JPH0153266B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2-amino-3-[hydroxy(phenyl)methyl]phenylacetic acid, its metal salts, hydrates, esters, and amides, which have pharmacological activity in warm-blooded animals.

2-amino-3-(5 or 6)benzoylphenylacetic acid, its esters, metal salts, and hydrates having anti-inflammatory activity are disclosed in US Pat. Nos. 4,045,576 and 4,126,635.
It is disclosed in the specification of No.

South African Patent No. 6814682 generally discloses benzoyl phenyl acetamides having various substituents at undefined positions on the phenyl ring. All of the specific compounds disclosed therein are aminophenylacetamides.

The compound of the present invention is represented by the following general formula 2-
Amino-3-(hydroxy(phenyl)methyl)
Phenyl acetic acid, its metal salts, hydrates, esters,
It is an amide.

(wherein R ¹ is H, R ² is OH or OM, M is a pharmaceutically acceptable cation or a part thereof when the cation is polyvalent, and Am is a primary amino ( -NH ₂ ), X is H or a halogen substituted at the 5-position, Y is H or a halogen, and n is 1. Furthermore, the present invention described in the claims above Although outside the scope, each substituent in the formula may be in the following cases in addition to the above: R ¹ is lower alkyl, R ² is -O-lower alkyl or -NR ³ R ⁴ and R ³ and R ⁴ are H, lower alkyl, cycloalkyl,
phenyl, lower alkyl, lower alkoxy,
phenyl substituted with halogen or trifluoromethyl, or R ³ and R ⁴ may be combined with adjacent atoms to form a heterocyclic residue; Am is dimethylamino; is halogen, lower alkyl or trifluoromethyl substituted at position other than the 5-position, Y is lower alkyl, lower alkoxy, trifluoromethyl or methylthio, n is 2 or 3, and in this case Y may or may not be the same. This is a case where it is okay to be different. The following description in the Detailed Description of the Invention section refers to R ¹ , R ² , Am, X,
It should be noted that this also includes compounds in which at least one of Y and n represents each of the above-mentioned substituents or numbers that are not included in the scope of the present invention described in the claims.

The meanings of the terms used in this specification are as follows.

"Lower alkyl" is a straight or branched chain group having up to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, S-butyl, t-butyl, amyl, isoamyl, hexyl, heptyl, octyl, etc. This is exemplified by the following group. "Lower alkoxy" is represented by the formula: -O-lower alkyl.

"Cycloalkyl" is a primary cyclic alkyl having 3 to 9 Cs, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and the like.

"Halogen" is F, Cl, Br, I, preferably F, Cl, Br.

"Heterocyclic group" includes groups such as morpholino, pyrrolidino, piperidino, piperazino, and the like.

The "pharmaceutically acceptable cation" that forms the salt of the acid and its hydrate may be any metal cation that is acceptable for internal administration in warm-blooded animals, including Na, K,
Examples include Ca, Mg, Zn, Cu, Al and water of hydration. Na cations are preferred.

The anti-inflammatory activity of Sancilio L.F.
(Sancilio L.F.)'s modified Evans-Blue Karagenan footpad edema exudation assay was demonstrated in experimental animals.

The compound also has uses as an antipyretic, analgesic, and as a platelet aggregation inhibitor.

Preferred compounds because of their anti-inflammatory activity are those represented by the following general formula-1.

(wherein R ¹ is H or methyl; R ² is OH, OM or O-lower alkyl; Am is NH ₂ or dimethylamine; X is H, halogen, lower alkyl or trifluoromethyl; Y is H, halogen, lower alkyl, lower alkoxy, trifluoromethyl or -S-lower alkyl; M is a pharmaceutically acceptable cation or a part thereof when the cation is polyvalent; n is 1 to 3.) Therefore, the novel 2-amino-3-[hydroxy(phenyl)methyl]phenylacetic acid, its metal salt,
The first aspect of the present invention is to provide hydrates, amides, and esters.
This is the purpose of

The second purpose is to use 2-amino-3-[hydroxy(phenyl)methyl]phenylacetic acid and its derivatives and pharmaceutical compositions thereof to reduce inflammation in the body of living animals, especially mammals. Providing a new method for treatment.

Other purposes will be revealed in due course.

The 2-amino-3-[hydroxy(phenyl)
Methyl]phenylacetic acid and its metal salts, esters,
As shown in the following reaction formula, most of the amides, except for the exceptions mentioned below, are derived from the starting material 2-amino-3.
-benzoylphenylacetic acid, salt, ester, prepared by reducing the carbonyl moiety of the amide from Pd/C by hydrogenation with NaBH ₄ .

(In the formula, R ¹ , R ₂ .XY, Am, and n are as defined above.) When R ² in the formula is OH, cyclization occurs by hydrogenation with Pd/C. In this case, the stoichiometric amount is 2
Just use twice the amount of NaBH ₄ . However, the salt (OM) converts R ² into its equivalent in basic solution,
It is then preferably hydrogenated with Pd/C-hydrogen and then carefully acidified with a weak acid such as acetic acid.
The above is expressed by the following reaction formula.

Heating to temperatures above about 30°C results in loss of hydroxyl groups to yield phenylmethyl derivatives.

A compound in which X or Y is halogen is
Since halogen is lost in Pd/C hydrogenation,
It is prepared from a suitable precursor of the formula by reduction with _NaBH4 .

When Y in the formula is -S-lower alkyl, the S-lower alkyl group is lost upon hydrogenation. Therefore, the process represented by the following reaction scheme starting from a compound in which Y is F is preferred for the preparation of compounds in which Y is -S-lower alkyl.

(In the formula, R ¹ , X, and Am are as defined above. R ²
is OM, -O-lower alkyl or -NR ³ R ⁴ ) The following method can be used to prepare compounds where R ² is OH.

(In the formula, R ¹ , X, Am, and M are as defined above.) Formulas a to g are included in the formula.

In the starting material, R ² in the formula is OH, OM or -O-
Lower alkyl and Am is _-NH2 or dimethylamino are prepared as described in US Pat. No. 4,045,576. Among the starting materials, those in which R ² is -NR ³ R ⁴ are prepared according to the following reaction scheme as disclosed in US Patent Application No. 078,860, filed September 26, 1909.

^{( wherein , _} A compound of formula b where Am is dimethylamino can be prepared by reacting a compound of formula b where Am is NH ₂ with formaldehyde and cyanoborohydride.

Preparations 1-29 are illustrative of the preparation of compounds of formula b and intermediates thereof.

Production example 1 4-[2-(methylthioacetyl)]morpholine 40.2 g (0.3 mol) of ethyl methylthioacetate and
A mixture with 130 g (1.5 mol) of morpholine was heated at reflux for 70 hours. 45g by fractional distillation under reduced pressure
(86%) product (bp104-105℃/0.05mmHg)
was obtained in the second distillation.

Analysis: Calculated value (C ₇ H ₁₃ NO ₂ S):
C, 47.98; H, 7.48; N, 7.99 Measured value: C, 47.55; H, 7.59; N, 8.18 Production example 2 2-Methylthio-N-methylacetamide 134 g (1.0 mol) of ethyl methylthioacetate and
A mixture with 310 g (10.0 mol) of methylamine
Heated in a bomb at 150°C for 72 hours. Excess amine and produced ethanol were distilled off and the remaining dilute syrup was distilled to yield 112 g (94%) of the title compound as a colorless liquid (bp 76-78°C/0.4 mmHg).

Analysis: Calculated value (C ₄ H ₉ NOS):
C, 40.31; H, 7.61; N, 11.75 Measured value: C, 39.78; H, 7.69; N, 11.88 Production example 3 2-Methylthio-N,N-dimethylacetamide 134 g (1.0 mol) of ethyl methylthioacetate and
A mixture with 360 g (8.0 mol) of dimethylamine
Heated in a bomb at 150°C for 90 hours. Excess amine and produced ethanol are distilled off, and the residue is distilled.
129 g (97%) of the title compound was converted into a clear colorless liquid (b.
p.76-77℃/0.5mmHg).

Analysis: Calculated value (C ₅ H ₁₁ NOS):
C, 45.08; H, 8.32; N, 10.51 Measured value: C, 43.88: H, 8.41; N, 10.60 Production example 4 2-(2-propylthio)acetamide 46.7 g (0.5 mol) of 2-chloroacetamide was added to 200 ml of Mix in anhydrous ethyl alcohol and slowly add 2-propanethiol [38.1g]
(0.5 mol)] of absolute ethyl alcohol (100 ml)/
A solution of 50% NaOH in water (40 g) was added.
Heated at reflux for 1 hour and then filtered. The liquid was concentrated under reduced pressure, and the residue was dissolved in methylene chloride and dried over magnesium sulfate. The solution was concentrated again. When left alone, the syrupy residue crystallized.
Recrystallized from isopropyl ether to give 59.0g (89
%) mp. of 52-54°C was obtained.

Analysis: Calculated value (C ₅ H ₁₁ NOS):
C, 45.08; H, 8.32; N, 10.51 Measured value: C, 45.05; H, 8.32; N, 10.55 Production Example 5 2-(1-Propylthio)acetamide Using the method of Production Example 4 instead of 2-propanethiol, etc. Using a molar amount of 1-propanethyl
61.2g (92%) of the title compound was obtained. white crystals
Melted at 49.5-51.0°C.

Analysis: Calculated value (C ₅ H ₁₁ NOS):
C, 45.08; H, 8.32; N, 10.51 Measured value: C, 44.97; H, 8.24; N, 10.40 Production example 6 2-amino-3-benzoyl-5-chloro-2
-(Methylthio)phenylacetamide 2-amino-5-chlorobenzophenone [12.77 g (0.055 mol)] in methylene chloride (300 ml)
To a cold (-70°C) solution (under nitrogen) was added 6.0 g (0.0552 moles) of t-butyl hypochlorite in 20 ml of methylene chloride. After stirring for an additional 15 minutes, a suspension of α-(methylthio)acetamide [5.8 g (0.055 mol)] in methylene chloride (150 ml) was added. −
Stirred at 65°C for 1 hour. Triethylamine [5.6
g (0.055 mol)] and left to warm to room temperature.
Extracted several times with water and dried the organic layer over magnesium sulfate. The volume was reduced in vacuo to approximately 200ml and the product crystallized out as a yellow solid. mp173.5~174.5
℃; Yield 6.86g (37.3%) Analysis: Calculated value (C ₁₆ H ₁₅ N ₂ O ₂ SC ₁ ):
C, 57.40; H, 4.52; N, 8.37 Measured value: C, 57.38; H, 4.50; N, 8.51 Production example 7 2-amino-3-benzoyl-α-(methylthio)phenylacetamide 2-amino-benzophenone [ 95% t-butyl hypochlorite [11.5 g (0.10 mol)] in methylene chloride (30 ml) in a cold (-70°C) solution (under nitrogen atmosphere) of 19.7 g (0.10 mol)] in methylene chloride (300 ml). The solution was added, and after 10 minutes, methylthioacetamide [10.5 g (0.1 mol)] was added to tetrahydrofuran (300
ml) solution was added. During these additions, the temperature was -55℃
Maintained below. After a further 1 hour at -60°C, the mixture was allowed to cool to room temperature and the precipitate was collected. the precipitate
Make a slurry in 200 ml of methylene chloride, 11
g (0.11 mol) of triethylamine was added. 5
Stir for a minute. After washing twice with 100 ml of water, the organic phase was dried over Mg sulfate and concentrated under reduced pressure. The residue was washed with diethyl ether and dried to yield 13.0 g (43%) of a pale yellow powder (mp 153-155°C).

Analysis: Calculated value (C ₁₆ H ₁₆ N ₂ O ₂ S):
C, 63.98; H, 5.37; N, 9.33 Measured value: C, 63.64; H, 5.39; N, 9.25 Production example 8 2-amino-3-(4-chlorobenzoyl)-
α-(phenylthio)phenylacetamide 2-amino-4′-chlorobenzophenone [34.6
17.3 g (0.15 mol) of 95% t-butyl hypochlorite was added to a medium-cold (-70°C) solution of 100 g (0.15 mol)] of methylene chloride (500 ml), and then, after 10 minutes, phenylthioacetamide [25.0 g (0.15 mol)] in tetrahydrofuran (400 ml) was added over 20 minutes.
The temperature was maintained below -64°C during these additions. 2
After an hour, 20 g (0.2 mol) of triethylamine was added and the mixture was allowed to warm to room temperature. Concentrated and the residue was partitioned between water and methylene chloride. Remove insoluble matter from each phase, wash with 20% ethanol aqueous solution, and dry for 36 hours.
g (61%) of pale yellow powder (mp 189-191°C) was obtained.

Analysis: _{Calculated value ( C21H17N2O2SC1 )} :
C, 63.55; H, 4.32; N, 7.06 Measured value C, 63.73; H, 4.36; N, 7.16 Production example 9 4-[2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetyl [Morpholine] A solution of 2-aminobenzophenone [9.9 g (0.05 mol)] and 4-(α-methylthio)acetylmorpholine [8.8 g (0.05 mol)] in methylene chloride (200 ml) at -65°C) 95% hypochlorous acid t
A solution of -butyl [5.8 g (0.05 mol)] in methylene chloride (20 ml) was added dropwise. After an additional hour at -60°C, 5.1 g (0.05 mol) of triethylamine was added and the mixture was allowed to cool to room temperature. Wash twice with 100ml of water,
It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed (600 g of silica gel; eluting first with diisopropyl ether and finally with 10% acetone in diisopropyl ether). The eluate was concentrated, and the residue was dissolved in 150 ml of ethanol and poured into 400 ml of water. Collect insoluble solids,
Crystallized from diethyl ether and dried. Yield: 12.3g (62%) of yellow crystals (mp 119-121℃)
It was.

Analysis: _{Calculated value} ( _C20H22N2O3S ) _:
C, 64.84; H, 5.99; N, 7.56 Measured value: C, 65.01; H, 5.99; N, 7.57 Production example 10 2-amino-3-benzoyl-5-chloro-α
-[(4-chlorophenyl)thio]phenylacetamide 2-amino-5-chlorobenzophenone [20g
(0.0863 mol)] in methylene chloride (500 ml) in a cold (-70°C) solution (under nitrogen atmosphere) of hypochlorous acid t.
A solution of -butyl [9.48 g (0.088 mol)] in methylene chloride (50 ml) was added. After stirring for another 15 minutes, α-
(4-chlorophenylthio)acetamide [17.35
g (0.0863 mol)] in a 50/50 tetrahydrofuran/methylene chloride mixture (500 ml) was added. −
The mixture was stirred at 70° C. for 2 hours, 8.72 g (0.0863 mol) of triethylamine was added, and the mixture was allowed to warm to room temperature over 2 hours. Extracted several times with water and dried the organic layer over magnesium sulfate. The capacity was reduced to approximately 500ml. Methylene chloride (500ml) was added to precipitate the product.
After filtering and drying, it was 16.62g (44.7%).

This yellow solid melted at 198-200°C.

Analysis: _{Calculated value} ( _{C21H16N2O2SCl2 ) :}
C, 58.48; H, 3.74; N, 6.49 Measured value: C, 58.49; H, 3.77; N, 6.67 Production example 11 2-amino-3-benzoyl-5-chloro-α
-(Phenylthio)phenylacetamide 2-amino-5-chlorobenzophenone (80.72 g (0.349 mol)) in methylene chloride (1.5)
Tert-butyl hypochlorite [39.1
g (0.360 mol)] was added. α- after stirring for 10 minutes
A solution of (phenylthio)acetamide [59.1 g (0.354 mol)] in tetrahydrofuran (1.5 mol) was added. Stir at -65℃ for 1.25 hours, 37.5g (0.371mol)
of triethylamine was added and allowed to warm to room temperature. It was extracted several times with water, and the organic layer was dried over anhydrous sodium sulfate. The volume was reduced in vacuo and the precipitated yellow solid was recrystallized from acetonitrile to give a yellow crystalline solid (mp 190-191°C (decomposed)).

_Analysis : _{Calculated value} ( _{C21H17N2O2SCl} ):
C, 63.55: H, 4.32; N, 7.06 Measured value: C, 63.62; H, 4.29; N, 7.08 Production Example 12 2-Amino-3-benzoyl-2-(phenylthio)phenylacetamide By the method of Production Example 11 The title compound was obtained in 57% yield by using an equimolar amount of 2-aminobenzophenone in place of 2-amino-3-chlorobenzophenone. After recrystallization from methylene chloride/diethyl ether/hexane, it melted at 153-154°C.

Analysis: _{Calculated value} ( _{C21H18N2O2S )} :
C, 69.59; H, 5.01; N, 7.73 Measured value: C, 69.33; H, 5.00; N, 7.76 Production example 13 2-amino-3-benzoyl-α-(methylthio)-N-methylphenylacetamide 2- A solution of aminobenzophenone (29.6 g (0.15 mol)) in methylene chloride (350 ml) was cooled to -70°C, and a solution of 2-methylthio-N-methylacetamide (7.9 g (0.15 mol)) in methylene chloride (20 ml) was cooled to -70°C. ]
added. A solution of 95% t-butyl hypochlorite [17.2 g (0.15 mol)] in methylene chloride (30 ml) was added dropwise to the resulting mixture (-70°C). The temperature was maintained below -65°C for 1.5 hours, then 15.1 g (0.15 moles) of triethylamine was added rapidly. It was left to stand at room temperature and washed with water. After concentration, the residue crystallized upon mixing with isopropyl ether. Recrystallization from isopropyl alcohol gave 31 g (65%) of yellow needles (mp 149.0-150.0°C).

Analysis: Calculated value (C ₁₇ H ₁₈ N ₂ O ₂ S):
C, 64.94; H, 5.77; N, 8.91 Measured value: C, 65.24; H, 5.83; N, 8.99 Production example 14 2-amino-3-benzoyl-α-(methylthio)-N,N-dimethylphenylacetamide A solution of 2-aminobenzophenone [29.6 g (0.15 mol)] in methylene chloride (350 ml) was cooled to -70°C, and 20.0 g (0.15 mol) of 2-methylthio-
N,N-dimethylacetamide was added. A solution of 95% t-butyl hypochlorite [17.2 g (0.15 mol)] in methylene chloride (30 ml) was added dropwise to the resulting mixture (-70°C). Maintain the temperature below -65℃ for 1.5 hours,
Then 15.1 g (0.15 mol) of triethylamine was added rapidly. It was left to come to room temperature and washed with water.
After concentration, the residue crystallized upon mixing with isopropyl ether. Recrystallized from isopropyl alcohol to give 39.8 g (81%) of light yellow crystals (mp153-
155°C).

Analysis: Calculated value (C ₁₈ H ₂₀ N ₂ O ₂ S):
C, 65.83; H, 6.14; N, 8.53 Measured value: C, 65.87; H, 6.15; N, 8.52 Production example 15 2-amino-3-(4-fluorobenzoyl)
-α-(n-propylthio)phenylacetamide A solution of 4'-fluoro-2-aminobenzophenone [21.5 g (0.1 mol)] in methylene chloride (400 ml) was cooled to -70°C, and the temperature was reduced to -66°C. 11.5g (0.1mol) of 95% hypochlorous acid while keeping lower
Butyl was added over 15 minutes. 2-n- in the generated solution
A solution of propylthioacetamide (13.3 g) in methylene chloride (50 ml) was added over 10 minutes. −65〜−
Stirred at 70°C for 1 hour, then allowed to reach 0°C, at which point 10.2g (0.1 mole) of triethylamine was added. Stir for 10 minutes and then wash with water. Dry with magnesium sulfate. Concentrate under reduced pressure,
The residue was crystallized from isopropyl alcohol and dried to give 19.5 g (56%) of yellow crystals (mp140~
142°C).

Analysis: Calculated value (C ₁₈ H ₁₉ N ₂ O ₂ SF):
C, 62.41; H, 5.53; N, 8.09 Measured value: C, 62.34; H, 5.58; N, 8.04 Production Example 16 In the same manner as Production Example 8, 2-amino-3-(2-fluorobenzoyl)
-α-(phenylthio)phenylacetamide, 2-amino-3-(4-trifluoromethylbenzoyl)-α-(phenylthio)phenylacetamide, 2-amino-3-(2,4-dichlorobenzoyl)-α -(phenylthio)phenylacetamide, 2-amino-3-(2,4-difluorobenzoyl)-α-(phenylthio)phenylacetamide, phenylthioacetamide, t-butyl hypochlorite and 2-amino- 2'-fluorobenzophenone, 2-amino-4'-trifluoromethylbenzophenone, 2-amino-2,4'-dichlorobenzophenone, 2-amino-2',4'-difluorobenzophenone Manufactured from.

Production example 17 2-amino-3-benzoyl-5-chloro-α
-(Methylthio)-N-methylphenylacetamide Add 18.05 g of 2-amino-5-chlorobenzophenone [38.3 g (0.166 mol)] to a methylene chloride (1) solution cooled to -70°C under a nitrogen atmosphere.
(0.167 mol) of t-butyl hypochlorite was added.
The mixture was stirred for 15 minutes, and then a solution of 2-methylthio-N-methylacetamide [20.3 g (0.171 mol)] in methylene chloride (100 ml) was added. Stir at -70°C for 2 hours and add 25ml of triethylamine. The mixture was allowed to reach room temperature with stirring, then extracted with water, and the organic layer was dried over magnesium sulfate. The volume was reduced to approximately 400 ml, ether was added, and the mixture was placed in a refrigerator at approximately 0°C overnight. The crystallized solid was dried under high vacuum at 50° C. for about 4 hours. The weight of the product is 31.56g (54.6%);
Melted at 170-171°C.

Analysis: Calculated value (C ₁₇ H ₁₇ N ₂ O ₂ SCl):
C, 58.53; H, 4.91; N, 8.03 Measured value: C, 58.68; H, 4.91; N, 8.13 Production example 18 3-benzoyl-2-(N-methylamine)-
α-(Methylthio)phenylacetamide The title compound was obtained by the method of Production Example 7 using an equimolar amount of 2-N-methylaminobenzophenone in place of 2-aminobenzophenone.

Production Example 19 2-Amino-3-benzoyl-5-chlorophenylacetamide 2-Amino-3-benzoyl-5-chloro-α-(methylthio)-phenylacetamide in a mixture of absolute ethanol (900 ml)/dimethylformamide (200 ml) [21.34 g (0.0639 mol)] and an excess amount of Raney N were mixed and stirred at room temperature for 45 minutes. The Raney Ni was removed by passing it through Celite. The solvent was removed in vacuo to give a yellow solid. When recrystallized, it melted at 213.5-215.0°C (decomposition).

Analysis: Calculated value (C ₁₅ H ₁₃ N ₂ O ₃ Cl):
C, 62.40; H, 4.54; N, 9.70 Measured value: C, 62.35; ) Phenylacetamide [9.7g (0.032mol)]
80 to a stirred solution in tetrahydrofuran (100 ml)
g of wet Raney-Ni (washed three times with water and three times with tetrahydrofuran) was added. Ranee Ni after 10 minutes
was removed and the liquid was concentrated in vacuo. The residue was crystallized from isopropyl alcohol to yield 6.0 g (73%) of yellow needles (mp 178.5-180.0°C).

Analysis: Calculated value (C ₁₅ H ₁₄ N ₂ O ₂ ):
C, 70.85: H, 5.55; N, 11.02 Measured value: C, 70.53; N, 5.53; N, 11.04 Production example 21 2-amino-3-(4-chlorobenzoyl)phenylacetamide 2-amino-3-( 4-chlorobenzoyl)-
To a stirred solution of α-(phenylthio)phenylacetamide [28.5 g (0.077 mol)] in tetrahydrofuran (1) was added 230 g of wet Raney Ni (washed three times with water and three times with tetrahydrofuran). After 15 minutes, concentrate the liquid under reduced pressure to 17.4g (84%)
A yellow crystalline solid was obtained. Recrystallization from isopropyl alcohol and then twice from absolute ethanol gave yellow needles (mp 212-215°C).

Analysis: Calculated value (C ₁₅ H ₁₃ N ₂ O ₂ Cl):
C, 62.40; H, 4.54; N, 9.70 Measured value: C, 62.76; H, 4.58; N, 9.83 Production example 22 4-[2-(2-amino-3-benzoylphenyl)acetyl]morpholine 4-( To a stirred solution of 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetyl]morpholine [18.5 g (0.05 mol)] in tetrahydrofuran (300 ml) was added 150 g of wet Raney Ni. 15 min. After filtering, the liquid was concentrated under reduced pressure. After recrystallizing the residue from isopropyl alcohol, 13.3
g (82%) of bright yellow crystals (mp 156.5-158.5°C) were obtained.

Analysis: Calculated value (C ₁₉ H ₂₀ N ₂ O ₃ ):
C, 70.35; H, 6.22; N, 8.64 Measured value: C, 70.24; H, 6.21; N, 8.63 Production example 23 2-amino-3-benzoyl-N-methylphenylacetamide 2-amino-3-benzoyl- α-(Methylthio)-N-methylphenylacetamide [22.5g
(0.072 mol)] in tetrahydrofuran (400 ml) was treated with 160 g of wet Raney Ni (washed three times with water and three times with tetrahydrofuran) for 10 minutes. The solution was concentrated. The residue was crystallized from isopropyl alcohol to give 17.2g (89%) of yellow needles (mp 145-146°C).

Analysis: Calculated value (C ₁₆ H ₁₆ N ₂ O ₂ ):
C, 71.62; H, 6.01; N, 10.44 Measured value: C, 71.76; H, 6.05; N, 10.52 Production example 24 2-amino-3-benzoyl-N,N-dimethylphenylacetamide 2-amino-3- Benzoyl-α-(methylthio)-N,N-dimethylphenylacetamide [33.0 g (0.1 mol)] in tetrahydrofuran (500
ml) solution was treated with 240 g of wet Raney Ni (washed three times with water and three times with tetrahydrofuran) for 10 minutes. The solution was concentrated. The residue was crystallized from isopropyl alcohol to give 27.2g (96%) of yellow needles (mp 123-124°C).

Analysis: Calculated value (C ₁₇ H ₁₈ N ₂ O ₂ ):
C, 72.32; H, 6.43; N, 9.92 Measured value: C, 72.34; H, 6.42; N, 9.98 Production example 25 2-amino-3-(4-fluorobenzoyl)
Phenylacetamide 2-amino-3-(4-fluorobenzoyl)
-A solution of α-(n-propylthio)phenylacetamide [24.2 g (0.07 mol)] in tetrahydrofuran (300 ml) was mixed with 250 g of wet Raney Ni (3 times with water,
(washed three times with tetrahydrofuran).
Stir for 1 hour and filter. The liquid was concentrated in vacuo and the residue was recrystallized from 95% ethyl alcohol to give 14.8
g (78%) of yellow needles (mp 184-186°C) were obtained.

Analysis: Calculated value (C ₁₅ H ₁₃ N ₂ O ₂ F):
C, 66.17; H, 4.81; N, 10.29 Measured value: C, 66.32; H, 4.81; N, 10.48 Production example 26 In the same manner as in Example 2, 2-amino-3-(2-fluorobenzoyl)
Phenylacetamide, 2-amino-3-(2,4-dichlorobenzoyl)phenylacetamide, 2-amino-3-(2,4-difluorobenzoyl)phenylacetamide, 2-amino-3-(4-tri fluoromethylbenzoyl)phenylacetamide, 2-amino-3-(2-fluorobenzoyl)
-α-(phenylthio)phenylacetamide, 2-amino-3-(2,4-dichlorobenzoyl)-α-(phenylthio)phenylacetamide, 2-amino-3-(2,4-difluorobenzoyl)-α -(phenylthio)phenylacetamide, produced from 2-amino-3-(4-trifluoromethylbenzoyl)-α-phenylthio)phenylacetamide.

Production example 27 2-amino-3-benzoyl-5-chloro-N
-Methylphenylacetamide 2-amino-3-benzoyl-5-chloro-α
A solution of -(methylthio)-N-methylacetamide [28.33 g (0.081 mol)] in tetrahydrofuran (1) was treated with excess Raney Ni at room temperature for 2 hours. I spent it on Celite. The Raney Ni residue was washed with acetone, and the washing liquid was filtered. The organic liquid was dried over magnesium sulfate and reduced to approximately 300 ml.
Excess ether was added and left at room temperature for 1 hour, then refrigerated overnight. Once the yellow solid is collected and dried
It weighed 20.94g (85.68%) and melted at 179-180°C.

Analysis: Calculated value (C ₁₆ H ₁₅ N ₂ O ₂ C1):
C, 63.48; H, 4.99; N, 9.25 Measured value: C, 63.44; H, 4.99; N, 9.27 Production Example 28 3-benzoyl-2-(N-methylamino)phenylacetamide 3 by the method of Production Example 20 -benzoyl-2-(N-
methylamino)-α-(methylthio)phenylacetamide to 2-amino-3-benzoyl-α-
(Methylthio)phenylacetamide was used to obtain the title compound.

Production example 29 3-benzoyl-2-(N,N-dimethylamino)phenylacetamide A solution of 2-amino-3-benzoylphenylacetamide [12.7 g (0.05 mol)] in acetonitrile (150 ml) was added to 16 ml (0.2 mol). of 37% formalin, 6.4 g (0.1 mol) of sodium cyanoborohydride, and 2 ml of glacial acetic acid four times with a 15 minute stirring period between each treatment. Finally rare NaOH
and extracted three times with diethyl ether.
The ether extracts were combined, dried over magnesium sulfate, and concentrated. The product was isolated by column chromatography.

The following examples are illustrative of the invention.

Example 1 2-Amino-3-[hydroxy(phenyl)methyl]phenylacetic acid-hydrate (1:1) Sodium 2-amino-3-benzoylphenylacetate dihydrate [2 g (0.0072)] Water (25ml)
25 ml of 3NNaOH then 0.285 g into a medium stirring solution
(0.0075 mol) of _NaBH4 was added. The resulting yellow solution was stirred for 18 hours (during which time the color of the solution became considerably lighter). It was filtered, cooled, and slowly neutralized with glacial acetic acid. The white precipitate obtained was 1.3g (65%)
It was hot. mp: Sintered at 115℃, melted at 160℃.

Analysis: Calculated value (C ₁₅ H ₁₇ NO ₄ ):
C, 65.44; H, 6.22; N, 5.09 Measured value: C, 65.13; H, 6.21; N, 5.08 Example 2 Sodium 2-amino-3-[hydroxy(phenyl)methyl]phenylacetate 2-amino-3- A solution of sodium benzoylphenylacetate monohydrate (14.8 g (0.05 mol)) in tap water (250 ml) was hydrogenated over 10% Pd/C at ambient temperature overnight. It was filtered through Celite, and the liquid was concentrated under reduced pressure. A white solid was obtained by treating the residue three times with 50 ml each of absolute ethanol. This solid was recrystallized from methanol/diethyl ether and ethanol/water to yield 7.0 g (53%) of a white solid (mp 273°C).

Analysis: Calculated value (C ₁₅ H ₁₄ NO ₃ Na):
C, 64.51; H, 5.05; N, 5.02 Measured value: C, 64.37; H, 5.07; N, 5.03 Example 3 2-amino-5-chloro-3-[hydroxy(phenyl)methyl]phenylacetic acid 2-amino To a stirred solution of sodium -3-benzoyl-5-chlorophenylacetate [12.58 g (0.04 mol)] in water (100 ml) was added 100 ml of 3NaOH followed by 1.6
g (0.04 mol) of _NaBH4 was added. The mixture was stirred for 3 hours until it became a clear orange solution. Neutralized with acetic acid (foaming). Excess acetic acid was added to cause precipitation, and the precipitate was collected, washed with water, and dried. A cream colored solid [10.2 g (79%), mp 134°C (decomposed)] was obtained.

Analysis: Calculated value (C ₁₅ H ₁₄ ClNO ₃ ):
C, 61.76; H, 4.84; N, 4.80 Measured value: C, 61.69; H, 4.81: N, 4.76 Example 4 Sodium 2-amino-3-[hydroxy(4-chlorophenyl)methyl]phenyl acetate hydrate (4:1) Sodium 2-amino-3-(4-chlorobenzoyl)phenylacetate [9.0 g (0.029 mol)] was mixed in water (200 ml)/2% NaOH aqueous solution (100 ml), filtered through Celite, The solution was treated with 1.1 g (0.03 mol) NaBH ₄ . Stir at ambient temperature for 3 hours and pass again through Celite. The liquid was acidified with glacial acetic acid (foaming). The white solid produced was collected and washed with water. This solid was mixed with water (150 ml)/NaON [1.1
g (0.03 mol)] with stirring. The solution was titrated with a 15% hypochlorous acid solution until the pH reached 8.5. After standing overnight at ambient temperature, pass through Celite.
The liquid was concentrated under reduced pressure. The residue was crystallized using absolute ethanol to obtain a white solid. After recrystallizing from water and drying, it weighed 4.2 g (47%) [mp 138°C (decomposed)].

Analysis: Calculated value (C ₁₅ H ₁₃ ClNO ₃ Na・1/4H ₂ O):
C, 56.60; H, 4.28; N, 4.42 Measured value: C, 56.62; H, 4.28; N, 4.40 Example 5 Sodium 2-amino-3-benzoyl-5-chlorophenylacetate dihydrate by the method of Example 1 In place of equimolar amounts of sodium 2-amino-3-benzoyl-5-chlorophenylacetate, sodium 2-amino-3-(4-chlorobenzoyl)phenylacetate hydrate, 2-amino-3-( 4-chlorobenzoyl) ethyl phenyl acetate, 2-amino-3-(4-fluorobenzoyl)
Using sodium phenylacetate, 2-amino-3-[hydroxy(phenyl)methyl]-5-chlorophenylacetic acid, 2-amino-3-[hydroxy(4-chlorophenyl)methyl]phenylacetic acid, 2-amino-3 -[hydroxy(4-chlorophenyl)methyl]ethyl phenyl acetate, 2-amino-3-[hydroxy(4-fluorophenyl)methyl] phenyl acetate, were obtained.

Example 6 In the method of Example 2, instead of sodium 2-amino-3-benzoylphenylacetate monohydrate, equimolar amounts of ethyl 2-amino-3-benzoylphenylacetate, 2-amino-3- Using methyl benzoylphenylacetate, 2-amino-3-benzoylphenylacetate potassium hydrate, ethyl 2-amino-3-[hydroxy(phenyl)methyl]phenylacetate, 2-amino-3-[hydroxy (Phenyl)methyl]methyl phenyl acetate, 2-amino-3-[hydroxy(phenyl)methyl] phenyl acetate, were obtained.

The present invention also encompasses novel compositions containing the compounds of the present invention as active ingredients. Any of the pharmacologically active compounds described above may be administered in effective amounts in any of a variety of ways, for example as capsules or tablets, parenterally in the form of a sterile solution or suspension, and optionally. can be administered in vivo via intravenous injection in the form of a sterile solution. In preparing the novel compositions of this invention, the active ingredient is incorporated into a suitable carrier, such as a pharmaceutical carrier. Suitable pharmaceutical carriers useful in formulating the compositions of this invention include starch, gelatin, glucose, magnesium carbonate, lactose, malt, and the like. Liquid compositions are also within the scope of this invention; suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerin, glucose syrup, and the like.

The pharmacologically active compounds of this invention are advantageously used in unit dosages of 0.1 to 250 mg or more, depending on the size of the subject animal. For example, large animals such as horses may require tablets containing 500-1000 mg of active ingredient. The unit dosage may be administered an appropriate number of times daily to give a daily dose of 0.3 to 450 mg. A unit dosage of 5 to 25 mg appears optimal.

It is only necessary that the active ingredient occupies an effective amount, ie, that a suitable effective amount is obtained in the dosage form used. The exact individual dosage and daily dose will, of course, be determined according to standard medical principles according to the instructions of the physician or veterinarian.

The active ingredients of the invention may be combined with other pharmacologically active agents for administration, or with buffers, antiacids, etc., and the proportion of active ingredients in the composition can vary within a wide range. .

The following are examples of compositions formed according to the present invention.

1 Capsules Capsules containing 5 mg, 25 mg and 50 mg of active ingredient per capsule were produced. The increase in the amount of active ingredient was adjusted with the amount of lactose. Typical Blend mg/Capsule for Capsule Filling Active Ingredients 5.0 Lactose 296.7 Starch 129.0 Magnesium Stearate 4.3 Total 435.0 mg Preferred capsule formulations with increased active ingredient content were as follows. Ingredients mg/capsule Active Ingredients 25.0 Lactose 306.5 Starch 99.2 Magnesium Stearate 4.3 Total 435.0 mg In each case, the selected active ingredients were uniformly blended with lactose, starch, magnesium stearate, and the resulting blend was filled into capsules.

2 Tablets A typical formulation for tablets containing 5.0 mg of active ingredient per tablet is as follows. This example formulation could be used with other active ingredients by adjusting the amount of dicalcium phosphate.

mg/tablet (1) Active ingredient 5.0 (2) Cornstarch 13.6 (3) Cornstarch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9 170.1mg Ingredients (1), (2) ), (4), and (5) were uniformly blended. Component (3) was prepared as a 10% paste in water. The resulting blend was granulated with this starch paste and the resulting wet mass was passed through an 8 mesh screen. The wet granules were dried and sized using a 12 mesh screen. The dry granules were blended with calcium stearate and compressed into tablets.

3 2% sterile solution for injection per c.c. Active ingredient 20 mg Preservative (e.g. chlorobutanol)
0.5W/V% water for injection The residual solution was prepared, clarified by filtration, filled into vials, sealed, and autoclaved.

Various alterations, modifications, equivalents, and equivalent means of the present invention will be apparent to those skilled in the art without departing from the spirit or scope of the invention.
You can do them in a way.

Claims (1)

[Claims] 1. General formula: (wherein R ¹ is H, R ² is OH or OM, M is a pharmaceutically acceptable cation or a part thereof when the cation is polyvalent, and A _n is a primary amino acid. (-NH ₂ ), X is H or halogen, Y is H or halogen, n is 1) and its hydrate. 2 2-amino-3-[hydroxy(phenyl)
methyl] phenyl acetic acid hydrate (1:1),
A compound according to claim 1. 3 2-amino-3-[hydroxy(phenyl)
The compound according to claim 1, which is sodium methyl]phenylacetate. 4. The compound according to claim 1, which is 2-amino-5-chloro-3-[hydroxy(phenyl)methyl]phenylacetic acid. 5. The compound according to claim 1, which is sodium 2-amino-3-[hydroxy(4-chlorophenyl)methyl]phenyl acetate hydrate (4:1).