JPS6022694B2 - Novel 2-(2-fluoro-4-biphenyl)propionic acid ester derivative - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (where n is an integer of 1 or 2, RI is a hydrogen atom or a lower alkyl group, R2 is a hydroxyl group, [o' trihalomethyl group, pyridyl group, B phenyl group, or ■
The present invention relates to a novel 2-(2-fluoro-4-biphenyl)propionic acid ester derivative represented by a phenyl group substituted with a halogen atom, a lower alkyl group, or a trifluoromethyl group.

The compound of the present invention is a novel compound that has not been described in any literature, and has significant analgesic and anti-inflammatory effects and is industrially useful as a pharmaceutical.

To explain RI and R2 in the general formula (1) more specifically, RI represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and R2 represents a trihalogen group such as a hydroxyl group, a trichloromethyl group, or a trifluoromethyl group. Methyl group, pyridyl group is 2-pyridyl group, 3-pyridyl group and 4-pyridyl group.
- Pyridyl group, phenyl group, halogen atom such as chlorine, bromine, iodine, fluorine, methyl, ethyl, propyl,
It represents a phenyl group substituted with 1 or 2 lower alkyl groups such as isopropyl, n-butyl, isobutyl, tert-butyl, or trifluoromethyl group at any position.

Conventionally, 2-(2
-fluoro-4-biphenyl)propionic acid is known.

Although this compound exhibits excellent pharmacological activities such as analgesic and anti-inflammatory effects, it has the disadvantage that it has side effects such as gastrointestinal disorders and must be administered with caution.
Therefore, the present inventors conducted intensive research in search of a new compound that reduces such side effects and has strong analgesic and anti-inflammatory effects, and as a result, the compound represented by the general formula (la) was converted into an ester derivative (1). When converted, gastrointestinal disorders were significantly alleviated, and the compound (la
), and when applied topically for the purpose of developing a non-steroidal topical anti-inflammatory agent, it was found to have a remarkable anti-inflammatory effect and was highly absorbable through the skin. They discovered that the method was superior and completed the present invention. Representative compounds related to the present invention are listed below.

2-(2-fluoro-4-biphenyl)propionic acid-
o-Fluorobenzyl ester 2-(2-fluoro-4
-biphenyl)propionic acid-m-fluorobenzyl ester 2-(2-fluoro-4-biphenyl)propionic acid-p-fluorobenzyl ester 2-(2-fluoro-4-biphenyl)propionic acid-o-chlorobenzyl ester 2 1-(2-fluoro-4-biphenyl)propionic acid-m-chlorobenzyl ester 2-(2-fluoro-4-biphenyl)propionic acid-p-chlorobenzyl ester 2-(2-fluoro-4-biphenyl)propionic acid-o -Methylbenzyester 2-(2-fluoro-4-biphenyl)propionic acid-m-Methylbenzyester 2-(2-fluoro-4-biphenyl)
Probionic acid-p-methylbenzyl ester 2-(2-
fluoro-4-biphenyl)propionic acid-o-trifluoromethylbenzylesterol2-(2-fluoro-4-biphenyl)propionic acid-m-trifluoromethylbenzylesterol2-(2-fluoro-4-biphenyl)propionic acid- p-Trifluoromethylbenzylester 2-(2-fluoro-4-biphenyl)p.

2-pyridylmethyl propionate 2-(2-fluoro-4-biphenyl) 3-pyridylmethyl propionate 2-(2-fluoro-4-biphenyl) 4-pyridyl methyl propionate 2-(2-fluoro-4-biphenyl) 2-(2-fluoro-4-biphenyl)propionic acid-Q-methylbenzyl ester 2-(2-fluoro-4-biphenyl)
Propionic acid-Q-ethylbenzyl ester 2-(2-
fluoro-4-biphenyl)propionate-Q-methyl-o-methylbenzylester 2-(2-fluoro-
4-biphenyl)propionic acid-Q-methyl-m-methylbenzylester-2-(2-fluoro-4-piphenyl)propionic acid-Q-methyl-p-methylbenzylester-2-(2-fluoro-4-biphenyl)propionic acid- Q-Methyl-o-chlorobenzylester-2-(2-fluoro-4-biphenyl)propionic acid-
Q-Methyl-m-chlorobenzylesterol2-(2-fluoro-4-biphenyl)propionic acid-Q-methyl-p-chlorobenzylesterol2-(2-fluoro-4-biphenyl)propionic acid-Q-methyl-o -Fluorobenzylester 2-(2-fluoro-4-biphenyl)propionic acid-Q-methyl-m-fluorobenzylester 2-(2-fluoro-4-piphenyl)propionic acid-Q-methyl-p-fluorobenzylester /2-(2-fluoro-4-biphenyl)propionic acid-Q-methyl-o-trifluoromethylbenzyl ester2-(2-fluoro-4-biphenyl)propionic acid-Q-methyl-m-trifluoromethylbenzyl ester 2-(2 -Fluoro-4-biphenyl)propionic acid-Q-Methyl-p-trifluoromethylbenzylester 2-(2-fluoro-4-biphenyl)propionic acid-phenethylester 2-(2-fluoro-4-biphenyl)propionic acid-p- Fluorophenethyl ester 2-(2-fluoro-4-biphenyl)propionic acid-penzyl ester 2-(2-fluoro-4-biphenyl)propionic acid-2,2-Z-trifluoroethyl ester 2-(2-fluoro-4-biphenyl) Propionic acid-2-hydroxyethyl ester A method for producing the compound according to the present invention will be described below.

The compound of the present invention can be obtained in good yield by the method described below, but this is only an example, and of course it can also be produced by other chemically similar methods. Manufacturing method A However, n, RI and R2 have the same meanings as above.

Manufacturing method B However, X is a halogen atom or an organic sulfonyl group, M is an alkali metal, and n, RI and R2 have the same meanings as above.

Manufacturing method C However, n, RI and R2 have the same meanings as above.

Manufacturing method D However, n, RI and R2 have the same meanings as above.

Manufacturing method E However, n, RI and R2 have the same meanings as above.

Manufacturing method F However, n, RI and R2 have the same meanings as above.

Manufacturing method G However, n, RI and R2 have the same meanings as above.

Manufacturing method: However, R represents a lower alkyl group, and RI and R2 have the same meanings as above.

Manufacturing method I However, n, RI and R2 have the same meanings as above.

Next, a method for implementing the present invention will be specifically explained.

Production method A involves compound (la) and a compound represented by general formula (D) in the presence of a dehydrating agent such as sulfuric acid, polyphosphoric acid, p-toluenesulfonic acid, etc., and an alcohol represented by general formula (b) as a solvent. or benzene,
The reaction may be carried out under reflux using an organic solvent such as toluene or xylene. Production method B involves treating compound (la) with an alkali metal to form (lb), and then converting the compound represented by general formula (m) into benzene, toluene, xylene, tetrahydrofuran, dioxane, diglyme, dimethylformamide, dimethylsulfoxide. The reaction proceeds quickly in an organic solvent at room temperature or with heating if necessary.

In production methods C and D, the target compound (1) can be obtained by catalytic reduction of the compounds represented by the general formulas (lc) and (ld) in the presence of a catalyst such as palladium-carbon or platinum oxide. .

Production method E is produced by diazotizing the amine/group of compound (le) in the presence of a fluorinating agent to produce a fluorodiazonium derivative, and then thermally decomposing it to produce the corresponding fluoro compound using the Schiemann reaction. be done.

In production method F, compound (la) is treated with a halogenating agent to form an acid halide (lf), and then the alcohol represented by (b) is treated with an organic solvent that does not participate in the reaction (e.g., tetrahydrofuran, diglyme, dioxane, acetone). , chloroformbenzene, toluene, etc.) in the presence of a deoxidizing agent such as pyridine, trimethylamine, triethylamine, triethylamine, potassium carbonate, and sodium carbonate.

Production method G involves reacting the compound (1g) with an alcohol represented by the general formula (b) in the presence of scale acid (sulfuric acid, hydrochloric acid, etc.) with the alcohol (0) used also serving as a solvent, or using benzene, The reaction may be carried out under reflux in an organic solvent that does not participate in the reaction, such as toluene.

The production method uses an excess molar amount of the alcohol represented by the general formula (0) relative to the compound (lh), and the alcohol or organic solvent used (for example, benzene, toluene, If the reaction is carried out under heating at or near the boiling point of xylene, etc., the transesterification reaction will proceed.

Production method 1 involves heating the compound (li) and the alcohol represented by the general formula (0) in the presence of an acid catalyst or directly, or heating the compound (li) and the alcohol represented by the general formula (0) in an organic solvent that does not participate in the reaction in an excess amount of the alcohol (
0) under heating.

Next, the results of pharmacological experiments regarding the compounds of the present invention will be shown.

Experimental Example 1 Experiment on the inhibitory effect of carrageenan on paw edema in rats (experimental method): A group of 5 male Wistar rats weighing 140-150 kg were fasted for 1 hour, and then the test compound was orally administered for 1 hour. Afterwards, a 0.1 M circle of 1% carrageenan aqueous solution was injected into the rat's foot pad.

The paw volume was measured 3 hours after the injection of the inflammatory agent, and the paw edema rate and edema suppression rate were calculated from the following formula. The test compound was suspended in a 0.5% aqueous solution of gum tragacanth, and only the solvent was administered to the control group. Edema rate (%) = carrageenin injection hind paw volume - carrageenin injection paw volume X.

〇Carrageenin injection paw volume edema suppression rate (%) = edema rate of control group, drug-treated group. Edema rate XI.

〇The edema rate results for the control group are shown in Table 1.

Table 1 Comparative effect of carrageenin on paw edema inhibition in Lacito This shows that there is a significant difference.

Experimental Example 2 Actual risk of gastric ulcer-inducing effect in rats (experimental method): Groups of 7 male Wistar rats weighing 170-180 kg were given oral administration of the test compound after fasting for 2 hours. ．． After incubation, the rats were sacrificed in a plate and their stomachs were removed.

After 10 minutes of 1% formalin solution was injected into the stomach and fixed, the stomach was incised and the presence or absence of erodion was observed.

The test compound was suspended in a 0.5% aqueous solution of gum tragacanth, and only the solvent was administered to the control group. Table 2 shows the experimental results.
Shown below.

Table 2 Gastric ulcer-inducing effect in rats *The comparative compound is the same compound used in Experimental Example 1.

As is clear from the experimental results of Experimental Examples 1 and 2 above,
The compound of the present invention has a remarkable anti-inflammatory effect, and furthermore,
It was also found that the formation of gastrointestinal tracts in the stomach was significantly reduced.

EXAMPLES The present invention will be explained in more detail with reference to Examples below. Example 1 2-(2-fluoro-4-biphenyl)propionic acid 2
．． On the evening of April 44, a mixture of 8 parts of 2', 2, 2-trifluoroethyl alcohol and 3 parts of concentrated sulfuric acid was heated to 90 to 100 o'clock on an oil bath.
The mixture was heated at o for 6 hours.

After the reaction was completed, the reaction product was poured into ice water, poured out with ether, and the ether layer was thoroughly washed with a 5% sodium carbonate solution and water, and then dehydrated. The oil obtained by distilling off the ether was adsorbed onto a column packed with silica gel and developed with dichloromethane. The solvent in the first outflow portion was removed under reduced pressure, and 2-(2-fluoro-4-biphenyl)propionic acid-2',2,2-trifluoroethyl ester was obtained as a pale yellow oil.
I got 3 nights. The IR spectrum and MS spectrum of this material were as follows.

IR spectrum: Rec = 0 175 Specific spectrum - IMS spectrum: M 326 Example 2 2.66% of sodium 2-(2-fluoro-4-biphenyl)propionate was dissolved in 20% of dimethylformamide, and p-fluorobenzylchloride was dissolved in 20% of dimethylformamide. Added 2.16 hours of hydroxide and allowed to react at 80 to 9 degrees for 3 hours.

After the reaction was completed, the solvent was removed under reduced pressure, water was added to the solution, and the mixture was extracted with ether. After dehydration, the ether was removed and the residue was adsorbed onto a column packed with silica gel and developed with chloroform. The solvent in the first outflow portion was removed under reduced pressure, and 2-(2-fluoro-4-biphenyl)propionic acid was obtained as a pale yellow oil.
2.50 g of p-fluorobenzyl ester were obtained. The R spectrum and MS spectrum of this material were as follows.

m spectrum: ReCni0 173 ratio N-IM memory spectrum: M+ 352 Example 3 2-(2-fluoro-4-bifenyl)acrylic acid-o
- Methyl benzyl ester 1.73 m, platinum oxide 0.0
Hydrogenation was carried out at room temperature using an atmospheric pressure catalytic reduction apparatus over 3 hours and 20 hours of ethanol.

After the reaction was completed, the catalyst was removed and the reactor liquid was distilled off under reduced pressure. The resulting residue was adsorbed onto a column packed with silica gel and developed with chloroform. The solvent in the first outflow portion was removed under reduced pressure, and 1.62% of mono(2-fluoro-4-biphenyl)propionic acid mono-methylbenzyl ester was obtained as a pale yellow oil.
I got the evening. The IR spectrum and MS spectrum of this material were as follows.

IR spectrum: c=0 173 ratio N-IMS spectrum: M 8 Example 4 2-dimethylamino-2-(2-fluoro-4-biphenyl)propionic acid-m-trifluoromethylbenzyl ester 1.48 Evening, 10% palladium-carbon 0.25
A mixture of alcohol and 40% ethanol was hydrogenated at 80°C using an autoclave.

After the reaction was completed, the reaction solution was filtered through a furnace, and the furnace liquid was distilled off under reduced pressure, and the resulting residue was adsorbed on a column filled with silica gel and developed with chloroform. The solvent in the first outflow portion was removed under reduced pressure to obtain 0.96 g of 2-(2-fluoro-4-biphenyl)propionic acid-m-trifluoromethylbenzyl ester as a pale yellow oil. The IR spectrum and MS spectrum of this material were as follows.

m spectrum: RES C=0 173&S-IMS spectrum: M+ 402 Example 5 2-(2-Fluoro-4-bifuunyl)propionic acid 2
．． 44 evening, thionyl chloride 2. A mixture of 20% of paper and benzene was reacted under reflux for 3 hours.

Next, the solvent and excess thionyl chloride were distilled off under reduced pressure, and 20 parts of tetrahydrofuran and 1.64 parts of 3-pyridine methanol were added to the bound residue, and then 1.50 parts of triethylamine was added to the water. I lit it for 2 hours at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was sequentially washed with a 5% sodium carbonate solution and water, then dehydrated and removed under reduced pressure.The remaining residue was adsorbed onto a column packed with silica gel, developed with ether, and the solvent in the eluted portion was distilled off. 2.05 g of 2-(2-fluoro-4-biphenyl)propionic acid-3-pyridylmethyl ester was obtained as a pale yellow oil. The IR spectrum and MS spectrum of this material were as follows.

IR spectrum: Rec 0 173 ratio - IMS spectrum: M+ mottling 5 Example 6 2-(2-fluoro-4-biphenyl)propionic acid 2
．． 44 evening, thionyl chloride 2. A mixture of 20% of soybean and benzene was reacted under reflux for 3 hours.

Next, the solvent and excess thionyl chloride were removed under reduced pressure, and to the resulting residue were added 20 parts of benzene and 1.83 parts of Q-methylbenzyl alcohol, and then 1.50 parts of triethylamine was added under ice-cooling. The reaction mixture was then allowed to react for 1 hour at room temperature under the current of the Liao stream. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was sequentially washed with 5% sodium carbonate solution, dehydrated, and evaporated under reduced pressure. The resulting liquid was adsorbed onto a column packed with silica gel, developed with ether, and the solvent in the eluate was removed to form prism crystals. 2.3 ml of 2-(2-fluoro-4-biphenyl)propionic acid-Q-methylbenzyl ester was obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 90-920 Elemental analysis value C23 days 2, F02 theoretical value C:79.29H:6. Measured value C: 79.36H: 602 Example 7 2.66 g of sodium 2-(2-fluoro-4-biphenyl)propionate was dissolved in 20 g of dimethylformamide and 2.6 g of ethylene bromohydrin was added. 60-7 including mezuyu
The reaction was carried out for 1 hour at 0.

After the reaction was completed, the solvent was removed under reduced pressure, water was added to the residue, extracted with ether, washed with water, dried, the ether was removed, and the resulting clear liquid was adsorbed onto a column packed with silica gel and developed with chloroform. The solvent in the first outflow portion was removed to obtain colorless prismatic crystals of 2-(2-fluoro-4-piphenyl)propionic acid-2-hydroxyethyl ester (2.54 g). The melting point and elemental analysis values of this substance were as follows.

Melting point 73-7 is ○ Elemental analysis value C,? Sun, 7F03 Theoretical value C: 70.82H: 5.94 Actual value C: 70.75H: 5. Nada Examples 8-20

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, n is an integer of 1 or 2, R^1 is a hydrogen atom or a lower alkyl group, R^2 is (i) ) hydroxyl group, (b)
2-(2-fluoro- 4-biphenyl)
Propionate ester derivative.