f) Resorption enhancers, such as quaternary ammonium compounds; (2) surfactant,
For example, cetyl alcohol, glycerin monostearate, etc.; (h) Adsorption carriers, such as kaolin, bentonite, etc.; (1) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, etc. Coatings commonly used for tablets and capsules obtained by molding the pharmaceutical composition of the present invention;
An envelope and a protective matrix can be included, and these can include opacifying agents.

The coating, envelope and protective matrix can be made of, for example, polymeric materials or waxes. Diluents used in pharmaceutical compositions suitable for shaping into suppositories include, for example, common water-soluble or water-insoluble diluents, such as polyethylene glycols, fats (for example cocoa oil, higher esters [for example C16
- C14-alcohol esters of fatty acids, etc.) or a mixture of these diluents. Pharmaceutical compositions which are ointments, liniments and creams may, for example, contain the usual diluents such as animal or vegetable fats, waxes, paraffin, starches, tragacanth, cellulose derivatives, etc.
4, polyethylene glycol, silicone, bentonite, silicic acid, talc, zinc oxide, or mixtures of these materials. Pharmaceutical compositions in powders and sprays can, for example, contain the usual diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder or mixtures of these substances. Aerosol sprays can include, for example, common propellant bases such as chlorofluorohydrocarbons. Pharmaceutical compositions which are liquids and emulsions may, for example, contain common diluents such as solvents, solubilizers and emulsifiers. Representative examples of such diluents include water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3
Examples include fatty acid esters of -phthylene gelicol, dimethylformamide, oils (such as peanut oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol or sorbitol, or mixtures thereof. Pharmaceutical compositions that are solutions and emulsions for parenteral administration should be prepared in a sterile manner and suitably blood isotonic. Pharmaceutical compositions that are suspensions may contain common diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated isostearyl alcohol,
Liquid diluents such as polyoxyethylene sorbitol, sorbitan esters, etc.), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or mixtures thereof may be included. All pharmaceutical compositions of the invention may also include coloring agents, preservatives, aroma and flavor additives (eg mint oil, eucalyptus oil, etc.), sweetening agents (eg saccharin, etc.), and the like.

EXAMPLES The present invention will be specifically explained below using examples. Note that the present invention is not limited to these Examples.

Example 1 2-(2-fluoro-4-biphenylyl)flopionic acid 18°3f (75 mmole) 'f: Dissolved in benzene 10011, and thionyl chloride 6,6 rrtl (90 mmole) was added to the resulting solution under reflux. dripped. After refluxing for 2 hours, benzene was distilled off from the reaction tank under reduced pressure, and 20 ylf of diethyl ether was added to the residue to dissolve the residue. The obtained solution was diluted with 3.7.11-trimethyl-2゜6.10-dodecatrien-1-ol 2
Of(90rrmole), pyridi: / 8.9 L
The mixture was added dropwise to a mixed solution of iI (112.5 mmole) and 100 ml of diethyl ether under reflux. After refluxing for 2 hours, the reaction solution was poured into ice water and separated. The organic layer was dried over anhydrous magnesium sulfate, the solvent was then distilled off, and the residue was subjected to silica gel column chromatography.
(Developed with a mixed solution of ethyl acetate and hexane), 3,7.11-) Rimeter-2゜6.10-dodecatrien-1-yl-2-
(2-Fluoro-4-biphenylyl) Globioto 2
5,6f was obtained as a pale yellow liquid. Yield: 76%.

7.6-6.95 (m, 8H), 5.26 (t,
J=7f(z, IH).

5.15-4.9 (m, 2H), 4.53 (d,
J=7ffz, 2H).

3.65(q, J=7Hz, 1.1(), 2.1
5-1.80 (m, 8H).

1.79 (S, 6H), 1.51 (s, 6F
i).

1.44 (d, J=7Hz, 3Ff) GC-Mas
s spectrum (mle) knee 18 = 244 (M-204), 199 (M-249) Examples 2 and 3 In Example 1 3,7.11-)dimethyl-2,6°10-dodecatriene-1- Instead of using all 90M01e, 3,7-dimethyl-2,6-octadiene 1-
Oh k 90 mgle or 3,7,11.15-
Tetramethyl-2,6,10,14-hexadecanato 2
By carrying out the reaction and separation procedure in the same manner except using 90 mmole of en-1-ol, the corresponding 2
-(2-fluoro-4-biphenylyl)propionic acid ester was obtained. The results are shown in Table 1.

1st Table 2 1 1 81 (M]”380 3 3 3 70 [MJ+516 Next, 2-(2-fluoro-4
An example of a formulation containing utiflurbipro7ene farnesyl ester of -biphenylyl) phlopionic acid ester is shown as an active ingredient.

Example 4 Hard gelatin capsules Oral hard gelatin capsules containing all of flurbiprofen farnesyl ester 502Q in 1 capsule 1.0
00 pieces are prepared using the following ingredients and dosage.

Flurbiprofen 7-arnesyl ester
501 lactose
10 (1 corn starch
209 talc 20
2 Magnesium stearate 21 Add flurbiprofen φ farnesyl ester to other finely powdered ingredients, mix with the tip, and then mix with capsules according to the usual method.

The above capsules are for inflammation treatment, 1 capsule at a time, 1 capsule at a time.
It is effective when administered orally four times a day.

Example 5 Soft gelatin capsules Oral soft gelatin capsules containing 25 μm of flurbiprofen 7-arnesyl ester were prepared by first suspending the compound in 0.5 d of corn oil to enable encapsulation. Thereafter, it is prepared by encapsulating it using the above method.

The above capsules are for inflammation treatment, 2 capsules at a time, 1 capsule at a time.
It is effective when administered orally four times a day.

Example 6 1,000 d of an oral aqueous suspension containing 100 μl of flurbiprofen farnesyl ester was mixed with the following ingredients:
Prepare by dose.

Flurbiprofen-7 arunesyl ester
201 Citric acid 22 Benzoic acid 12 Sugar
7001 Tragacanth 52-Lemon oil
2f semen water
Add appropriate amount 1. OOOme citric acid, benzoic acid, sucrose, tragacanth and lemon oil are dispersed in enough water to give an smi of 8501. Add flurbiprofen farnesyl ester to the syrup and stir until uniform distribution. Add enough water 1,
000-.

The following drug is prepared and used for the treatment of inflammation: 1 tablespoon (51
Ll), is effective when administered three times a day.

Example 7 Injection lt contains 7 lurhyclofene and 7 arnesyl ester 1
A sterile aqueous solution for injection (intravenous injection) containing 5(lW'i) is prepared using the following ingredients and dosage.

Flurbiprofen farnesyl ester 1
50■ Add appropriate amount of distilled water for injection and 1,000 yen
After adding all the sterile flurbiprofen farnesyl ester to sterile water, fill it into a sealed sterile container.The prepared drug is effective for the treatment of inflammation at 1 ton every 12 hours.

Effects of the Invention The 2-( represented by the general formula (1) provided by the present invention)
As is clear from the results of the above test, 2-fluoro-4-biphenylyl) flopionate has superior anti-inflammatory effects compared to the control drug flurbiprofen. According to the present invention, an anti-inflammatory agent containing the 2-(2-fluoro-4-biphenylyl)propionic acid ester as an active ingredient is provided.

[Brief explanation of drawings]

Figures 1 and 2 are diagrams showing the edema of the flurbiprofen farnesyl ester administration group and the flurbiprofen administration group, respectively, in the n-carrageenan sieve edema suppression test, along with the elapsed time after administration of heavy metal carrageenan. be. In these figures, the landmarks, △ marks, and hym marks indicate flurbiprofen farnesyl ester and flurbiprofen doses of 0.03 per rat body weight, 0.
The edema rates of the 1"+9 administration group and the 1■ administration group are shown. Also, in the figure, the * mark, the middle mark, and the *** mark each have the following meanings.

Claims (1)

[Claims] 1. 2-(2-fluoro-4-biphenylyl)propionic acid represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein n represents an integer from 1 to 3) ester. 2. Contains 2-(2-fluoro-4-biphenylyl)propionic acid ester represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n represents an integer from 1 to 3) as an active ingredient. Anti-inflammatory agent.