JPS6332064B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel benzoylaminophenyl carboxylic acid derivatives and pharmaceutically acceptable salts thereof, and further relates to a method for producing the same and a pharmaceutical composition containing at least one thereof. Conventionally, salicylic acid preparations, piratuolone preparations,
There are anthranilic acid preparations, phenyl acetic acid preparations, indole acetic acid preparations, etc., but each has a high rate of serious side effects such as gastrointestinal disorders, granulocytopenia, and liver damage, and these side effects can be alleviated by improving the dosage form and chemical modification. has been attempted. The present invention was developed as a result of extensive research aimed at avoiding such side effects and discovering compounds with medicinal efficacy equivalent to or superior to conventional non-steroidal drugs. The present invention was completed based on the discovery that the compound has significant anti-inflammatory and analgesic effects against various types of inflammation, and is a low-toxic pharmaceutically useful compound. The purpose of the present invention is to provide a novel benzoylaminophenylcarboxylic acid derivative useful as a therapeutic agent, and also to provide a method for producing the compound of the present invention, as well as a pharmaceutical composition containing the compound of the present invention as an active ingredient. The goal is to provide products and how to use them. The compounds of the present invention include novel benzoylaminophenyl carboxylic acid derivatives represented by the following general formula () and pharmaceutically acceptable salts thereof. (In the formula, X ₁ is halogen, X ₂ is hydrogen or halogen, A is a direct bond, alkylene having 1 to 5 carbon atoms or alkenylene having 2 to 5 carbon atoms,
R ₁ is hydrogen, alkyl having 1 to 8 carbon atoms, cycloalkyl-substituted alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 6 carbon atoms, and R ₂ is hydrogen Or it represents an alkyl group having 1 to 8 carbon atoms. ) In the general formula (), X ₁ represents a halogen such as fluorine, chlorine, bromine, iodine, etc., and X ₂ represents hydrogen or a halogen similar to X ₁ ; A is a direct bond, that is, the group -COOR ₂ is A linear or branched alkylene having 1 to 5 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, which is directly bonded to the phenyl group without intervening another atomic group, and specifically, Represents the following groups. ―CH ₂ ―, ―CH ₂ CH ₂ ―, CH(CH ₃ )―, ―
CH ₂ CH ₂ CH ₂ ―, ―CH (CH ₃ ) CH ₂ ―, ―C
(CH ₃ ) ₂ --(CH ₂ ) ₄ --, --CH ₂ C(CH ₃ ) ₂ --, --
CH ₂ CH (CH ₃ ) CH ₂ ―, ―CH (CH ₃ ) CH ₂ CH ₂
―, ―(CH ₂ ) ₅ ―, ―CH ₂ C(CH ₃ ) ₂ CH ₂ ―, ―
CH ₂ CH (C ₂ H ₅ ) CH ₂ ―, ― CH ₂ CH ₂ CH (CH ₃ )
CH ₂ --, --CH(CH ₃ )(CH ₂ ) ₃ -- or linear or branched alkenylene having 2 to 5 carbon atoms, such as vinylene, propenylene, butenylene, and pentenylene, specifically the following: represents a group such as -CH=CH-, -CH ₂ -CH=CH
-, -C( _CH3 )=CH-, _-CH2CH = _CHCH2- ,
-CH=C( _CH3 ) _CH2 -,-CH=CHCH( _CH3 )
-, -CH ₂ CH=CHCH ₂ CH ₂ -, -CH ₂ CH=C
(CH ₃ )CH ₂ -; R ₁ is hydrogen, linear or branched with 1 carbon number
to 8 alkyls, such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and branched versions thereof; cycloalkyl-substituted alkyl having 4 to 8 carbon atoms, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclo Butylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl; cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl; or linear or branched carbon number 2 to 6
Alkenyl, such as vinyl, propenyl, butenyl, pentenyl, and hexenyl, specifically represents the following groups. ―CH＝CH ₂ , ―CH ₂ CH＝CH ₂ , ―CH ₂ CH＝
CHCH ₃ , -CH ₂ CH ₂ CH=CH ₂ , -CH ₂ CH=
CHCH ₂ CH ₃ , ―CH ₂ CH ₂ CH＝CHCH ₃ , ―
CH ₂ CH=C(CH ₃ ) ₂ , ―CH ₂ C(CH ₃ )=CH ₂ , ―
_CH2C ( _CH3 )= _CHCH3 , _-CH2CH =CH
(CH ₂ ) ₂ CH ₃ , - (CH ₂ ) ₂ CH=CHCH ₂ CH ₃ , -
(CH ₂ ) ₃ CH＝CHCH ₃ , -CH ₂ CH＝CHCH
(CH ₃ ) ₂ , —CH ₂ CH=C(CH ₃ )(C ₂ H ₅ ); and R ₂ represents hydrogen or the alkyl described above as R ₁ . Specifically, the compounds of the present invention include the following compounds. 2,6-Dichlorobenzoylaminobenzoic acid, 2,6-difluorobenzoylaminobenzoic acid, 2,6-dichlorobenzoylaminophenylacetic acid, 2,6-difluorobenzoylaminophenylacetic acid, 3-(2,6-dichloro Benzoylaminophenyl) propionic acid, 2-(2,6-dichlorobenzoylaminophenyl) propionic acid, 2-methyl-2-(2,6-dichlorobenzoylaminophenyl) propionic acid, 2-(2,6 -difluorobenzoylaminophenyl)propionic acid, 2-(2,6-difluorobenzoylamino-halogenophenyl)propionic acid, 2,6-dichlorobenzoylaminocinnamic acid, 2-[N-(2,6-difluorobenzoyl) ―
N-methylamino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-hexylamino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-(2-propyl)amino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-cyclopropylmethylamino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-cyclopentylamino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-(2-propenyl)amino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-(2-methyl-2-propenyl)amino]phenylpropionic acid, 2-[N-(2,6-difluorobenzoyl)-
N-(3-methyl-2-butenyl)amino]phenylpropionic acid and alkyl esters thereof. The present invention further encompasses pharmaceutically acceptable salts of the compounds of the present invention, particularly salts of alkali metals such as sodium and potassium, alkaline earth salts such as calcium and magnesium in the case of compounds of the present invention that are free carboxylic acids. and salts with ammonium. According to the present invention, a compound represented by the general formula (); By reacting with a compound represented by the general formula (), The compound of the present invention represented by the general formula () can be produced. (In the formula, X ₁ is halogen, X ₂ is hydrogen or halogen, A is a direct bond, alkylene having 1 to 5 carbon atoms or alkenylene having 2 to 5 carbon atoms,
R ₁ is hydrogen, alkyl having 1 to 8 carbon atoms, cycloalkyl-substituted alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 6 carbon atoms, R ₂ is hydrogen or Alkyl having 1 to 8 carbon atoms and X ₃ represent halogen. ) In the reaction, water, alcohols, or mixtures thereof, pyridine, dioxane, tetrahydrofuran, ether, etc. can be used as a solvent, and the reaction can be carried out for several minutes to 5 minutes at room temperature or with appropriate heating.
The target compound can be obtained in a short time. It is preferably carried out in the presence of a base, such as sodium hydroxide,
Potassium hydroxide, pyridine, etc. can be used. Furthermore, in order to obtain the compound of the present invention which is a free carboxylic acid, the ester compound of the present invention obtained by the above method can be hydrolyzed by a conventional method. For example, the desired carboxylic acid of the present invention can be obtained in an aqueous or alcoholic aqueous solution of a base such as sodium hydroxide or potassium hydroxide at room temperature to reflux conditions for 30 minutes to 5 hours. Furthermore, the compound of the present invention can be converted into a salt by a conventional method if desired. The obtained compound of the present invention can be purified by conventional means such as chromatography and recrystallization, and identified by elemental analysis, melting point, IR, NMR, etc. The substituted amine compound (R ₁ ≠ H) used in the above reaction was obtained by reacting the corresponding unsubstituted amine with a compound represented by the general formula () in a solvent such as acetone, tetrahydrofuran, or dimethylformamide. . R ₁ -X ₄ () (In the formula, X ₄ is a halogen, and R ₁ represents the above meaning.) The reaction is carried out at room temperature or by heating and stirring with the addition of potassium carbonate and, if necessary, potassium iodide. Ivy. Hereinafter, the method for producing the compound of the present invention will be shown in Examples. Reference Example 1 Methyl 2-(4-aminophenyl)propionate and potassium carbonate (2.5 equivalents) in a nitrogen atmosphere
was added in acetone, cyclopropylmethyl bromide (1.0 equivalent) was added dropwise, and the mixture was refluxed for 24 hours.
After filtration, the filtrate was concentrated, extracted with ether, washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and separated and purified using a silica gel column.
Methyl 2-(4-cyclopropylmethylaminophenyl)propionate was obtained. The following compounds were obtained in the same manner. Methyl 2-(4-methylaminophenyl)propionate, Methyl 2-(4-isopropylaminophenyl)propionate, Methyl 2-(4-cyclopentylaminophenyl)propionate, 2-[4-(2- propenylamino) phenyl]
Methyl propionate, 2-[4-(2-methyl-2-propenylamino)phenyl]methyl propionate, 2-[4-(3-methyl-2-butenylamino)
methyl phenyl]propionate, methyl 2-[4-hexylaminophenyl)propionate. Example 1 In 50 ml of 6N-sodium hydroxide solution, 2-
Methyl (4-aminophenyl)propionate 1.9g
and 2,6-difluorobenzoic acid chloride 2.0
g was added thereto, and the mixture was stirred at room temperature. After the crystals solidify, they are suction filtered, dried and recrystallized with benzene to obtain white crystals of methyl 2-[4-(2,6-difluorobenzoylamino)phenyl]propionate 3.1
g (yield 91%) was obtained. 2.0 g of the obtained compound was added to 40 ml of methanol, 2 ml of water, and 2.0 g of potassium hydroxide, and the mixture was stirred at room temperature for 4 hours. Methanol was distilled off under reduced pressure, water was added, and the mixture was washed with chloroform. Concentrated hydrochloric acid was added to the aqueous layer, and the resulting white crystals were recrystallized from chloroform-acetone to produce 2-[4-(2,6-difluorobenzoylamino)phenyl]propionic acid.
1.7 g (yield 90%) was obtained. (Compound 1) MP.177-179℃ IR (KBr) 3600-2200, 3280,
3040, 1700, 1651, 1622, 1595,
1528, 1452, 1401, 1315, 1226,
1006, 830, 790, 760 cm ^-1 NMR (acetone-D ₆ ) δ1.48 (d,
3H), 3.80 (q, 1H), 7.36 (d,
2H), 7.77 (d, 2H), 6.8-7.6 (m,
3H), 9.06 (br.s, 1H), 9.75 (br.s,
1H) Example 2 Add and dissolve 2.3 g of methyl 2-(4-cyclopropylmethylaminophenyl)propionate in 25 ml of pyridine in a nitrogen atmosphere, and slowly dropwise add 21 g of 2,6-difluorobenzoic acid chloride under ice cooling. did. After stirring at room temperature for 1 hour, ethyl acetate was added, and the mixture was washed with 5% hydrochloric acid, water, an aqueous sodium bicarbonate solution, and brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off and purified using a silica gel column, and the 2-
{4-[N-cyclopropylmethyl-N-(2,
6-difluorobenzoyl)amino]phenyl}
Methyl propionate was obtained with a yield of over 90%. Further, this compound was dissolved in 35 ml of methanol, 4 ml of 50% aqueous potassium hydroxide solution was added, and the mixture was refluxed for 1 hour. The mixture was concentrated under reduced pressure, water was added thereto, washed with ether, and concentrated hydrochloric acid was added under cooling to obtain crystals. This was recrystallized from hexane-acetate to obtain white needle-like crystals of 2-{4-[N-cyclopropylmethyl-
N-(2,6-difluorobenzoyl)amino]
Phenyl}propionic acid was obtained quantitatively. (Compound 2) MP.155-156℃ IR (KBr) 3700-2200, 2950,
1725, 1611, 1590, 1510, 1465,
1301, 1174, 1001, 798, 556 cm ^-1 . NMR (DMSO-D ₆ ) δ0.06-1.1 (m,
5H), 1.26 (d, 3H), 3.61 (q,
1H), 3.71 (d, 2H), 6.5-7.6 (m,
7H), 12.0 (br.s, 1H) The following compounds were obtained in the same manner. ethyl 4-(2,6-dichlorobenzoylamino)benzoate, methyl 4-(2,6-dichlorobenzoylamino)phenylacetate, methyl 4-(2,6-difluorobenzoylamino)phenylacetate, 2-[4- Methyl (2,6-dichlorobenzoylamino)phenyl]-2-methylpropionate, methyl 3-[4-(2,6-dichlorobenzoylamino)phenyl]propionate, 2-[4-(2,6-dichloro Methyl benzoylamino)phenyl]propionate, 2-[3-chloro-4-(2,6-difluorobenzoylamino)phenyl]methyl propionate, 2-{4-[N-methyl-N-(2,6- difluorobenzoyl)amino]phenyl}methyl propionate, 2-{4-[N-isopropyl-N-(2,6-
methyl difluorobenzoyl)amino phenylpropionate, 2-{4-N-cyclopentyl-N-(2,6-
difluorobenzoyl)amino]phenyl}methyl propionate, 2-{4-[N-(2-propenyl)-N-
(2,6-difluorobenzoyl)amino]phenyl}methyl propionate, 2-{4-[N-(2-methyl-2-propenyl)-N-(2,6-difluorobenzoyl)amino]phenyl}propionic acid Methyl, 2-{4-[N-hexyl-N-(2,6-difluorobenzoyl)amino]phenyl}methyl propionate, 2-{4-[N-(3-methyl-2-butenyl)
-N-(2,6-difluorobenzoyl)amino]phenyl}methyl propionate, 2-(3-benzoylaminophenyl)methyl propionate, 2-[3-(2,6-dichlorobenzoylamino)phenyl]propion Methyl acid, methyl 2-[3-(2,6-difluorobenzoylamino)phenyl]propionate, ethyl 4-(2,6-difluorobenzoylamino)benzoate, 3-(2,6-difluorobenzoylamino)benzoate Ethyl acid, ethyl 2-(2,6-difluorobenzoylamino)benzoate. 4-(2,6-dichlorobenzoylamino)benzoic acid (compound 3) MP.253-255℃ IR (KBr) 3550-2200, 3220,
3000, 1680, 1660, 1592, 1520,
1425, 1310, 1266, 1175, 850,
800, 770, 705cm ^-1 NMR (acetone-D ₆ ) δ5.5-6.7
(br.s, 1H), 7.49 (br.s, 3H), 7.90
(d, 2H), 8.09 (d, 2H), 10.02
(br.s, 1H) 4-(2,6-dichlorobenzoylamino)phenylacetic acid (compound 4) MP.193-195℃ IR (KBr) 3500-2200, 3210,
3110, 1705, 1638, 1600, 1535,
1506, 1422, 1401, 1320, 1232,
832, 792, 763 cm ^-1 NMR (acetone-D ₆ ) δ3.63 (s,
2H), 7.43 (br.s, 3H), 7.30 (d,
2H), 7.74 (d, 2H), 7.9-8.9 (br.
s, 1H), 9.68 (br.s, 1H) 4-(2,6-difluorobenzoylamino)phenylacetic acid MP.198-200℃ IR (KBr) 3500-2000, 3300,
1692, 1651, 1619, 1598, 1540,
1461, 1402, 1320, 1222, 1004,
805, 759, 660 cm ^-1 NMR (DMSO-D ₆ ) δ3.56 (s,
2H), 6.6-8.0 (m, 8H), 10.77 (br.
s, 1H) 2-[4-(2,6-dichlorobenzoylamino)phenyl]-2-methylpropionic acid MP.247-249℃ IR (KBr) 3600-2200, 3210,
2960, 1715, 1680, 1640, 1590,
1520, 1422, 1402, 1317, 1265,
898, 823, 798, 775cm ^-1 NMR (acetone-D ₆ ) δ1.59 (s,
6H), 4.5-6.1 (br.s, 1H), 7.48 (br.
s, 3H), 7.42 (d, 2H), 7.79 (d,
2H), 9.67 (br.s, 1H) 3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid MP.214-216℃ IR (KBr) 3600-2200, 3280,
3110, 3040, 1700, 1659, 1600,
1530, 1505, 1422, 1406, 1319,
830, 796, 771 cm ^-1 NMR (acetone-D ₆ ) δ2.74 (t,
2H), 2.83 (t, 2H), 6.2-7.2 (br.
s, 1H), 7.44 (br.s, 3H), 7.28 (d,
2H), 7.72 (d, 2H), 9.62 (br.s,
1H) 2-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid MP.145-147℃ IR (KBr) 3700-2250, 3220,
3030, 1695, 1657, 1600, 1500,
1400, 1315, 794, 772cm ^-1 NMR (acetone-D ₆ ) δ1.47, (d,
3H), 3.77 (q, 1H), 5.25 (br.s,
1H), 7.47 (br.s, 3H), 7.38 (d,
2H), 7.78 (d, 2H), 9.67 (br.s,
1H) 2-[3-chloro-4-(2,6-difluorobenzoylamino)phenyl]propionic acid MP.166-168℃ IR (KBr) 3450-2100, 3310,
1700, 1680, 1660, 1622, 1589,
1535, 1471, 1320, 1238, 1222,
1010, 900, 787 cm ^-1 NMR (DMSO-D ₆ ) δ1.40 (d,
3H), 3.75 (q, 1H), 6.9-7.9 (m,
6H), 10.47 (br.s, 1H) 2-{4-[N-methyl-N-(2,6-difluorobenzoyl)amino]phenyl}propionic acid MP.141-142℃ IR (KBr) 3600-2200 ,2930,
1724, 1618, 1591, 1510, 1469,
1238, 1062, 798, 650cm ^-1 NMR (acetone-D ₆ ) δ1.33
(d.3H), 3.40 (s, 3H), 3.67 (q,
1H), 6.5-7.6 (m, 7H), 8.26 (br.
s, 1H) 2-{4-[N-isopropyl-N-(2,6-
Difluorobenzoyl)amino]phenyl}propionic acid (compound 5) MP.174-175℃ IR (KBr) 3600-2200, 2970,
1726, 1618, 1598, 1510, 1467,
1420, 1238, 1117, 1005, 793,
763, 600, 550cm ^-1 NMR (Acetone-D ₆ /DMSO-
D ₆ ) δ1.17 (d, 6H), 1.29 (d,
3H), 3.61 (q, 1H), 4.98 (sep,
1H), 6.5-7.6 (m, 7H), 8.50 (br.
s, 1H) 2-{4-[N-cyclopentyl-N-(2,6
-difluorobenzoyl)amino]phenyl}propionic acid MP.190-191℃ IR (KBr) 3700-2200, 2970,
1730, 1613, 1588, 1512, 1470,
1178, 1004, 799, 560cm ^-1 NMR (DMSO-D ₆ ) δ1.24 (d,
3H), 1.1-2.2 (m, 9H), 3.60 (q,
1H), 4.5-5.2 (m, 1H), 6.2-7.6
(m, 8H) 2-{4-[N-(2-propenyl)-N-
(2,6-difluorobenzoyl)amino]phenyl}propionic acid MP.144-145℃ IR (KBr) 3700-2200, 2970,
1729, 1612, 1590, 1508, 1469,
1300, 1172, 1000, 791, 550cm ^-1 NMR (acetone-D ₆ ) δ1.32 (d,
3H), 3.67 (q, 1H), 4.48 (br.d,
2H), 4.9-5.4 (m, 2H), 5.6-6.3
(m, 1H), 6.5-7.5 (m, 7H),
9.20 (br.s, 1H) 2-{4-[N-(2methyl-2-propenyl)
-N-(2,6-difluorobenzoyl)amino]phenyl}propionic acid MP.145-146℃ IR (KBr) 3700-2200, 2960,
1720, 1608, 1585, 1508, 1463,
1205, 1170, 1000, 790, 550cm ^-1 NMR (acetone-D ₆ ) δ1.31 (d,
3H), 1.82 (br.s, 3H), 3.68 (q,
1H), 4.49 (br.s, 2H), 4.7-5.0
(m, 2H), 6.5-7.5 (m, 7H),
8.08 (br.s, 1H) 2-{4-[N-hexyl-N-(2,6-difluorobenzoyl)amino]phenyl}propionic acid (compound 6) MP.113-114℃ IR (KBr) 3600- 2200, 2920,
1725, 1612, 1590, 1470, 1210,
1175, 1000, 795, 552 cm ^-1 NMR (acetone-D ₆ ) δ0.87 (t,
3H), 1.32 (d, 3H), 1.0-1.9 (m,
8H), 3.68 (q, 1H), 3.90 (t,
2H), 6.5-7.6 (m, 7H), 8.04 (br.
s, 1H) 2-{4-[N-(3-methyl-2-butenyl)
-N-(2,6-difluorobenzoyl)amino]phenyl}propionic acid MP.128-129℃ IR (KBr) 3700-2200, 2970,
1725, 1615, 1588, 1510, 1465,
1300, 1238, 1168, 1001, 791, 551
cm ^-1 NMR (CDC1 ₃ ) δ1.39 (d, 3H),
1.50 (s, 3H), 1.71 (s, 3H),
3.59 (q, 1H), 4.45 (d, 2H),
5.31 (t, 1H), 6.4-7.5 (m, 7H),
10.48 (br.s, 1H) 2-[3-(2,6-dichlorobenzoylamino)phenyl]propionic acid MP.152-154℃ IR (KBr) 3500-2500, 3280,
1695, 1640, 1550, 1425, 1200,
675cm ^-1 NMR (acetone-D ₆ ) δ1.46 (d,
3H), 3.77 (q, 1H), 5.00 (br.s,
1H), 7.00-7.90 (m, 7H), 9.70
(br.s, 1H) 2-[3-(2,6-difluorobenzoylamino)phenyl]propionic acid MP.137-138℃ IR (KBr) 3500-2300, 3340,
1710, 1650, 1595, 1540, 1435,
690cm ^-1 NMR (acetone-D ₆ ) δ1.47 (d,
3H), 3.77 (q, 1H), 6.80-7.90
(m, 7H), 8.85 (br.s, 1H), 9.75
(br.s, 1H) 4-(2,6-difluorobenzoylamino)benzoic acid MP.272-274℃ IR (KBr) 3400, 3100-2500,
1695, 1650, 1620, 1600cm ^-1 NMR (DMSO-D ₆ ) δ11.1 (1H),
8.2-7.0 (m, 8H) 3-(2,6-difluorobenzoylamino)benzoic acid MP.261-262℃ IR (KBr) 3270, 3150-2600,
1685, 1658, 1620, 1589, 1538,
1465cm ^-1 NMR (DMSO-D ₆ /CDC1 ₃ ) δ10.9
(1H), 8.5-6.9 (m, 8H) 2-(2,6-difluorobenzoylamino)benzoic acid MP.203-204.5℃ IR (KBr) 3400-2800, 1680,
1660, 1620, 1600cm ^-1 NMR (DMSO-D ₆ ) δ11.85 (1H),
8.7-7.0 (m, 8H) Example 3 30 ml of 6N sodium hydroxide aqueous solution was added to 2.0 g of ethyl 3-aminocinnamate, and while stirring, 2,6-
2.5 g of dichlorobenzoic acid chloride was added dropwise.
Water was added and the solids were filtered. The obtained product was dissolved in 20 ml of ethanol, 20 ml of 1N aqueous potassium hydroxide solution was added, and the mixture was heated under reflux for 4 hours. The reaction solution was returned to room temperature, hydrochloric acid was added under ice-cooling, and the precipitate was collected by filtration, washed with water, dried, and recrystallized with methanol and ethyl acetate to obtain 2.6 g of 3-(2,6-dichlorobenzoylamino)cinnamic acid. I got it. MP.258℃ (decomposition) IR (KBr) 3600-2300, 3240,
1685, 1660, 1625, 1425, 885cm ^-1 NMR (DMSO-D ₆ ) 6.45 (d,
1H), 7.20-8.00 (m, 8H), 10.88
(br.s, 1H) The following compounds were obtained in the same manner. 3-[3-(2,6-dichlorobenzoylamino)phenyl]propionic acid MP.174-175℃ IR (KBr) 3600-2400, 3250,
1705, 1660, 1612, 1558, 1495,
1430, 700cm ^-1 NMR (acetone-D ₆ ) δ2.47-3.06
(m, 4H), 5.60 (br.s, 1H), 6.95―
7.85 (m, 7H), 10.30 (br.s, 1H) 3-(2,6-dichlorobenzoylamino)benzoic acid MP.252-255℃ (decomposition) IR (KBr) 3500-2300, 3300,
1695, 1680, 1640, 1530, 1320,
745, 690cm ^-1 NMR (DMSO-D ₆ ) δ7.20-8.45
(m, 7H), 10.46 (br.s, 1H), 12.50
(br.s, 1H) Among the compounds of the present invention, particularly benzoylaminophenyl acetic acid derivatives, a separate production method is also possible. An acetophenone derivative represented by the general formula (), (In the formula, R ₃ represents hydrogen or an alkyl group.) The compound obtained by acylation in the same manner as above ()
For example, It can be converted into an acetate ester derivative according to the method described in "Journal of Organic Synthetic Chemistry Society 36 , 875 (1978)" and further hydrolyzed if desired to obtain the target compound (2). An example of the production of the compound of the present invention by this method is shown below. Example 4 (1) Add 3.0 g of 3-aminoacetophenone to 50 ml of 6N aqueous sodium hydroxide solution, and add 2.
5.0 g of 6-dichlorobenzoic acid chloride was added dropwise. After 30 minutes, the formed precipitate was collected by filtration, washed with dilute hydrochloric acid and water, and recrystallized from methanol.
6.0 g of 3-(2,6-dichlorobenzoylamino)acetophenone was obtained. (Yield 88%) (2) 10 ml of methanol and 10 ml of methyl orthoformate were added to 4.9 g of thallium nitrate trihydrate, and 10 g of silica gel was added and stirred. The solvent was distilled off and the mixture was dried. To this, add 3.1 g of the compound obtained above dissolved in 60 ml of benzene,
Stirred at room temperature for 1 hour. After removing the silica gel, the residue was washed with water, an aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and the solvent was distilled off to obtain 3.6 g of a crude product. Furthermore, dissolve this crude product in 20 ml of methanol, add 20 ml of 10% aqueous sodium hydroxide solution, and
Refluxed for an hour. Methanol was distilled off, the residue was washed with ether, the aqueous solution was acidified, and the precipitate was recrystallized from ethanol water to obtain 2.5 g of 3-(2,6-dichlorobenzoylamino)phenylacetic acid. (Yield 78.6%) MP.176-178℃ IR (KBr) 3600-2300, 3250,
1695, 1660, 1610, 1425, 790,
775, 430cm ^-1 NMR (DMSO-D ₆ ) δ3.58 (s,
2H), 6.80-7.70 (m, 7H), 10.76
(br.s, 1H), 12.0 (br.s, 1H) The following compounds were obtained in the same manner. 2-(2,6-difluorobenzoylamino)phenylacetic acid MP.199-201℃ IR (KBr) 3500-2100, 3250,
1686, 1650, 1620, 1583, 1530,
1468, 1318, 1230, 1009, 795,
760, 680, 532 cm ^-1 NMR (DMSO-D ₆ ) δ3.72 (s,
2H), 6.85 (br.s, 1H), 6.9-7.8
(m, 7H), 10.34 (br.s, 1H) The compound of the present invention has analgesic and antiinflammatory effects and is useful as a medicine. Examples of pharmacological tests are shown below. (1) Carrageenin paw edema inhibitory effect Using 6 Wistar rats per group, the volume of the right hind paw was measured in advance, and then the test drug was orally administered. 60 minutes later 1% carrageenin aqueous solution 0.1
ml was injected subcutaneously into the right hind foot pad, and the volume was measured over time over the next 5 hours. The edema rate was expressed as the volume increase rate before and after carrageenan treatment. An example of the results is shown in FIGS. 1 and 2. (2) Analgesic test using Hafner's modified method DD mice were used, 10 mice per group, and 2 mg/Kg of morphine hydrochloride was administered subcutaneously to the back 30 minutes after oral administration of the test drug. 15 minutes, 30 minutes after morphine treatment
The base of each mouse was pinched with forceps for 4 minutes, 45 minutes, and 60 minutes, and the presence or absence of reactions such as turning around and biting was examined.The number of animals that did not react was considered the effective number, and The measurement value indicating the maximum effective number of animals was taken. (3) Analgesic test using acetic acid stretching method A group of 10 male DD mice weighing around 18 g were given 0.6% acetic acid at 0.1% 30 minutes after oral administration of the test drug.
ml/10g was injected intraperitoneally. After the acetic acid treatment, an observation period of 5 minutes was set from 25 minutes, during which time the presence or absence of stretching symptoms was examined, and the number of mice that did not develop stretching symptoms was determined as the effective number of mice. An example of the results of the analgesic test according to (2) and (3) is shown in Table 1.

[Table] (4) Acute toxicity test A test compound dissolved or suspended in a 0.5% CMC aqueous solution was orally administered to 5 to 10 ICR male mice (approximately 4 weeks old) per group. LD ₅₀ was determined from the mortality rate up to that time. An example of the results is shown in Table 2.

[Table] As is clear from the above animal experiments, the compound of the present invention has excellent anti-inflammatory and analgesic effects, and is therefore effective against various redness, fever, swelling, and pain, as well as rheumatism and arthritis. For the accompanying inflammation,
Anti-inflammatory and therapeutic agents useful for treating acute or chronic pain, pain associated with inflammation, trauma, lower back pain, and various other symptoms.
It is a painkiller. The compound of the present invention can be made into a medicament by combining with a suitable pharmaceutical carrier or diluent, and can be formulated into a solid, semisolid, liquid or gaseous dosage form for oral or parenteral administration by a conventional method. Can be prescribed. For formulation, the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and the compounds of the present invention may be used alone or in appropriate combinations, or in combination with other pharmaceutically active ingredients. It can also be used as a medicine. for oral administration, at least one excipient;
For example, using starch, lactose, sucrose, mannitrate, carboxymethyl cellulose, etc.
It can be formulated into capsules, powders, powders, granules, etc. In addition to the above-mentioned excipients, this type of preparation may optionally contain:
For example, magnesium stearate, sodium lauryl sulfate, lubricants such as talc, dextrin,
Binders such as crystalline cellulose, polyvinylpyrrolidone, gum arabic, corn starch, and gelatin, and disintegrants such as potato starch and carboxymethyl cellulose can be used.
It can also be administered as a suspension, emulsion, syrup, or elixir, and these dosage forms may contain flavoring agents and coloring agents. Parenteral preparations can be sterile aqueous or non-aqueous solutions or suspensions for injection. As a diluent, distilled water for injection, physiological saline, aqueous dextrose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, etc. can generally be used. Furthermore, isotonizing agents, solubilizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate. In the case of this type of dosage form, in the form of a sterile solid composition,
It may also be in a dosage form that can be dissolved in sterile water or other sterile injectable medium at the time of use. Other parenteral preparations can be made into creams, ointments, poultices, or suppositories by mixing with suitable bases. Furthermore, the compound of the present invention can be formulated into an aerosol in the form of a liquid or fine powder together with a gas or liquid propellant, and if desired, auxiliary agents such as wetting agents and dispersants may be added. The preferred dosage of the compound of the present invention is to
Although it varies depending on the administration method, administration period, etc., in order to obtain the desired effect, it is generally preferable to orally administer 0.1 to 2.5 g of the compound of the present invention per day to adults, and contain an appropriate amount of the compound of the present invention. 1 unit dosage
One to several units can be administered per day. In the case of parenteral administration (for example, injection), the daily dose is preferably at a dose level of 1/3 to 1/10 of the above-mentioned dose. Examples of formulations of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below, but the present invention is not limited thereto. Prescription example 1 (tablet) Ingredients per tablet (mg) Compound of the present invention 100 Lactose 130 Corn starch 60 Magnesium stearate 10 Total 300mg Prescription example 2 (Capsule) Ingredients per capsule (mg) Compound of the present invention 50 Milk Sugar 250 Total 300mg Prescription example 3 (injection) per ml of ingredient (mg) Compound of the present invention 10 Sodium chloride Appropriate amount Distilled water for injection Appropriate amount Total amount 1ml Prescription example 4 (ointment) Component weight (g) Invention Compound 1 Emulsified wax 30 White petrolatum 50 Liquid paraffin 20 Total 101g Prescription example 5 (Suppositories) Per unit of component (mg) Compound of the present invention 20 Cocoa butter 1980 Total 2000mg Prescription example 6 (Aerosol) Component weight (%) ) Compound of the present invention 1 Isopropyl myristate 1 Dichlorodifluoromethane 39 Dichlorotetrafluoroethane 59 Total 100%

[Brief explanation of the drawing]

FIGS. 1 and 2 are graphs showing the anti-inflammatory effects of the compounds of the present invention.

Claims (1)

[Scope of Claims] 1. A benzoylaminophenylcarboxylic acid derivative represented by the following general formula () and a pharmaceutically acceptable salt thereof. (In the formula, X ₁ is halogen, X ₂ is hydrogen or halogen, A is a direct bond, alkylene having 1 to 5 carbon atoms or alkenylene having 2 to 5 carbon atoms,
R ₁ is hydrogen, alkyl having 1 to 8 carbon atoms, cycloalkyl-substituted alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 6 carbon atoms, and R ₂ is hydrogen Or it represents an alkyl group having 1 to 8 carbon atoms. ) 2 A compound represented by the general formula () and React with a compound represented by the general formula (), The following general formula () is characterized by hydrolyzing the compound obtained as desired and further converting it into a salt.
A method for producing a benzoylaminophenylcarboxylic acid derivative and a pharmaceutically acceptable salt thereof. (In the formula, X ₁ is halogen, X ₂ is hydrogen or halogen, A is a direct bond, alkylene having 1 to 5 carbon atoms or alkenylene having 2 to 5 carbon atoms,
R ₁ is hydrogen, alkyl having 1 to 8 carbon atoms, cycloalkyl-substituted alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 6 carbon atoms, R ₂ is hydrogen or Alkyl having 1 to 8 carbon atoms and X ₃ represent halogen. ) 3 An anti-inflammatory analgesic agent containing at least one benzoylaminophenyl carboxylic acid derivative represented by the general formula () or a pharmaceutically acceptable salt thereof as an active ingredient. (In the formula, X ₁ is halogen, X ₂ is hydrogen or halogen, A is a direct bond, alkylene having 1 to 5 carbon atoms or alkenylene having 2 to 5 carbon atoms,
R ₁ is hydrogen, alkyl having 1 to 8 carbon atoms, cycloalkyl-substituted alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 6 carbon atoms, and R ₂ is hydrogen Or it represents an alkyl group having 1 to 8 carbon atoms. ) 4. The anti-inflammatory analgesic agent according to claim 3, which is in the form of a tablet. 5. The anti-inflammatory analgesic agent according to claim 3, which is in the form of a capsule. 6. The anti-inflammatory analgesic agent according to claim 3, which is in the form of an injection. 7. The anti-inflammatory analgesic agent according to claim 3, which is in the form of an ointment. 8. The anti-inflammatory analgesic agent according to claim 3, which is in the form of a suppository. 9. The anti-inflammatory analgesic agent according to claim 3, which is in an aerosol form.