Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
:~ '
AHR- ~589
1 156B55
2 -AMI~0-3-[ HYDROXY( PHE~YL) l!fETHYL~
PHENYI~CETIC ACIDS, ESTERS AND AMIDES
1. FIELD OF INVENTION
The present invention relates to 2-amino-3-
thydroxy(phenyl)methyl~phenylacetic acids, metal salts and
hydrates thereof, esters and amides which have pharmacological
activity in warm-blooded animals and pharmaceutical methods
and compositions utilizing the same.
2. DESCRIPTION OF THE PRIOR ART
2-Amino-3-(5 and 6)benzoylphenylacetic acids,
esters, metal salts and hydrates having anti-inflammatory
activity are disclosed in U. S. Pat~nts 4,045,576 and
4,126~6~5.
South African patent 68/4682 discloses benzoyl-
phenylacetamides generically having a variety of substituents
in indefinite positions on phenyl. ~one of the specific
compounds disclosed therein are aminophenylacetamides.
OBJECTS A~D SUMM?,RY OF THE I~VENTION
The compounds of the present invention are 2-amino-3-
rhydroxy~phenyl)methyl]phenylacetic acids~ metal salts and
hydrates thereof, esters and amides illustrated generally
by the following formula: R1
X~ 1H_C_R2
~ Am
2 5 H-C-OH
Formula I
~L(Y)n
30 wherein;
~k
~ ~5~65~
R is hydrogen or loweralkyl, R is OH, OM, -O-loweralkyl or -NR R , R and
R are hydrogen, loweralkyl, cycloalkyl, phenyl and phenyl substituted by
loweralkyl, loweralkoxy, halogen, or trifluoromethyl and R and R taken
together with the adjacent nitrogen form a morpholino, pyrrolidino, piperi-
dino, piperazino group. M is a pharmaceutically acceptable cation or Erac-
tion thereof when the cation is multivalent, Am is primary amino (-NH2), or
dimethylamino, X is hydrogen, halogen, loweralkyl or trifluoromethyl, Y is
hydrogen, halogen, loweralkyl, loweralkoxy, trifluoromethyl or methylthio,
and n is 1 to 3 inclusive, and when n is greater than one, Y may be the same
or different and hydrates of all the above.
In the further definition of symbols in the formulae hereof and
where they appear elsewhere throughout this specification the terms have
the following significance:
The term "loweralkyl" as used herein includes straight and branched
chain radicals of up to eight carbons inclusive and is exemplified by such
groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary
butyl, amyl, isoamyl, hexyl, heptyl and octyl radicals and the like. The
term "loweralkoxy" has the formula -O-loweralkyl.
The term "cycloalkyl" as used herein includes primarily cyclic
2Q alkyl radicals containing 3 to 9 carbon atoms inclusive and includes such ,
groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, ,
cycloheptyl and the like.
The term "halogen" when referred to herein includes fluorine,
chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
The term "pharmaceutically acceptable cation" forming salts of
the acids and hydrates thereof when referred to herein includes any metal
cation acceptable Eor internal
~,j - 2 -
~89
.,,_.
I 15~655
administration to warm-blooded animals as exemplified by
sodium/ potassium~ calcium, magnesium, zinc~ c~pper and
aluminum and water of hydration. Sodium cation is preferred.
Anti-inflammatory activity was demonstrated in
laboratory animals using a modification of the Evans-Blue
Carrageenan Pleural Effusion Assay of Sancilio, L. F.,
J. Pharmacol. Exp. Ther. 168, 199-204 (1969).
The compounds also have application as anti-pyretics,
analgesics and in inhibiting blood-platelet aggregation.
Compounds preferred for their anti-inflammatory
activity have the formula:
R
l O
X ~ CH -C- ~2
~ Am
H-C-OH Formula I-l
~(Y)n
wherein;
Rl is hydrogen or methyl,
R2 is OH, OM, or O-loweralkyl,
Am is NH~ or di-methylamino,
X is hydrogen, halogen, loweralkyl and trifluoromethyl,
Y is hydrogen, halogen, loweralkyl, loweralkoxy,
trifluoromethyl and -S-loweralkyl,
M is a pharmaceutically acceptable cation or fraction
thereof when the cation i5 multivalent, and
n is 1 to 3 inclusive.
It is, therefore, an object of the present invention
to provide novel 2-amino-3-rhydroxy(phenyl)methyl]phenyl-
acetic acids, metal salts, hydrates, amides and esters.
Another object is to provide a novel m~thod for the
treatment of a living animal body and especially a mammalian
body for the purp~se of alleviating inflammation, utilizing
the 2-amino-3-rhydroxy(phenyl)methyl]phenylacetic acids and
aforesaid derivatives thereof and therapeutic compositions
therefor.
1~L56~5~
The compounds of formula I can be prepared as follows:
(a) to prepare a compound of formula I wherein Y is other than
S-loweralkyl, reducing a compound oE formula II
R O
X ~ CH_C_
~ Am II
C=O ~:
( )n
wherein R , R , X, Y, Am and n are as defined above, or
(b) to prepare a compound of formula I wherein Y is S-loweralkyl
and R is OM, -O-loweralkyl or -NR R , reacting a compound of formula Id :
R O ``
I 11 2
~ CH-C--R ,,,
Am
H-C-OH Id ,;
[~ (F)n
wherein R , X, n and Am are as defined above and R is OM, -O-loweralkyl or ~:
-NR R with Na loweralkyl sulfide; or
(c) to prepare a compound of formula I wherein Y is S-loweralkyl
and R is OH, reacting a compound of formula Ig
R O
X ~ CH-~-OM
~ ~ '~ .
H-C-OH Ig
~ (F)n
wherein R , X, n, Am and M are as defined above, with Na loweralkyl sulfide,
followed by acidification.
.. ~ 4
1 15~55
DETAILED DESCRIPTION OF THE INVENTION
AND PREFERRED ~MBODIMENTS
The 2-amino-3-~hydroxy(phenyl)methyl]phenylacctic acids and me-tal
salts thereof, esters and amides are for the most part, with eXceptions
noted hereinbelow, prepared by reducing the carbonyl moiety oE the starting
2-amino-3-benzoylphenylacetic acids, salts, esters and amides by an approp-
riate choice between hydrogenation over palladium-on-carbon or with sodium
borohydride as represented by the following equation:
Rl O R O
CH-C-R X ~ CH-C-R
AmReduction > Am
C=O H2~pd/c 20 -30 C H-C-OH
1 or NaBH4
( )n ~ ( )n ~
II I :
wherein R , R , X, Y, Am and n are as defined hereinabove. When R iS OH in
compounds of Eormula II, hydrogenation over palladium-on-carbon causes
cyclization. Sodium borohydride in double stoichiometric amount may be used
in this instance; however, it is preferred to convert R to a salt (OM) or
its equivalent in basic solution and then hydrogenate with hydrogen over :~
palladium-on-carbon followed by careful acidification with a weak acid such
as acetic acid as represented by the following equation:
~ ~ - 4a -
, 389
~56~
R
O Rl
~ CH-~-OM ¦
X ~ Am X ~ CH-C-OM
C=O H2,Pd/C, 20 -30 C. ~ Am
I ~~~~' H-C-OH
(Y)n ~ IIa Rl ~ (Y)n ~ Ib
X ~ CH-C-OH
~ Am ~ HOAC
H-C-OH
(Y)n ~ Ia
overheating above about 30C. results in loss of hydroxyl
group to give a phenylmethyl derivative.
compounds of Formula I wherein X or Y is halogen are
prepared from the appropriate precursor of Formula II by
reducing with sodium borohydride as hydrogenation with
palladium-on-carbon causes loss of halogen.
When Y is -S-loweralkyl in compounds of Formula IIJ
hydrogenation results in loss of the S-loweralkyl radical.
ThereforeJ the following procedures are preferred for
25 preparation of compounds of Formula I wherein Y is -S-lower-
alkyl as represented by the equations starting with a compound
of Formula I wherein Y is F.
Rl o Rl
30 X ~ IH C_~2 X ~ C~_C_R2
~ ~a loweralkyl- Am
F sulfide _ ~ H-C-OH
~ S-loweralkyl
Id Ic
85~
wherein R , X and Am are as defined hereinabove and R is OM, -O-loweralkyl
3 4
or -NR R . The following procedure may be used to prepare compounds of the
invention wherein R is OH:
R O R O
X ~ 1H-C-OM X ~ `1r- 1H~C~M
Am + Na alkylsulfide ~ ~m
H-C-OH > H-C-OH
F ~ S-loweralkyl
Ig If
R O
~ -1H-C-OH /
X ~ ¦ / CareEul Acidifi-
Am ~ cation HOAC
H-C-OH
S-loweralkyl
Ie
and wherein R , X, Am and M are as defined hereinabove. Formulae Ia to Ig
are encompassed by formula I.
Starting materials of formula II wherein R is OH, Om or -O-lower-
alkyl and Am is -NH2, or dimethylamino are prepared as in United States
Patent 4,045,576. Starting materials of formula II wherein R is -NR R are
prepared as disclosed in Canadian Patent No. 1,128,512 according to the
following equations:
X ~ O 1) t~ ocl
C=O + R SCHR CNR R 2 ~t3N
1 (about 70 C. in
~ Formula IV methylene chloride
~ ( )n solution)
Formula V
,~...
~; - 6 -
,
~9
115~655
SR5
x~cRlcNl~3R4 X~cHRl-c-NR3R4
C=O Raney ~i ~
Tetrahydrofuran ç=o
Y)n~ ( Y)n~
Formula III Formula IIb
wherein X, Y, n, Am, Rl, R3 and R~ are as hereinabove
definedJ except Y cannot be -S-loweralkyl and Rs is lower-
alkyl and phenyl. The compounds of Formula Ilb wherein Am
is dimethylamino may be prepared by reacting compounds of
IIb wherein Am = NH2 with formaldehyde and cyanoborohydride.
Preparations 1 to 29 illustrate the preparation of compounds
of Formula IIb and intermediates therefor.
389
1 1 56B55
Preparation
4-[2-(Methylthioacetyl)]morpholine.
A mixture of 40.2 g (0.3 mole) of ethyl methylthio-
acetate and 130 g (1.5 mole) of morpholine was heated at
reflux for 70 hr. Fractional distillation at reduced
pressure gave 45 g (86%) of product b.p. 104-105C./0.05 mm Hg.
on second distillation.
Analysis: Calculated for C7Hl3NO2S: C,47.98, H,7.48, N,7.99
Found : C,47.55; H,7.59; N,8.18
Preparation 2
?-Methylthio-N-methylacetamide.
A mixture of 134 g (1.0 mol) of ethyl methylthioacetate
and 310 g (10.0 mol) of methylamine was heated in a bomb at
150C. for 72 hr. The excess amine and the ethanol produced
were removed by distillation and the remaining thin syrup
15 was distilled to give 112 g (94%) of the titled compound as
a colorless liquid, b.p. 76 -78C./o.4 nun Hg.
Analysis: calculated for C4H9NOS: C,40.71; H17.61; N,11.75
Found : C,39.78; H,7.69; N,11.88
PreParation 3
2-Methylthio-N,N-dimethylacetamide.
A mixture of 134 g (1.0 mol) of ethyl methylthioacetate
and 360 g ~8.o mol) of dimethylamine was heated in a bomb
at 150C. for 90 hr. The excess amine and the ethanol
produced were removed by distillation and the residue was
25 distilled to give 129 g (97%) of the titled compound as a
clear colorless liquid~ b.p. 76-77C./0.5 mm Hg.
Analysis: Calculated for C5HllNOS: C,45.08, H,8.32; NglO.51
Found : C,43.88: H,8.41, ~,10.60
Pre~aration 4
2-(?-Propylthio~acetamide.
To a mixture of 46.7 g (0.5 mole) of 2-chloroacetamide
in 200 ml of absolute ethyl alcohol was added in a 610w
stream, a solution of 38.1 g (0.5 mole) of 2-propanethiol in
100 ml of absolute ethyl alcohol and 40 g of 50% aqueous
35 sodium hydroxide. q~he m~xture was heated at reflux for 1 hr.,
:'
~9
11~6~55
then filtered. The filtrate was concentrated under reduced
pressure; the residue was dissolved in methylene chloride
and the solution was dried over magnesium sulfate. The
mixture was filtered and the filtrate was again concentrated.
On standing, the syrupy residue crystallized. Recrystal-
lization from isopropyl ether gave 59.0 g (89%) of white
platelets, melting at 52-54C.
Analysis: Calculated for CsHllNOS: C,45.08; H,8.32; N,10.51
Found : C,45.05; H,8.32; N,10.55
Preparation 5
2~ Propvlthio)acetamide.
Utilizing the pro~edure of Preparation 4 but substituting
an equal molar amount of l-propanethiol for 2-propanethiol,
there was oktained 61.2 g (92%) of the title compound~ The
white crystals melted at 49.5-51.0 C.
Analysis: Calculated for C5Hll~OS: C,45.08; H,8.32; ~,10.51
Found : C,44.97, H,8.24; N~10.40
Pxeparation 6
2-Amino-3-benzoYl-5-chloro~ -tmethylthio)phenylacetamide.
To a cold (-70 C.) solution of 12.77 g (0.055 mole) of
2-amino-5-chlorobenzophenone in 300 ml of methylene chloride,
under nitrogen atmosphere3 was added 6.o g (0.0552 mole~ of
t-butylhypochlorite in 20 ml of methylene chloride. Ater
an additional 15 min stirring period, a su~pension of 5.8 g
(0.055 mole) of ~-(methylthio)acetamide in 150 ml of
methylene chloride was added. The mixture was stirred at
-65C. for one hour. Triethylamine (5.6 g (0.055 mole))
was added and the solution was allowed to warm to room
temperature. The reaction mixture was cxtracted with several
portions of water and the organic layer dried over magnesium
sulfate. ~he volume of solution was reduced ln vacuo to
about 200 ml and the proauct crystallized as a yellow solid,
m.p. 173.5-174.5C. Yield was 6.86 g ~37O3%).
Analysis: calculated for Cl~HlsN2O2SCl: C,57.40; H~4.52;
~,8.37
Found : C,57.38. H,4.50,
~8.51
389
~ ~5~55
Preparation 7
2-Amino-3-benzoyl~x-(methylthio)phenylacetamide.
To a cold (-70 C.) solution of 19.7 g (0.10 mole of
2-amino-benzophenone in ~00 ml of methylene chloride, under
nitrogen atmosphere, was added a solution of 11.5 9 (0.10
mole) of 95% t-butylhypochlorite in ~0 ml of methylene
chloride followed after 10 min by a solution of 10.5 g
(0.1 mole) of methylthioacetamide in 300 ml of tetrahydro-
furan. The temperature was maintained at or below -55 C.
during these additions. After one additional hour at -60 C.
the mixture was allowed to warm to room temperature and the
precipitate was collected by filtration. The precipitate
was slurried in 200 ml of methylene chloride and 11 g
(0.11 mole) of triethylamine was added. The mixture was
stirred for 5 min. The solution was washed two times with
100 ml of water and the organic phase dried over magnesium
sulfate and concentrated under reduced pressure. The
residue was washed with diethylether and dried to yield
13.0 g ~43%) of a light yellow powder, m.p. 153-155 C.
Analysis: calculated for C16Hl~N202S: C,63.98; HJ 5.~7;
~,9-3~
Found : C,63.64; H,5.39;
N,9-25
Preparation 8
2-Amino-3-(4-chlorobenzoyl)-~-(phenylthlo)phenyl-
acetamide.
To a cold (-70 C.) solution of 34.6 g (0.15 mole) of
2-amino-4'-chlorobenzophenone in 500 ml of methylene chloride
was added 17.~ g (0.15 mole) of 95% t-butylhypochlorite,
followed after 10 min by a solution of 25.0 g (0.15 mol) of
phenylthioacetamide in 400 ml of tetrahydrofuran which was
added over a 20 min period. The temperature was maintained
at -64C. or bel~w during these additions. A~ter two hours,
20 g (0.2 mole) of triethylamine was added and the mixture
was allowed to warm to room temperature. The mixture was
concentrated and the residue partitioned between water and
methylene chloride. Material insoluble in either phase was
collected by fil~ration~ wa~he,d with 20~ aqueous ethanol
:,
~89
1 15BB55
11
solution and dried to yield 36 9 (61%) of light yellow powder,
m.p. 189-191C.
Analysis: Calculated for C2lHl7N202SCl: C,63.55; H,4.32,
N,7 .o6
Found : C,63~73; H,4.36
~,7.16
~ ~ 5 Preparation 9
4-l2-(2-Amino-3-benzoylphenyl)-2-(methylthio)acet
morpholine.
To a cold (-65 C.) solution of 9.9 g (0.05 mole) of
2-aminobenzophenone and 8.8 g (0.05 mole) of 4-(~-methylthio)
acetylmorpholine in 200 ml of methylene chloride was added
dropwise a solution of 5.8 g (0.05 mole) of 95% t-butyl-
hypochlorite in 20 ml of methylene chloride. After one
additional hour at -60C., 5.1 g (0.05 mole) of triethylamine
was added and the mixture was allowed to warm to room tempera-
ture. The solution was washed two times with 100 ml of water,dried over magnesium sulfate and concentrated under reduced
pressure. The residue was chromatographed on 600 g of silica
gel eluting first with diisopropylether and finally wi~h
10~ acetone in diisopropylether. The eluate was concentrated,
the residue dissolved in 150 ml ethanol and the solution
poured into 400 ml water. The undissolved solid was
collected and crystallized from diethylether and dried.
yield was 12.3 g (62~) of yellow crystals, m.p. 119-121C.
Analysis: Calculated for C20~22N203S: C,64-84; H,5-99;
~7.56
Found : C~65.01; H,5.99;
N,7-57
Preparation 10
2-Amino-~-benzoyl-5-chloro-y-[(4-chlorophenyl)thio~-
phenylace_amide .
~o a cold (-70C.) solution of 20 g (0.0863 mole) of
2-amino-5-chlorobenzophenone in 500 ml of methylene chloride
under nitrogen atmosphere was added a solution of 9.48 g
(o.o88 mole) of t-butyl hypochlorite in 50 ml of me~hylene
chloride. After an additional 15 min stixring, a solution
35 of 17.35 g (0.0863 mole) of ~-(4-chlorophenylthio)acetamide
389
.
1 15~55
12
in 500 ml of a 50/50 mixture of tetrahydrofuran and methylene
chloride was added. The mixture was stirred at -70C. fo~
2 hrg 8.72 g (0.0863 mole) of triethylamine was added, and
the stirred solution was allowed to warm to room temperature
over a period of 2 hr. The reaction mixture was extracted
with several portions of water and the organic lay~r dried
over magnesium sulfate. The volume of liquid was reduced
to about 500 ml. Methylene chloride, 500 mi, was added to
precipitate the product which after filtration and drying
weighed 16.62 g (44.7~). The yellow solid melted at 198-
~ OOC .
Analysis: calculated for C2 lHl6Nz02SCl2: C,58.48; H,3.74;
~,6.49
Found : CJ58.49; H~3.77;
N,6.67
PreParation 11
2-Amino-3-benzoyl-5-chloro-~-(phenylthio)phenyl-
acetamide.
To a cold (-70 C.) solution of 80.72 g (0.349 mole) of
2-amino-5-chlorobenzophenone in 1.5 liter of methylene-
chloride, under nitrogen atmosphere, was added 39.1 g(0.760 mole) of t-butyl hypochlorite in 100 ml of methylene
chloride. Ater stirring for 10 min, a solution of 59.1 g
(0.354 mole) of ~-(phenylthio)acetamide in 1.5 liter of
tetrahydrofuran was added. The mixture was stirred for
1.25 hr at -65C. J 37.5 g (0.371 mole) of triethylamine was
added and the solution was allowed to warm to room temperature.
The reaction mixture was extracted with several portions of
water and the organic layer was dried over anhydrous sodium
sulfate. The volume of solution was reduced ln vacuo and
30 yellow solid precipitated which when recrystallized from
acetonitrile was a yellow crystalline solid, m.p. 190-191C.(d).
Analysis: Calculated for C2lHlT~202SCl: C,63.55; HJ4.32
N,7 .o6
Found : C,63.62; H,4.29;
~,7 .o8
,
~89
15~ 55
13
Pre~arat ion t2
2-Amino-3-benzoyl~x-(phenylthio)phenylacetamide.
Following the procedure of Preparationll but substituting
equal molar amounts of 2-aminobenzophenone for 2-amino-5-
chlorobenzophenone the title compound was obtained in 57~
yield. Recrystallized from methylene chloride-diethylether-
hexane, the compound melted at 153-154 C.
Analysis: calculated for C2lHl8~zO2S: C~69-59; H,5-01:
~,7-7~
Found : C,69.3~; H,5.00,
~,7.76
Preparation 13
2-Amino-3-ben~oyl~-(methylthio)-N-methylphenylacetamide.
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone
in 350 ml of methylene chloride was cooled to -70 C. and
17.9 g (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml
of methylene chloride was added. To the (-70C.) mixture
was added dropwise a solution of 17.2 g (0.15 mole) of 95
t-butylhypochlorite in 30 ml of methylene chloride. The
temperature was maintained at or below -65C. for 1.5 hr,
then 15.1 g (0.15 mole) of triethylamine was added rapidly.
The solution was allowed to warm to room temperature and was
washed with water. The organic solution was concentrated
and the residue crystallized when mixed with isopropyl ether.
The solid was recrystallized from isopropyl alcohol to give
31 g (65~o) Of yellow needles, m.p. 149.0-150.0 C.
25 Analysis: Calculated for Cl7Hl8~202S: C,64.94; H,5.77;
~J8.91
Found : C,65.24, H,5.83;
N,8.99
Preparation 14
2-Amino-~-benzoyl-x-(methylthio)-~ dimethylphenyl-
0 acetamide.
A solution of 29.6 g (0.15 mole~ of 2-aminobenzophenone
in 350 ml of methylene chloride was cooled to -70C. and
20.0 g (0.15 mole) of 2-methylthio-~,~-dimethylacetamide was
added. To the mixture (-70C.) was added dropwise a solution
of 17.2 g (0.15 mole) of 95~ t-butylhypochlorite in 30 ml of
~8
L 156655
14
methylene chloride. The temperature was maintained at or
below -55C. for 1.5 hr, then 15.1 g ~0.15 mole) of tri-
ethylamine was added rapidly. The solution was allowed to
warm to room temperature and was washed with water. The
organic solution was concentrated and the residue cxystal-
lized when mixed with isopropyl ether. The solid was
r~crystallized from isopropyl alcohol to give ~9.8 g (81%)
bright yellow crystals, m.p. 153-155 C.
Analysis~ Calculated for Cl8H2~N202S: C,65.83; H,6 14;
10Found : C,65.87, H,6.15;
N,8.52
Preparation 1~
2-Amino-3-(4-fluorobenzoyl)-~-(n-propylthio)phenyl-
.
acetamide.
15A solution of 21.5 g ~0.1 mole) of 4'-fluoro-2-amino-
benzophenone in 400 ml of methylene chloride was cooled to
-70 C. and 11.5 g (0.1 mole) of 95% t-butylhypochlorite was
added over a period of 15 min, keeping the temperature below
-66 C. To this solution was added a solution of 13.3 g of
2-n-propylthioacetamide in 50 ml of methylene chloride over
a 10 min period. The solution was stirred for 1 hr at -65
to -70 C. and then allowed to warm to 0 C. at which point
10.2 g (0.1 mole) of triethylamine was added. ~he solu~ion
was stirred for 10 minutes and then washed with water. The
organic solution was dried over magnesium sulfate. After
concentrating under reduced pressure, the residue was
crystallized from isopropyl alcohol and dried to give 1~.5 g
~560 of yellow crystals melting at 140-142C.
Analysis: calculated for Cl~HlgN202SF: C~62.41; H ~ 53;
Found : CJ62.~4; H,50 54
389
~_.
115~55
PreParation 16
In the same manner as given in Preparation 8,
2-amino-3-(2-fluorobenzoyl)~x-(phenylthio)phenyl-
acetamide,
2-amino-3-(4-trifluoromethylbenzoyl)-~-(phenylthio)
phenylacetamide,
2-amino-~-(2,4-dichlorobenæoyl)-~-(phenylthio)
phenylacetamide, and
2-amino-3-(2,4-difluorobenzoyl)-~-(phenylthio)
phenylacetamide,
are prepared from phenylthioacetamide, t-butyl-
hypochloriteJ and
2-amino-2'-fluorobenzophenone,
2-amino-4'-trifluoromethylbenzophenoneJ
2-amino-2',4'-dichlorobenzophenoneJ and
2-amino-2',4'-difluorobenzophenone.
Preparation 17
2-Amino-3-benzoyl-5-chloro-x-(methylthio)-N-methyl-
phenylacetamide.
To a solution of 38.3 g (0.166 mole) of 2-amino-5-
chlorobenzophenone in 1 liter of methylene chloride cooledto -70 C. under an atmosphere of nitrogen was added 18.05 g
(0.167 mole) of t-butylhypochlorite. The solution was
stirred for 15 min and then a solution of 20.3 g (0.171
~ole) of 2-methylthio-N-methylacetamide in 100 ml of methylene
chloride was added. The solution was stirred at -70 C. for
2 hrs and 25 ml of triethylamine was added. While stirring,
the solution was allowed to warm to room temperature followed
by extraction with water and drying of the organic layer
with magnesium sulfate. The volume of the solution was
reduced to about 400 ml~ ether was added and the solution
placed in a refrigerator at about 0C. overnight. The solid
which crystallized was dried under high vacuum for about 4 hr
at 50C. Weight of the product was ~1.56 g (54.6%) which
melted at 170 171 C.5 Analysis: calculat~d for Cl7Hl7~202SCl: C,58.53; H,4.91; N,8.o3
Found : C,58.68; E,4.91;
N,8.13
~8g
,---
1 156~5
16
Preparation 18
3-Benzoyl-2-(N-methylamino)~-(methylthio)phenyl-
acetamide.
When in accordance with the procedure of Prepara~ion 7J
2-N-methylaminobenzophenone is substituted in equimolar
amount for 2-aminobenzophenone, the title compound is
obtained.
Preparation 19
2-Amino-3-benzoyl-5-chlorophenylacetamide~
A mixture of 21.34 g (0.0639 mole) of 2-amino-3~
benzoyl-5-chloro-x-(methylthio)-phenylacetamide and excess
Raney nickel in a mixture of 900 ml of absolute ethanol and
200 ml of dimethylformamide was stirred at roomcte/m~er~ture
for 45 min. The mixture was filtered through ee~e to
B remove the Raney nickel. The solvent was removed ln vacuo
to give a yellow solid which when recrystalli~ed melted at
213.5-215.0C.(d).
10 Analysis: calculated for C1sHl3Nz03Cl: C,62.40: H,4.54;
N 9.70
Found : CJ62.35; H,4.58;
N,9.74
Preparation 20
2-Amino-3-benzoyl-phenylacetamide.
To ~n agitated solution of 9.7 g (0.032 mole) of
2-amino-3-benzoyl-~-(methylthio)-phenylacetamide in 100 ml
of tetrahydrofuran was added 80 g of wet Raney nickel
(washed 3 times with water and 3 times with tetrahydro~uran).
After 10 minutes the mixture was filtered to remove Raney
nickel and the filtrate concentrated under vacuum. The
residue was crystallized from isopropyl alcohol to give
6.0 g (73~) of yellow needles, m.p. 178.5-180.0C.
Analysis: calculated for Cl5Hl4NzO2: C,70-85; H,5-55;
N,11.02
Found : C,70.53; N,5-53;
~,11.04
~ /~ M~rl~
389
.
B55
17
Preparation 21
2-Amino-3-(4-chlorobenzoyl)phenylacetamide~
To an agitated solution of 28.5 g (0.077 mole) of
2-amino-3-(4-chlorobenzoyl)-~-(phenylthio)phenylacetamide
in one liter of tetrahydrofuran was added 230 g of wet
Raney nickel (washed 3 times with water and ~ times with
tetrahydrofuran). After 15 minutes the mixture was
filtered and the filtrate concentrated under reduced
pressure to give 17.4 g (84%) of yellow crystalline solid.
Recrystallization from isopropyl alcohol followed by
recrystallizing twice from absolute ethanol gave yellow
needles, m.p. 212-215 C.
Analysis: Calculated for Cl5Hl3Nz02Cl: C,62.40; H,4.54;
N~9.70
Found : C,62.76; H,4.58;
N,9-83
Preparation 22
4-~2-(2-Amino-3-benzoylphenyl)acetyl]morpholine.
To an agitated solution of 18.5 g (0.05 mole) of
4-[2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetyl~
morpholine in 300 ml of tetrahydrofuran was added 150 g
of wet ~aney nickel. After 15 minutes the mixture was
filtered and the filtrate concentrated under reduced
pressure. After recrystalliæation of the residue from
isopropyl alcohol, there was obtained 13.3 g (820 of
bright yellow crystals~ m.p. 156.5-158.5 C.
Analysis: Calculated for ClgH20NzO3: CJ7-35; ~6.22;
~,8.64
Found : C,70.24; H,6.21;
N ~ 8 . 63
Preparation ?3
2-Amino-~-benzoyl-N-methylpheny~acetamide.
A solution of 22.5 g (0.072 mole) of 2-amino-~-benzoyl-
~-(methylthio)-N-methylphenylacetamide in 400 ml of tetra-
hydrofuran was treated with 160 g of wet Raney nickel
(washed 3 timès with water and 3 times with tetrahydrofuran)
for 10 minutes. The mixture was filtered and,the filtrate
was concentrated. The residue was crystallized from
389
18
isopropyl alcohol to give 17.2 g (890 of yellow needles,
m.p. 145-146 C.
Analysis: Calculated forCl~Hl6N202: C,71.62, H,6.01;
N,10.44
Found :C,71.76; HJ 6.o5,
N,10.52
Preparation 24
2 -Amino-~-benzoyl-N~-dimethylphenylacetamide.
A solution of 33.0 g (0.1 mol) of 2-amino-3-benzoyl-
~-(methylthio)-~,N-dimethylphenylacetamide in 500 ml of
tetrahydrofuran was treated with 240 g of wet Raney nickel
(washed 3 times with water and ~5 times with tetrahydro-
furan) for 10 minutes. The mixture was filtered and the
filtrate was concentrated. The residue was crystallized
from isopropyl alcohol to give 27.2 g (96%) of yellow
needles, m.p. 123-124 C.
Analysis: Calculated for Cl7Hl8N202: C,72.32; H,6.43t
N,9.92
Found : C,72.34; H,6.42;
N,9.98
Preparatlon ?~
2-Amino-3-(4-fluorobenzoyl)phenylace~amlde.
A solution of 24.2 g (0.07 mole) of 2-amino-3-(4-
fluorobenzoyl)-" -(n-propylthio)phenylacetamide in 300 ml
of tetrahydrofuran was treated with 250 g of wet Raney
nickel (washed 3 times with water and ~5 times with tetra-
hydrofuran). The mixture was stirred for one hour and
filtered. The filtrate was concentrated under vacuum and
the resi~ue was recrystallized from 95~ ethyl alcohol to
give 14.8 g (78~) of yellow needles melting at 184-186 C.
Analysis: Calculated for C15Hl9N202F: C,66.17; ~,4.81,
~,10.29
Found : C,66.32t H,4.81;
N,10.48
389
19
Preparation 26
In the same manner as given in Example 2J
2-Amino-3-(2-fluorobenzoyl)phenylacetamide,
2-Amino-3-~2J4-dichlorobenzoyl)phenylacetamide,
2-Amino-3-t2,4-difluorobenzoyl)phenylacetamide, and
2-Amino-3-(4-trifluoromethylbenzoyl)phenylacetamide
are prepared from
2-Amino-3-(2-fluorobenzoyl)-~-(phenylthio)phenyl-
acetamide,
2-Amino~3-(2,4-dichlorobenzoyl)-~-(phenylthio)phenyl-
acetamide,
2-Amino-3-(2,4-difluorobenzoyl)~-(phanylthio)phenyl-
acetamide, and
2-Amino-3-(4-trifluoromethylbenzoyl)-~-(phenylthio)-
phenylacetamide.
Preparatin ?7
2-Amino-3-benzoyl-~-chloro-N-methylphenylacetamide.
A solution of 28.33 g (0.081 mole) of 2-amino~3
benzoyl-5-chloro~-(methylthio)-N-methylacetamide in one
liter of tetrahydrofuran was treated with excess Raney
nickel at room temperature for 2 hrs. The solution was
filtered through celite. The Raney nickel residue was
washed with acetone and the wash filtered. The combined
organic filtrates wer~ dried over magnesium sulfate and the
volume reduced to about 300 ml. Excess ether was added and
the solution allowed to stand at room temperature for one hr
followed by refrigeration overnight. The yellow 501 id
collected and dried weighed 20.94 g ~85.680 and melted at
179-180C .
Analysis: Calculated for Cl5Hl5N202Cl: CJ63.48~ H,4.99;
Ng9~25
Found : C,63.44; HJ4.99;
~J9.27
389
1 ~58~5
Preparation 28
~-Benzoyl-2~ methylamino)phenYlacetamide.
When in the procedure of Preparation 20J 3~benzoyl-2-
(N-methylamino)-~-(methylthio)phenylacetamide is substituted
for 2-amino-~-benzoyl-a-(methylthio)phenylacetamide, the
title compound is obtained.
Preparation 29
~-Benzoyl-2-(~,~-dimethylamino)phenylacetamide.
A solution of 12.7 g (0.05 mol) of 2-amino-3-benzoyl-
phenylacetamide in 150 ml of acetonitrile is treated four
times with 16 ml (0.2 mole) of ~7% formalin, 6.4 g (0.1
mole) of sodium cyanoborohydride and 2 ml of glacial
acetic acid with a 15-minute stirring period between each
treatment. The mixture is finally poured into dilute
sodium hydroxide and extracted three times with diethyl-
ether. The ether extracts are combined, dried overmagnesium sulfate and concentrated. The product is
isolated by column chromatography.
The following examples illustrate the invention.
3~9
115~55
21
2-Amino-3-[hydroxy(phenyl)methyl]phenylacetic Acid
Hydrate r ~
~ o a stirred solution of 2 g (0.0072 mole) of sodium
2-amino-3-benzoylphenylacetate dihydrate in 25 ml of water
was added 25 ml of 3N sodium hydroxide followed by 0.285 g
(0.0075 mole) of sodium borohydride. The resulting yellow
solution was stirred for 18 hr during which time the solution
lightened in color considerably. The solution was filteredl
cooled and neutralized slowly with glacial acetic acid. The
10 white precipitate obtained weighed 1.~ g (65O , m.p.
sintering at 115~C. and melting at 160C.
Analysis: Calculated for ClsHl7N04: C,65.44; HJ6.22;
N,5.09
Found : C,65.13; ~,6.21;
~. 5 .o8
Example 2
Sodium 2 -Amino-3-rhydroxy(phenvl)methvll~henvlacetate.
A solution of 14.8 g (0.05 mole) of sodium 2-amino-3-
benzoylphenylacetate monohydrate in 250 ml of tap water was
hydrogenated over lO~o palladium-on-charcoal at ambient
20 temperature overnight. The mixture was filtered through
celite and the filtrate concentrated under reduced pressure.
The residue was crystallized with the aid o chasing with
three 50 ml portions of absolute ethanol to give a white
solid. The solid was recrystallized from methanol-diethyl-
ether and ethanol-water to yield 7.0 g (53O of white solid,
m.p. 273C.
Analysis: Calculated for Cl5Hl4NO3Na: C,64.51; H,5.05;
~,5.02
C,64.~7; H,5.07;
N,5.03
3 Example ~
2-Amino-5-chloro-3-~hydroxy(phenyl)methyl]phenylacetic
Acid.
To a stirred solution of 12.58 g (0.04 mole) of sodium
2-amino-3-benzoyl-5-c~lorophenylacetate in 100 ml of water
was added 100 ml of ~ sodium hydroxide followed by 1.6 g
389
_, ~
5 ~
22
(o.04 mole) of sodium borohydride. The mixture was stirred
for ~ hr until it became a clear orange colored solution.
The solution was neutralized with acetic acid (foaming). A
precipitate developed with excess acetic acid which was
collected by filtration, washed with water and dried. Cream
colored solid 10.2 g (79 O , m.p. 134C(d) was obtained.
Analysis: Calculated for ClsHl4Cl~O3: C,61.76; ~,4.84;
N,4O80
Found : C,61.69; H,4.81;
N,4.76
Example 4
Sodium 2-amino-3 lhydroxy(4-chlorophenyl)methyll-
~henylacetic Acid Hydrate r4:1].
A mixture of 9.0 g (0.029 mole) of sodium 2-amino-3-(4-
chlorobenzoyl)phenylacetate monohydrate in 200 ml of water
15 and 100 ml of 2~ aqueous sodium hydroxide solution was
filtered through celite and the filtrate was treated with
lol g (0.03 mole) of sodium borohydride. The mixture was
stirred at ambient temperature for 3 hrs and filtered again
through celite. The filtrate was acidified with acetic acid
20 (foaming). The resulting white solid was collected by
filtration and washed with water. The solid was stirred in
solution of 150 ml water and 1.1 g to-o~ mole) of sodium
hydroxide. The solution was filter~d and the filtrate
titrated to pH 8.5 with 15% hydrochlori~ acid solution.
25 After standing at ambient temperature overnight) the mixture
was filtered through celite and the filtrate concentrated
under reduced pressure. The residue was crystallized with
the aid of absolute ethanol to produce a whi~e solid which
recrystallized from water and dried weighed 4.2 g (47 O ,
30 m.p. 138C.(d).
Analysis: Calculated for Cl5Hl3Cl~O3~a-
H,4.28; ~,4.42
Found : C,56.62;
H~4.28; N,4.40
~89
5 5
23
. Example 5
When in accordance with the procedure of Example 1,
equal molar amounts of the following are substituted for
sodium 2-amino-3-benzoylphsnylacetate dihydrate
Sodium 2-amino-3-benzoyl-5-chlorophenylacetate,
Sodium 2-amino-3-(4-chlorobenzoyl)phenylacetate
hydrate,
Ethyl 2-amino-3-~4-chlorobenzoyl)phenylacetate,
Sodium 2-amino-3-~4-fluorobenzoyl)phenylacetate,
Sodium 2-amino~3-(3,4-dichlorobenzoyl)phenylacetate,
Sodium 2-amino-3-(3-methoxy-4-chlorobenzoyl)
phenylacetate,
there are obtained
2-Amino-3-~hydroxy(phenyl)methyl]-5-chlorophenyl
acetic acid,
2-Amino-3-~hydroxy(4-chlorophenyl)methyl~phenyl
acetic acid,
Ethyl 2-amino-3-~hydroxy(4-chlorophenyl)methyl]
phenylacetate,
2-Amino-3-~hydroxy(4-fluorophenyl)methyl]phenyl
acetic acidJ
2-Amino-3-[hydroxy(~,4-dichlorophenyl)methyl]phenyl
acetic acidg
2-Amino-3-~hydroxy(3-methoxy-4-chlorophenyl)methyl]
phenylacetic acid.
Example 6
When in accordance with the procedure of Example 2
equal molar amounts of the following are substituted for
sodium 2-amino-~-benzoylp~enylacetate monohydrate
Sodium 2-amino-3-benzoyl-5-methoxyph~nylacetate
sesquihydrate,
Ethyl 2-amino-3-benzoylphenylacetate,
Methyl 2-amino-3-benzoylphenylacetate,
Methyl 2-dimethylamino-3-benzoylphenylacetate,
Sodium 2-amino-3-benzoyl-~-methylphenylacetate
hydrate)
: 389
, ,_
~ 15~55
24
Potassium 2-amino-3-benzoylphenylacetate hydrate,
Sodium 2-amino-3-(4-methoxybenzoyl)phenylacetate,
there are obtained
2-Amino-3-[hydroxy(phenyl)methyl]-5-methoxyphenyl-
acetic acid,
Ethyl 2-amino-3-~hydroxy(phenyl)methyl]phenylacetate,
Methyl 2-amino-3-~hydroxy(phenyl)methyl]phenylacetate,
Methyl 2-dimethylamino-3-chydroxy(phenyl)methyl~
phenylacetate,
2-Amino-3-rhydroxy(phenyl)methyl~phenylacetic acid,
2-Amino-3-~hydroxy(phenyl)methyl]phenylacetic acid,
2-Amino-3-rhydroxy(4-methoxyphenyl)methyl]phenyl-
acetic acid.
ExamPle l
When in accordance with the procedure of Example 1,
equal molar amounts of the following are subst.ituted for
sodium 2-amino-3-benzoylphenylacetate:
2-Amino-3-benzoyl-5-chlorophenylacetamide,
2-Amino-3-benzoyl-phenylacetamide,
4-~2-(2-Amino-3-benzoylphenyl)acetyl]morpholine,
2-Amino-3-benzoyl-~-methylphenylacetamide,
2-Amino-3-benzoyl-NJN-dimethylphenylacetamlde,
2-Amino-3-(4-fluorobenzoyl)phenylacetamideJ
2-Amino-3-(2-fluorobenzoyl)phenylacetamide,,
2-Amino-3-(2,4-dichlorobenzoyl)phenylacetamideJ
2~Amino-3-(2,4-difluorobenzoyl)phenylacetamide,
2-Amino-3-(4-trifluoromethylbenzoyl)phenylacetamide,
2-Amino-3-benzoyl-5-chloro-~-methylphenylacetamide,
3-Benzoyl-2-(N,~-dimethylamino)phenylacetamide,
3 there are obtained
2-Amino-3-~hydxoxy(phenyl)methyl]-5-chlorophenyl-
acetamideJ
2-Amino-3-~hydroxy(phenyl)methyl]phenylac2tamide,
4-{2--{2-Amino-3-~hydroxy(phenyl)methyl]phenyl3acetyl~
morpholine,
38g
I 1 5~55
2-Amino-3-[hydroxy(phenyl)methyl]-~-methylphenyl
acetamide)
2-Amino-3-[hydroxy(phenyl)methyl]~ -dimethylphenyl
acetamide,
2-Amino-3-[hydroxy(4-fluorophenyl)methyl]phenyl
acetamide,
2-Amino-3-~hydroxy~2-fluorophenyl)methyl]phenyl
acetamide,
2-Amino-3-~hydroxy~2,4-dichlorophenyl)methyl]phenyl
acetamide,
2-Amino-3-~hydroxy(2,4-difluorophenyl)methyl]phenyl
acetamide,
2-Amino-3-[hydroxy(4-trifluoromethylphenyl)methyl]
phenylacetamide~
2-Amino-3-~hydroxy(phenyl)methyl]-5-chloro-~-methyl
phenylacetamide,
2-(N~N-dimethylamino)-3-[hydroxy(phenyl)methyl]
phenylacetamide.
Example 8
Sodium 2-amino-2-rhydroxy(4-methylthiophenyl)methyl
~henylacetate.
The title compound is prepared by preparing a solution
of 2 amino-3-[hydroxy(4-fluorophenyl)methyl~phenylacetic
acid and equivalent amount of sodium hydroxide and refluxing
in ethanol with excess methyl mercaptide and isolated by
suitable means.
Example 9
2-Amino-3-~hydroxy(4-methylthioPhenyl~methyl~henyl
acetamide.
The title compound is prepared by refluxing 2-amino-
3-[hydroxy(4-fluorophenyl)methyl~phenylacetamide with excess
sodium methyl mercaptide in ethanol and isolated by suitable
means.
~89
15~55
26
Formulation and Administration
The present invention also contemplates novel
compositions containing the compounds of the invention as
active ingredients. Effective quantities of any of the
foregoing pharmacologically active compounds may be
a~ministered to a living animal body in any one of various
ways, for example, orally as in capsules or tablets,
parenterally in the form of sterile solution~ or suspensions,
and in some cases intravenously in the form of sterile
solutions. In forming the novel compositions of this
invention, the active ingredient is incorporated in a
suitable carrier, illustratively, a pharmaceutical carrier.
Suitable pharmaceutical carriers which are useful in
formulating the compositions of this invention include
starchJ gelatin, glucose, magnesium carbonate, lactose,
malt and the like. Liquid compositions are also within the
purview of this invention and suitable liquid pharmaceutical
carriers include ethyl alcohol, propylene glycol, glycerine,
glucose syrup and the like.
The pharmacologically active compounds may be
advantageously employed in a unit dosage of from 0.1 to 250
milligrams or more depending on the size of the animal.
For example, a large animal such as a horse may require
tablets of 500-lO00 mg active ingredient. The unit dosage
may be given a suitable number of times daily so that the
daily dosage may vary from 0.3 to 450 milligrams. Five to
25 milligrams appears optimum per unit dose.
It is only necessary that the active ingredient
constitute an effective amount, i.e., such that a suitable
effective dosage will be obtained consistent with th~ dosage
form employed. The exact individual dosages as well as
daily dosages will, of course, be determined according to
standard medical principles under the direction of a
physician or veterinarian.
The active agents of the invention may be combined with
other pharmacologically active agents, or with buffers)
antacids or the like, for administration and the proportion
389
115~5
27
of the active agent in the compositions may be varied
widely.
The following are examples of compositions formed in
accordance with this invention.
1. capsules
Capsules of 5 mg.l 25 mg., and 50 mg. of active
ingredient per capsule are prepared. With the higher
amounts of active ingredient, adjustment may be made in
the amount of lactose.
Typical blend for Per capsule,
encaPsulation mq.
Active ingredient 5.0
Lactose 296.7
Starch 129.0
Magnesium stearate 4.3
Total435.0 mg.
Additional capsule formulations preferably contain a
higher dosage of active ingredient and are as follows.
Per capsule,
Inqredients mq.
Active ingredient 25.0
Lactose 306.5
Starch 99.2
Magnesium stearate 4.~
~otal435.0 mg.
In each case, uniformly blend the selected active
ingredient with lactose, starch, and magnesium stearate and
encapsulate the blend.
2. Tablets
A typical formulation for a tablet containing 5.0 mg.
of active ingredient per tablet follows. The ormulation may
be used for other strengths of active ingredient by adjust-
ment of weight of dicalcium phosphate.
~89
,, ,
28
Per tablet, mq.
(1) Active ingredient 5.0
~2) Corn starch 13.6
3) Corn starch (paste) 3.4
4) Lactose 79.2
5) Dicalcium phosphate 68.o
_ 6) calcium stearate 0.9
170.1 mg.
Uniformly blend 1, 2, 4, and 5. Prepare 3 as a 10
percent paste in water. Granulate the bl nd with starch
paste and pass the wet mass through an eight mesh screen.
The wet granulation is dried and si~ed through a twelve
mesh screen. The dried granules are blended with the
calcium stearate and pressed.
3. Injectable - 2~ sterile solutions.
Per cc.
Active ingredient ~ 20 mg.
Preservative, e.g.,
cholorobutanol ............ 0.5% weight/volume
Water for injection .......... .....q.s.
Prepare solution, çlarify by filtration, fill into
vials, seal and autoclave.
Various modifications and equivalents will be apparent
to one skilled in the art and may be made in the compounds,
compositions, and methods of the present invention without
departing from the spirit or scope thereof, and it is
therefore understood that the invention is to be limited
only by the scope of the appended claims.
