JPH0332537B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to general formula (I): (wherein R is a lower alkyl group having 1 to 2 carbon atoms or an alkenyl group having 2 to 7 carbon atoms)
The present invention relates to alkylcarbonyloxyethyl ester derivatives and alkenylcarbonyloxyethyl ester derivatives of fluoro-4-biphenylyl)propionic acid and methods for producing them. 2-(2-fluoro-4-biphenylyl)propionic acid (generic name: flurbiprofen, hereafter
FP) is known as a powerful anti-inflammatory, analgesic, and antipyretic agent, and is already commercially available. However, since FP is irritating, it can be used in the form of injections, syrups, eye drops, suppositories, creams, blasters, and other external preparations to reduce its irritating properties when developed as a drug. It required some ingenuity in formulation and was difficult to manufacture. The inventors of the present invention have conducted extensive research to solve the above-mentioned problems, and have found that it is non-irritating and has medicinal efficacy.
We have discovered a safe drug that is several times more potent than FP and has fewer side effects, and have completed the present invention. That is, the compound of the present invention obtained by esterifying FP does not have irritating properties. In addition, the compounds of the present invention have high lipophilicity and are therefore excellent in mucosal and transdermal absorption, resulting in rapid onset and increase in medicinal efficacy. On the other hand, if an oily base is used as a formulation, it can be expected to increase and sustain the medicinal efficacy, expanding the range of pharmaceutical applications. Furthermore, due to the physicochemical properties of the compound of the present invention, namely, that it does not have a free polar group and is oily, it is difficult to bind to proteins in the body after administration. Subsequent biodistribution and metabolic patterns are different, resulting in increased drug concentration in the inflamed area and enhanced drug efficacy. Based on the above, the compound of the present invention is non-irritating compared to the parent compound FP, has excellent medicinal efficacy, and has both fast-acting and long-lasting properties, and is an excellent compound with a wide safety margin. It is a pharmaceutical product. Therefore, the object of the present invention is to have excellent anti-inflammatory, analgesic, and antipyretic effects, exhibit high safety with few side effects, and
Moreover, it is an object of the present invention to provide a novel FP derivative that is extremely useful as a drug that can be widely applied, and a method for producing the same. Specific examples of the compound represented by the general formula (I) of the present invention include Compound 1: 2-(acetyloxy)ethyl-2-
(2-fluoro-4-biphenylyl)
Propionate, compound 2: 2-(propionyloxy)ethyl-
2-(2-fluoro-4-biphenylyl)propionate, compound 3: 2-(crotonoyloxy)ethyl-
2-(2-fluoro-4-biphenylyl)propionate, Compound 4: 2-(3,3-dimethylacryloyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate, Compound 5: 2-(2, 4-hexadienoyloxy)ethyl-2-(2-fluoro-4
-biphenylyl)propionate, compound 6: 2-(3,7-dimethyl-2,6-octadienoyloxy)ethyl-2-
(2-fluoro-4-biphenylyl)
Examples include propionate. The compound of the present invention has the general formula (): (In the formula, Y is a hydrogen atom or a metal salt.) A propionic acid derivative or its salt and the general formula (): (In the formula, R is the same as above, and X is a halogen atom such as fluorine, chlorine, bromine, or iodine, or a hydroxyl group.) or Biphenylylpropionate ethyl hydroxyester represented by general formula (V): (wherein R is the same as above) or the general formula (): (In the formula, Z is a halogen atom such as fluorine, chlorine, bromine, iodine, etc.) Biphenylylpropionate ethyl halide ester and the general formula (): RCOOH () (wherein, R is the same as above) It can be obtained by reacting with an acid represented by Any conventionally known method can be used for this esterification reaction, and although it is not particularly limited, it is preferable to use the following reaction, for example, from the viewpoint of yield and industrialization. That is, the esterification reaction between the propionic acid derivative represented by the general formula () and the acyloxyethyl halide represented by the general formula () or the ethyl halide derivative represented by the general formula () and the acid represented by the general formula () is , usually alkali metal carbonates (potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali hydroxides (sodium hydroxide, potassium hydroxide, etc.),
Alkali metal hydrides (sodium hydride, potassium hydride, lithium hydride, etc.) and organic bases (pyridine, triethylamine, N,N-dimethylaniline, tetramethylethylenediamine)
or in the presence or absence of an alkali metal iodide such as sodium iodide, potassium iodide, or 15-crown-5, 18-crown-6
Crown ethers such as or [2,2,2]-
cryptate, [2,2,2]-benzocryptate, etc. in an aprotic organic solvent (N,N-dimethylformamide, dimethylsulfoxide, hexamethylsulfonyltriamide, etc.) in the presence of a phase transfer catalyst such as acetonitrile, dichloromethane, dichloroethane, chloroform, benzene,
It is carried out in an organic solvent such as ether or tetrahydrofuran. Incidentally, as the salt of the compound represented by the general formula (), a silver, copper salt, or an alkali metal salt such as lithium, sodium, or potassium is used. Further, a mixed solvent such as the above-mentioned aprotic organic solvent and ether, tetrahydrofuran, benzene, chloroform, dichloromethane, dichloroethane or acetone can also be used. On the other hand, the reaction between acyloxyethanol represented by the general formula () and the propionic acid derivative represented by the general formula () can be carried out under neutral conditions in an organic solvent without or in the presence of a catalyst, or in the presence of a dehydrating agent. Alternatively, dehydration condensation may be carried out in the absence of the compound. Preferred organic solvents used include dichloromethane, chloroform, ether, benzene, and tetrahydrofuran. The dehydrating agent used is N,N'-dicyclohexylcarbodiimide,
1-ethyl-3(3-dimethylaminopropyl)
Examples include carbodiimide (water-soluble carbodiimide) or its hydrochloride. Catalysts used include pyridine, halogenopyridine, tributylamine, aminopyridine, etc., but preferably P
- By using dimethylaminopyridine, the reaction yield is significantly increased. In addition, as an application of the active esterification method, a propionic acid derivative represented by the general formula () is reacted with carbonyldiimidazole to form an imidazoate, and then reacted with an alcohol derivative represented by the general formula () to obtain the desired product. Ester compounds may also be obtained. The target compound can also be obtained in high yield by a dehydration condensation reaction using triphenylphosphine or triethyl phosphite and azodicarboxylic acid dialkyl ester. On the other hand, the reaction between biphenylylpropionate ethyl hydroxyester represented by formula () and the acid anhydride represented by general formula (V) can be carried out in an organic base solvent such as pyridine or collidine or in benzene, dimethoxyethane, toluene, etc. It is carried out in a mixed solvent with an organic solvent. In each reaction described above, the amounts of compounds represented by general formula (), general formula (V), and general formula () to be used are relative to the compounds represented by general formula (), general formula (), and general formula, respectively. Equimolar or more, preferably 1.0 to 1.5 times the molar amount is economically advantageous. The reaction temperature is not particularly limited, but it is usually preferably carried out at 0 to 120°C. The reaction time varies depending on the solvent, catalyst, and reaction temperature used, but in general,
The duration ranges from a few minutes to more than ten hours. The alkylcarbonyloxyethyl ester derivatives and alkenylcarbonyloxyethyl ester derivatives of biphenylylpropionic acid of the present invention produced as described above have an excellent rate of hydrolysis in the body and exhibit strong anti-inflammatory, analgesic, and antipyretic effects. . Next, the pharmacological action of the compound of the present invention, the UD ₅₀ value,
The LD ₅₀ values and hydrolysis rates are shown in Table 1.

[Production of 2-hydroxyethyl-2-(2-fluoro-4-biphenylyl)propionate]

2-(2-fluoro-4-biphenylyl)propionic acid (hereinafter referred to as FP) 12.2g (50 mmol)
was dissolved in 45 ml of dry dimethylformamide, 6.9 (50 mmol) of anhydrous potassium carbonate was added, and 6.25 (50 mmol) of ethylene bromohydrin was added dropwise under ice-cooling. After the dropwise addition was completed, the mixture was heated and stirred at 60 to 70°C for 15 hours. The reaction mixture was ice-cooled, the inorganic substances were separated, and the solvent was distilled off under reduced pressure. Add 50ml of diethyl ether to the residue.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 13.8 g of a transparent oil. The obtained oil was purified by silica gel column chromatography (Merck Kieselgel 60F; developing solvent: dichloromethane dichloromethane:ether (9:
1) Purification with dichloromethane:ether (8:2)) to obtain 9.97 g (yield: 69.2%) of the target substance as white crystals with a melting point of 73-75°C. Mass spectrum (direct introduction, 20eV) m/e288 (M ⁺ ), 244, 199 (base peak), 184,
178, 45 Reference example 2 [2-bromoethyl-2-(2-fluoro-4
-Production of biphenylyl) propionate] 12.2 g (50 mmol) of FP was added to 40 ml of dichloromethane.
6.25 g (50 mmol) of ethylene bromohydrin and 0.3 g (2.5 mmol) of p-dimethylaminopyridine were added thereto under stirring at 0°C, followed by 10.3 g (50 mmol) of dicyclohexylcarbodiimide dissolved in dichloromethane. After the dropwise addition was completed, the mixture was heated and stirred at room temperature for 30 minutes. After cooling the reaction mixture on ice and separating insoluble materials,
The organic layer was washed successively with 0.1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to separate the precipitated dicyclohexylurea, and a yellow oil was obtained. was purified in the same manner as in Reference Example 1 to obtain 15.6 g (yield: 89%) of the target substance as a transparent oil. Mass spectrum (direct introduction, 20eV) m/e351 (M ⁺ ), 353 (M+2), 244, 199 (base
peak) 184, 178, 108, 110 Example 1 [Production of 2-(acetyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 1)] 2.44 g (10 mmol) of FP was added to dry dichloromethane.
2-[acetyloxy)ethyl alcohol (1.04 g: 10 mmol) was dissolved in 25 ml and stirred at 0°C.
and 0.13 g (1 mmol) of p-dimethylaminopyridine and 2.3 g (11 mmol) of dicyclohexylcarbodiimide dissolved in dry dichloromethane.
was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 1 hour. After cooling the reaction mixture on ice and separating insoluble materials,
The organic layer was washed successively with 0.1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the precipitated dicyclohexylurea was separated, resulting in a transparent solution. The oil is purified by vacuum distillation and the boiling point
Fractions at 234-238°C/1 mmHg were collected to obtain 2.6 g (yield: 80%) of the desired substance as a transparent oil. The characteristic values of the obtained target substance are shown. Elemental analysis value: C ₁₉ H ₁₉ FO ₄ (molecular weight: 330.4) Calculated value (%): C69.07 H5.75 Actual value (%): C69.28 H5.77 Nuclear magnetic resonance spectrum (in CCl ₄ , internal Standard: Tetramethylsilane) (ppm) δ1.55 (d, 3H,

【formula】) δ1.96(s, 3H,

【formula】) δ3.74(q, 1H,

【formula】) δ4.20(s, 4H,

[Formula]) δ6.90~7.42 (m, 8H, aromatic proton) Mass spectrum (direct introduction, 20eV) m/e330 (M ⁺ ) m/e226 m/e199 [base peak,

[Formula]] m/e43 [−COCH ₃ ] ⁺ m/e87

[Production of 2-(propionyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 2)]

2.44 g (10 mmol) of FP was dissolved in 25 ml of anhydrous dimethylformamide (hereinafter referred to as DMF), 1.38 g (10 mmol) of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Then, 1.77 g (13 mmol) of 2-(propionyloxy)ethyl chloride purified by distillation was added dropwise, and after the dropwise addition was completed, the mixture was stirred at 40°C to 50°C for 1 hour. The reaction mixture was ice-cooled, the inorganic substances were separated, and the solvent was distilled off under reduced pressure. Add 50ml of diethyl ether to the residue.
The organic layer was washed with water, a 10% aqueous sodium carbonate solution, and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting transparent oil was purified by distillation under reduced pressure to a boiling point of 225-228℃/
Collect the 0.5mmHg fraction and collect 2.5g of the target substance as a transparent oil.
(yield 74%). The characteristic values of the obtained target substance are shown. Elemental analysis value: C ₂₀ H ₂₁ FO ₄ (molecular weight: 344.4) Calculated value (%): C69.69 H6.10 Actual value (%): C69.90 H6.12 Nuclear magnetic resonance spectrum (in CCl ₄ , internal Standard: Tetramethylsilane) (ppm) δ1.08 (t, 3H, _-CH2CH ~ ₃ ) δ1.52 (d, 3H,

[Formula]) δ2.26 (q, 2H, -CH~ ₂ CH ₃ ) δ3.75 (q, 1H,

【formula】) δ4.22(s, 4H,

[Formula]) δ6.90-7.42 (m, 8H, aromatic proton) Mass spectrum (direct introduction, 20eV) m/e344 (M ⁺ ) m/e226 m/e199 [base peak

【formula】〕 m/e101

[Production of 2-(crotonoyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 3)]

The reaction was carried out in the same manner as in Example 2, except that 3.66 g (15 mmol) of FP, 10 ml of dry DMF, 2.07 g (15 mmol) of anhydrous potassium carbonate, and 2.89 g (15 mmol) of 2-(crotonoyloxy)-ethyl bromide were used. After post-treatment and purification, 3.39 g (yield: 63.4%) of the desired substance was obtained as a transparent oil with a boiling point of 205-215°C/1.5 mmHg. The characteristic values of the obtained target substance are shown. Elemental analysis value: C ₂₁ H ₂₁ FO ₄ (as molecular weight 356.4) Calculated value (%): C70.77 H5.89 Actual value (%): C70.98 H5.91 Nuclear magnetic resonance spectrum (in CCl ₄ , internal standard : Tetramethylsilane) (ppm) δ1.40 (d, 3H,

[Formula]) δ1.72 (dd, 3H, Olefinik CH ~ ₃ ) δ3.57 (q, 1H,

【formula】) δ4.06(s, 4H,

[Formula]) δ5.54, 5.51 (dd, 1H, olefinik proton) δ6.44-7.33 (m, 9H, aromatic, olefinik proton) Mass spectrum (direct introduction, 20eV) m/e356 (M ⁺ ) m/e226 m/e199 [base peak

【formula】〕 m/e113

[Production of 2-(3,3-dimethylacryloyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 4)]

3.66 g (15 mmol) of FP, 20 ml of dry DMF, 2.07 g (15 mmol) of anhydrous potassium carbonate and 2-
The reaction, post-treatment and purification were carried out in the same manner as in Example 2 except that 3.0 g (15 mmol) of (3,3-dimethylacryloyloxy)ethyl bromide was used, resulting in a transparent oil with a boiling point of 225-228°C/0.8 mmHg. 3.31g (yield 59.6%) of the target substance was obtained. The characteristic values of the obtained target substance are shown. Elemental analysis value: C ₂₂ H ₂₃ FO ₄ (as molecular weight 370.5) Calculated value (%): C71.32 H6.21 Actual value (%): C71.53 H6.24 Nuclear magnetic resonance spectrum (in CCl ₄ , internal standard : Tetramethylsilane) (ppm) δ1.44 (d, 3H,

[Formula]) δ1.72 (s, 3H, olefinik - CH ₃ ) δ2.03 (s, 3H, olefinik - CH ₃ ) δ3.62 (q, 1H,

【formula】) δ4.08(s, 4H,

[Formula]) δ5.40 (m, 1H, olefinic proton) δ6.82-7.52 (m, 8H, aromatic proton) Mass spectrum (direct introduction, 20eV) m/e370 (M ⁺ ) m/e226 m/e199〔base peak ] m/e127

[Production of 2-(3,7-dimethyl-2,6-octadienoyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 6)]

1.68 g (10 mmol) of 3,7-dimethyl-2,6-octadienoic acid, 10 ml of dry DMF, 1.38 g (10 mmol) of anhydrous potassium carbonate and 2-bromoethyl-2-(2-fluoro-4-biphenylyl) The reaction and post-treatment were carried out in the same manner as in Example 2 except that 3.51 g (10 mmol) of propionate was used.
The resulting residue was purified by silica gel column chromatography (Merck Kieselgel 60F; 60 g, developing solvent: dichloromethane-cyclohexane mixed solvent) to obtain 3.1 g (yield: 83.7%) of the target substance as a transparent oil. Boiling point: 250℃/1mmHg or higher Indicates the characteristic value of the target substance obtained. Elemental analysis value: C ₂₇ H ₃₁ FO ₄ (as molecular weight 438.6) Calculated value (%): C73.94 H7.07 Actual value (%): C74.16 H7.06 Nuclear magnetic resonance spectrum (in CCl ₄ , internal standard : Tetramethylsilane) (ppm) δ1.44 (d, 3H,

[Formula]) δ1.46, 1.55 (ss, 6H, Olefinik − CH ₃ ×
2) δ1.96 (m, 7H, olefinik-CH~ ₃ , olefinik, -CH _{~ 2} -CH~ ₂ -) δ3.50 (q, 1H,

【formula】) δ3.96(s, 4H,

[Formula]) δ4.66~4.92 (m, 1H, olefinik proton) δ5.24 (s, 1H, olefinik proton) δ6.64~7.18 (m, 8H, aromatic proton) Mass spectrum ( Direct introduction, 20eV) m/e438 (M ⁺ ) m/e226 m/e199 [base peak

[Production of 2-(2,4-hexadienoyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 5)]

18 crowns in 200 ml of dry acetonitrile
60.1 g, 1.5 g (20 mmol) of potassium sorbate, and 3.5 g (10 mmol) of 2-bromoethyl-2-2-(2-fluoro-4-biphenylyl)propionate were added, and the mixture was heated and stirred at 50° C. for 8 hours.
Thereafter, the product was post-treated and purified in the same manner as in Example 5 according to conventional methods to obtain 3.5 g (yield: 91.6%) of the desired substance as white crystals with a melting point of 59-61°C. The characteristic values of the obtained target substance are shown. Elemental analysis value: C ₂₃ H ₃₃ FO ₄ (as molecular weight 382.3) Calculated value (%): C72.26 H6.02 Actual value (%): C72.40 H6.04 Nuclear magnetic resonance spectrum (in CCl ₄ , internal standard : Tetramethylsilane) (ppm) δ1.44 (d, 3H,

[Formula]) δ1.71 (d, 3H, Olefinik-CH ₃ ) δ3.48 (q, 1H,

【formula】) δ4.00(s, 4H,

[Formula]) δ5.24, 5.38 (d, 1H, olefinik proton) δ5.63~5.72 (m, 2H, olefinik proton) δ6.60~7.18 (m, 9H, aromatik, olefinik proton) ) Mass spectrum (direct introduction, 20eV) m/e382 (M ⁺ ) m/e271

[Formula] m/e226 (base peak) m/e199

[Production of 2-(acetyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 1)]

2-hydroxyethyl-2-(2-fluoro-
Dissolve 7.55 g (26.2 mmol) of 4-biphenylyl propionate in 35 ml of dry pyridine, dropwise add 4 g (39.3 mmol) of acetic anhydride while cooling with ice, and after the dropwise addition, heat and stir at 40°C for 3 hours to cool the reaction mixture. After that, pour it into ice water and add diethyl ether.
Extracted with 400ml. This was washed sequentially with 10% hydrochloric acid and water, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting transparent oil was purified by vacuum distillation to obtain the target substance in the form of a transparent oil.
7.61g (yield: 88%) was obtained. The characteristic values of the target substance obtained were consistent with those of Example 1. Example 8 [Production of 2-(acetyloxy)ethyl-2-(2-fluoro-4-biphenylyl)propionate (compound 1)] Potassium salt of FP in 100 ml of dry acetonitrile
2.82 g (10 mmol), 60.1 g of 18-crown, and 1.22 g (10 mmol) of acetyloxyethyl chloride were added, and the mixture was stirred at room temperature for 8 hours. Thereafter, the product was post-treated according to a conventional method and purified in the same manner as in Example 1 to obtain 1.48 g (yield: 44.8%) of the desired substance in the form of a transparent oil. The characteristic values of the target substance obtained were consistent with those of Example 1. Example 9 [2-(propionyloxy)ethyl-2-(2
-Production of fluoro-4-biphenylyl) propionate (compound 2)] Potassium salt of FP in 100 ml of dry acetonitrile
2.82g (10mmol), propionyloxyethyl chloride 1.7g (10mmol), triethylamine
1 g of potassium iodide and 1.6 g of potassium iodide were added thereto, and the mixture was heated and stirred at 60°C for 5 hours. Thereafter, the product was worked up according to a conventional method and distilled under reduced pressure to obtain 2.86 g (yield: 83%) of the desired product as a transparent oil. The obtained characteristic values of the target substance were consistent with those of Example 2.

Claims (1)

[Claims] 1 General formula (I): (wherein R is a lower alkyl group having 1 to 2 carbon atoms or an alkenyl group having 2 to 7 carbon atoms) and alkenyl carbonyloxyethyl ester derivatives of biphenylylpropionic acid Carbonyloxyethyl ester derivative. 2 The above R is a methyl group, an ethyl group, a 1-propenyl group, a 2-methyl-1-propenyl group, a 1,3-
The derivative according to claim 1, which is a substituent selected from the group consisting of a pentadienyl group and a 2,6-dimethyl-1.5-heptadienyl group. 3 General formula (): (wherein, Y is a hydrogen atom or a metal salt) 2-(2-fluoro-4-biphenylyl)propionic acid or its salt and the general formula (): (wherein R is a lower alkyl group having 1 to 2 carbon atoms or an alkenyl group having 2 to 7 carbon atoms, and X is a halogen atom such as fluorine, chlorine, bromine or iodine, or a hydroxyl group. ) General formula (I) characterized by reacting with a compound represented by: (wherein R is a lower alkyl group having 1 to 2 carbon atoms or an alkenyl group having 2 to 7 carbon atoms) and alkenyl carbonyloxyethyl ester derivatives of biphenylylpropionic acid Method for producing carbonyloxyethyl ester derivative. 4 Formula (): Biphenylylpropionate ethyl hydroxyester represented by general formula (V): (wherein R is a lower alkyl group having 1 to 2 carbon atoms or an alkenyl group having 2 to 7 carbon atoms) (I): (wherein R is a lower alkyl group having 1 to 2 carbon atoms or an alkenyl group having 2 to 7 carbon atoms) and alkenyl carbonyloxyethyl ester derivatives of biphenylylpropionic acid Method for producing carbonyloxyethyl ester derivative. 5 General formula (): (wherein, Z is a halogen atom such as fluorine, chlorine, bromine, iodine, etc.) and the general formula (): RCOOH () (wherein, R is 1 to 2 General formula (I) characterized by reacting with an acid represented by a lower alkyl group having 5 carbon atoms or an alkenyl group having 2 to 7 carbon atoms: A method for producing an alkylcarbonyloxyethyl ester derivative and an alkenylcarbonyloxyethyl ester derivative of biphenylylpropionic acid represented by the formula (wherein R is the same as above).