Note: Descriptions are shown in the official language in which they were submitted.
AER-304
35~
2-AMINO-3-BENZOYL-PHENYLACETAMIDES
: A~D CYCLIC HOMOLOGUES
~ BACXGROUND OF THE INVENT IO~
.: 1. FIELD OF INVENTION
The present invention is concerned with certain
novel 2-amino-3-benzoylphenylacetamides and h0terocyclic
derivatives thereof and p~armacological methods of treatment,
pharmaceutical compositions and use thereof and methods of
producing the same. The compounds are anti-inflammatoryJ
antipyretic, anaLgetic and blood-platelet-aggregat.ion
inhibiting agents which exhibit minirnal undesirable side
effects of gastric irritation on oral administration to
living animal bodies.
102. DESCRIPTION OF THE PRIOR ART
2-Amino-3-benzoylphenylacetic acids, esters and
metal salts thereof having anti-inflammatory activity and
blood-platelet-aggregating inhibition properties are
disclosed in U. S. Patent 4,045,576.
15South African Patent 68/4682 discloses benzoyl-
phenylacetamides generically having a variety of substituents
in indefinite positions on phenyl. None of the specific
compounds disclosed therein are aminophenylacetamides.
GeneralLy, in the past, strong anti-inflammatory
20 drugs have been found to produce serious side effects of
gastric bleeding and ulceration when administered orally
to animals in the effective range. The compounds of the
present invention have been found to have the advantage
- that extremely low incidence of gastric irxitation is
25 observed when administered in the range effective for
reducing inflammation as compared to indomethacin and the
,
:
:,
~L: L;285~;~
.. . ..
less irritating 2-amino-3-benzoylphenylacetic acids disclosed in United
States Patent 4,045,576.
OBJECTS AND SUMMARY OF THE INVENTION
The compounds of the present invention are 2-amino-3-benzoyl-
phenylacetamides illustrated generally by the following formula:
R O Rl
~ CH-C-N
,~ X ~/ \R2
Am
Formula I
~--~Y)n
wherein R is hydrogen and lower alkyl; Rl and R2 are hydrogen, lower alkyl,
cycloalkyl, phenyl and phenyl substituted by lower alkyl, lower alkoxy,
halogen, nitro and trifluoromethyl, and Rl and R2 taken together with the
adjacent nitrogen form a morpholino, pyrrolidino or piperazino group;
X is hydrogen, lower alkyl, lower alkoxy, halogen and trifluoromethyl;
- Y is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower
alkylthio, lower alkyloxythio and lower alkyldioxythio; Am is primary amino
(-NH2~, methylamino or dimethylamino, and n is 1-3 inclusive.
The novel compounds of ~ormula I possess valuable pharmacolo-
gical properties and are useful when administered internally in effective
amount in alleviating inflammation, alleviating pain in an animal afflicted
with pain, inhibiting blood-platelet aggregation and combating temperature
elevation in living animal bodies but with minimal side effects as compared
to some other strong anti-inflammatory agents. Illustrative of the anti- -
inflammatory activity with minimal side effect.s is the compound of ~xample
3; namely, 2-amino-3-(~-chlorobenzoyl)phenylacetamide which was found to
have about the same potency as indomethacin but exhibited about only l/lOOth
as much irritation to the stomach as indomethacin.
'`
-2-
-~
' ~,.J 1
35~2
The 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 of Formula I ex~ibit inhibition of
platelet aggregation in the test method described by
BornJ J. of Phys. 162, 67-68 P. (1962) and Evans et al.,
. of Expt. Med. 128~ 877-894 (1968) . The test drugs are
administered to rats and after two hour~ the rats are
bled and platelet rich plasma obtained. Collagen was
added to the platelet rich plasma to induc0 platelet
- aggregation and comparisons were made between control and
treated samples.
The compounds of Formula I also act as analgetics as
determined by the Bradykinin Analgetic Test Method of
~ickerson et al., I,ife Sci. 4J 2063-2069 (1965) as modified
by sanciliO and Cheung, Fed. Proc. 3~, 774 (1976) .
Antipyretic activity of the compounds of Formula I is
demonstrated in the lowering of the febrile response in
hyperthermic animals without affecting the rectal tempera-
ture or normothermic animals. Hyperthermic response produced
by subcutaneous injection of Brewer's yeast in rats is
overcome by oral administration of as little as 4-8 mg/kg
of compounds of Formula I and no significant change in rectal
temperature of normothermic rats is observed.
It is an object of the present invention to provide
novel compounds and compositions. Another object is to
provide a novel method for the treatment of a living animal
body and especially mammalian bodies for the purposes of
alleviating inflammation and pain, inhibiting blood-platelet
aggregation and treating fevers all with a minimum of
undesirable side effects in the gastric and intestinal area.
Additional objects will become apparent to one skilled in
- the art and still other objects will become apparent
hereinafter.
In the definitions of symbols in the formulas hereof
and where they appear elsewhere throughout this specification,
~2
the terms have ~he following significance.
The term "lower alkyl" as used herein includes straight and branched
chain radicals of up to eight carbon atoms and is exemplified by such groups
as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary hutyl, amyl,
isoamyl, hexyl, heptyl and octyl. The term "lower alkoxy" has the formula
-O-lower alkyl.
The term "halogen" when referred to herein includes fluorine, chlor-
ine, bromine and iodine, preferably fluorine, chlorine and bromine.
- The term "cycloalkyl" as used herein includes primarily cyclic
alkyl radicals containing 3 to 12 carbon atoms inclusive and includes such
groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
the like.
DETAIL~D DeSCRIPTION OF T~IB INVENTION AND
PReFERReD eMBODIMeNl'S
Method of Preparation
The preparation of the compounds of Formula I may be accomplished by
reactions which involve the following sequence:
~ O
R SCHRCNR R 1) t-BuOCl
Am Formula III 2) Et3N
Formula IV (ca -70C.
~f J methylene chloride
~ SR3 solution)
(Y)n ' " 1 2 0
CRCNR R ~ CHR-c-NRlR2
X - ~ ~ Raney Ni ) ~ ~
~ Am (THF) ~ Am
c!o c o
~ Formula 11 ~ Formula I
(Y~n ( )n
s~
wherein RJ R1J R2 J X~ Y and n are as hereinabove defined,
except Y cannot be lower alkylthio o:r oxides thereof and
R3 is lower alXyl or phenyl. Additionally, compounds
wherein Y is -S-alkyl are prepared f:rom compounds of
Formula I wherein Y is F (fluorine) by the following
reaction sequence:
t~'
~: O O
CHR_C_NRlR2 CHR_C_NRlR2
Am ~ Am
NaS-loweralkyl
C=O ~ C=O
~ Ib ~ Ic
F S-loweralkyl
and compounds wherein Y is lower alkyloxythio or lower
alkyldioxythio may be prepared by reacting compounds wherein
Y is lower alkylthio with l or 2 moles of sodium meta-
periodate or metachloro perbenzoic acid by the following
reaction sequence:
o O
~ CHR_C _NR 1 R2 ~CHR_C _NR 1 R2
NaIO 4
C=O C=O
~ ~ S-loweralkyl
S-loweralkyl Ol
~,~ CHR-C-NRlR2
or 2NaIO4
~ C=O
~ I-loweralkyl
8~
Compounds of Formula I wherein Am is dimethylamino may
be prepared by reacting the corresponding 2-amino compound
with sodium cyanoborohydride/ formaldehyde9 acetonitrile and
acetic acid.
The preparation of intermediate compounds of Formula II
are more fully illustrated in Preparations 6 to 15
Generally, these intermediates are prepared by first reacting
the appropriate 2-aminobenzophenonss with t-butylhypochlorite
-~ and the appropriate thioacetamide in the cold (-60 to -70C.)
followed by addition of triethylamine.
The intermediates of Formula II are reduced with Raney
nickel to compounds of Formula I in solvent except when Y =
-S-lower alkyl such as tetrahydrofuran and isolated by
removing solvent and crystallizing. Compounds of Formula I
are prepared a5 illustrated in the foregoing equation due to
.interference of Raney Ni on -.S-lower alkyl in the reduction
step.
38ll
8~
Preparat~on 1
4-[2-~Methylthioacetyl)]morpholine.
A mixture of 40.2 g (0.3 mole) of ethyl m~thylthio-
acetate and 130 g (1.5 mole) of morp~loline was heated at
reflux fox 70 hr. Fractional distil~ation at reduced
pressure gave 45 g (86O ofproduct 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
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
~ 150 C. 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 (94O of the titled compound as
a colorless liquid, b.p. 76-78C./o.4 mm Hg
Analysis: Calculated for C~HgNOS: C,40.31; H,7.61; N,11.75
Found : C,39.78; H,7.69; ~,11.88
Preparation 3
2-Methvlthio-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 amin~ and the ethanol
produced were removed by distillation and the residue was
25 distilled to give 129 g (97O of the titled compound as a
clear colorless liquid, b.p. 76-77C./0.5 mm Hg.
Analysis: Calculated for C5Hll~OS: C,45.08, H,8.32; N,10.51
Found : C,43.88; H,8.41; N,10.60
Preparation 4
2-(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 slow
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
sodium hydroxide. The mixture was haated at reflux for 1 hr.,
~,~2~5~
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 (o9O 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.~2; ~,10.55
PreParation
2-(1-Propvlthio)acetamide.
Utilizing the procedure of Preparation 4 but substituting
an equal molar amount of l-propanethiol for 2-propanethiol,
there was obtained 61.2 g (92 O of the title compound. The
15 white crystals melted at 49.5-51.0 C.
Analysis: Calculated for C5HllNOS: C,45.08; H,8.~2; N,10.51
Found : C~44.97; H,8.21l; N,10.40
Preparation 6
? -Amino-3-benzoyl-5-chloro-x-(methylthio)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 atmosphere, was added 6.o g (0.0552 mole) of
t-butylhypochlorite in 20 ml of methylene chloride. After
an additional 15 min stirring period, a suspension of 5.8 9
25 (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 extracted with several
portions of water and the organic layer dried over magnesium
sulfate. The volume of solution was reduced in vacuo to
about 200 ml and the pro~uct crystallized as a yellow solid,
m.p. 173.5-174.5C. Yield was 6.86 g (37.3O .
Analysis: calculated for Cl6Hl5N2O2SCl: C,57.40; H,4.52;
M,8.37
Found : C,57.38; H,4.50;
N,8.51
8S:~Z
Pre~aration 7
2-Amino-3-benzoyl~-(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 g (0.10
~5 mole) of 95~ t-butylhypochlorite in 30 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 adclitional hour at -60 C.
~10 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 orgariic 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 Cl6Hl6N2OzS: CJ63.98; H,5.37:
~J9-33
Found : CJ6~64~ H,5.39;
~,g.25
~- Preparation 8
2-Amino-3-(4-chlorobenzoyl)-~-(phenylthio)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 17.3 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
~0 added over a 20 min period. The temperature was maintained
at -64C. or below during these additions. After 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 filtration~ washed with 20~ aqueous ethanol
solution and dried to yield 36 g ( 610 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
Preearation 9
4-l2--(2-Amino-3-benzoylphenyl)-2-(methylthl)aCetY
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 golution was washed two times with 100 ml of water,
dried over magnesium sulfate a~d concentrated under reduced
pressure. The residue was chromatographed on 600 g of silica
gel eluting first with diisopropylether and finally with
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 O of yellow crystals, m.p. 119-121C.
Analysis: Calculated for C2oH22NzO3S: C,64.84; H,5.99;
N~7.56
Found : C,65.01; H,5.99;
N,7-57
Preparation 10
2-Amino-3-benzoyl-5-chloro~y-[(4-chlorophenyl)thio]-
phenylacetamide.
To a cold (-70 C.) solution o~ 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 methylene
chloride. After an additional 15 min stirring, a solution
35 of 17.35 g (o.0863 mole) of ~-(4-chlorophenylthio)acetamide
~31 21E~5~2
in 500 ml of a 50~50 mixture of tetrahydrofuran and methylene
chloride was added. The mixture was stirred at -70C. for
2 hr, 8.72 g (0.0863 mole) of triethylamine was added, and
the stirred solution was allowed to 1warm to room temperature
over a period of 2 hr. The reaction mixture was extracted
- with several portions of water and the organic layer dried
over magnesium sulfate. The volume of liquid was reduced
to about 500 ml. Methylene chloride, 500 ml, was added to
precipitate the product which after filtration and drying
weighed 16.62 g (44.7~). The yellow solid melted at 198-
200C.
Analysis: Calculated for CzlHl6NzOzSC12: C~58.48; H,3.74;
N,6.49
Found : C,58.49; H,3.77;
N,6.67
Preparation 11
2-Amino-3-benzoyl-5-chloro-~-(phenylthio)phenyl-
. .
acetamide.
To a cold (-70C.) 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
(0.360 mole) of t-butyl hypochlorite in 100 ml of methylene
chloride. After 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.~ 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 in vacuo and
yellow solid precipitated which when recrystallized from
acetonitrile was a yellow crystalline solid, m.p. 190-191C.(d).
Analysis: Calculated for C2lHl7N2O2SCl: C,63.55; H,4.32
N,7.o6
Found : C,63.62; H,4029
N,7 .o8
, ~
~l285~
Preparation 12
2-Amino-3-benzoyl~-(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 C21H18N2O2S: CJ69~59; H,5-01;
N,7-73
Found : C,69.33; H,5.00;
N,7-76
Preparation ~
2-Amino-3-benzoyl~-(methylthio)-N-methylphenylacetamide.
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone
in 350 ml of methylene chloride was cooled to -70C. and
17.9 g (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml
o 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%) of yellow needles, m.p. 149.0-150.0C.
Analysis: Calculated for Cl7Hl~N2O2S: CJ64.94; H,5.77;
N,8.91
Found : C, 65 .24; H,5.83;
N,8.99
Preparation 14
2-Amino-3=benzoyl~y-(methylthio)-N,N-dimethylphenyl-
o 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-N,N-dimethylacetamide was
added. To the mixture (-70C.) was added dropwise a solution
of 17 .2 g (0.15 mole) of 95% t-buty~hypochlorite in 30 ml of
:
~L~Z~ 2
13
methylene chloride. The temperature was maintained at or
below -65C. for 1.5 hr, then 15.1 g (0.15 mole) of tri-
ethylamine was added ra~idly. The solution was allowed to
warm to room temperature and was washed with water. The
organic solution was concentrated and the residue crystal-
lized when mixed with isopropyl ether The solid was
recrystallized from isopropyl alcohol to give 39.8 g (810
bright yellow crystals, m.p. 153-155 C.
Analysis: Calculated for Cl8H~oN202S: C,65.83; H,6.14;
N,8-53
Found : C~65.87; H~6.15;
N,8-5
Preparation 15
- 2-Amino-3-(4-fluorobenzoyl)-~-~n-propylthio)phenyl-
acetamide
A 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) o 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. 'rhe solution
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 19.5 g
(560 of yellow crystals melting at 140-142C.
Analysis: calculated for Cl8H19N202SF: CJ62.41; H,5.53;
,~ N,8.og
Found : C,62.34; H,5.58;
~,8.o4
.
~l2~S~2
14
Preparatlon 16
In the same manner as given in Preparation 8J
2-amino-3-(2-fluorobenzoyl)~ (phenylthio)phenyl-
acetamide,
2-amino-3-(4-trifluoromethylbenzoyl)-~-(phenylthio)
phenylacetamide,
2-amino-3-(2,4-dichLorobenzoyl)-~-(phenylthio)
phenylacetamide, ana
2-amino-3-(2,4-difluorobenzoyl)-~-(phenylthio)
phenylacetamide,
are prepared from phenylthioacetamide, t-butyl-
; hypochlorite, and
2-amino-2'-fluorobenzophenone,
2-amino-4'-trifluoromethylbenzophenone,
2-amino-2'~4'-dichlorobenzophenone, and
2-amino-2',4'-difluorobenzophenone.
Preparation 17
2-Amino-3-benzoyl-5-chloro-Y-(methylthio)-N-methyl-
phen~lacetamide.
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
mole) of 2--methylthio-~-methylacetamide in 100 ml of methylene
chloride was added. The solution was stirred at -70C. 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 31.56 g (54.60 which
melted at 170-171 C.
Analysis: calculated for Cl7Hl7~202SCl: C~58.53; H,4.91;
~8.03
Found : C,58.68; H,4.91;
~,8.1~
~Z8S~Z
Preparation 18
3-Benzoyl-2-(N methylamino)~y-(methylthio)phenyl-
acetamide.
When in accordance w~th the procedure o~ Preparation 7,
2-~-methylaminobenzophPnone is substituted in equimolar
5 amount for 2-aminobenzophenone, the title compound i5
obtained.
16
Example
2 -Amino-3-benzoYl-5-chlorophenylacetamide.
A mixtur~ of 21.34 g (0.0639 mole) of 2-amino-3-
benzoyl-5-chloro~ -~methylthio)-phenylace'camide and excess
Raney nickel in a mixture of 900 ml of absolute ethanol and
5 200 ml of dimethylformamide was stirred at room temperature
for 45 min. The mixture was filtered through celite to
~ ~ remove the Raney nickel. The solvent was removed ln vacuo
- to give a yellow solid which when recrystallized melted at
213.5-215.0C.( d).
10 Analysis: Calculated for Cl5Hl3N2O3Cl: C,62.40; HJ4.54;
N 9.70
Found : C,62.~55; H,4.58;
N,9. 74
2-Amino-3-benzoyl-phenylacetamide.
-
To an 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 ~ times with water and 3 times with tetrahydrofuran).
After 10 minutes the mixture was filtered to remove Raney
20 nickel and the filtrate concentrated under vacuum. The
residue was crystallized from isopropyl alcohol to give
6.o y (73%) of yellow needles, m,p. 178.5-180.0C.
Analysis: Calculated for Cl5Hl4N2O2: C, 70 . 85; H, 5 55;
N,11.02
Found CJ70~53 N,5.5~;
N,11.04
ExamPle 3
2=Amino-~i-(4-chlorobenzoyl)phenylacetamide.
To an agitated solution of 28.5 g (0.077 mole) of
2-amino-3-(4-chlorobenzoyl) ~-(phenylthio)phenylacetamide
in 1 liter of tetrahydrofuran was added 2~i0 g of wet Raney
nickel (washed 3 times with water and ~ times with tetra-
hydrofuran). After 15 minutes the mixture was filtered and
the filtrate concentrated under reduced pressure to give
17.4 g (84%) of yellow crystalline solid. Racrystallization
from isopropyl alcohol followed by recrystalllzing twice
from absolute ethanol gave yellow needles, m.p. 212-215C.
12
17
Analysis: Calculated for Cl5Hl3M2O2Cl: C,62.40; H,4.54;
N,9.70
Found : C,62.76; H,4.58,
N,9.~3
Example 4
4-~2-(2-Amino-3~benzoylphenyl)acetylJmorpholine.
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 Raney nickel. After 15 minutes the mixture was
filtered and the filtrate concentrated under reduced
pressure. After recrystallization of the residue from
isopropyl alcohol~ there was obtained 13.3 g (82~) of
bright yellow crystals, m.p. 156.5-158.5 C.
Analysis: Calculated for Cl~H20N2O3: C,70.35; H 6 22;
Found : C,70.24; HJ6.21;
M,8.63
Example 5
2-Amino-3-benzoYl-N-methylphenylacetamide.
; A solution of 22.5 g (0.072 mol) of 2-amino-3-benzoyl-
~-(methylthio)-N-methylphenylacetamide in 400 ml of tetra-
hydrofuran was treated with 160 g of wet Raney nickel
(washed 3 times with water and 3 times with tetrahydrofuran)
for 10 minutes. The mixture was filtered and the filtrate
was concentrated. The residue was crystallized from
- isopropyl alcohol to give 17.2 g (890 of yellow needles,
25 m.p. 145-146C.
Analysis: Calculated for Cl~Hl~N202: C,71.62; H,6.01;
N,10.44
Found : C,71.76, H,6.o5;
N,10.52
Example 6
3G 2-Amino-3-benzoy7-~ N-dimethvlphenylacetamide.
A solution of 33.0 g (0.1 mol) of 2-amino-3-benzoyl-
~-(methylthio)-N,~-dimethylphenylacetamide in 500 ml of
tetrahydro~uran was treated with 240 g of wet Raney nickel
(washed 3 times with water and 3 times with trtrahydrofuran)
for 10 minutes. Ths mixture was filtered and the filtrate
.
851Z
was concentrated. The residue was crystallized from
isopropyl alcohol to give 27.2 g (960 of yellow needles,
m.p. 123-124 C.
Analysis: calculated for Cl7Hl8N202: C,72.32, H,6.43;
~,g.92
Found : C,72.34; H,6.42,
~,9.g8
Example I
2-Amino-3-(4-fluorobenzoyl~-phenylacetamide.
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 3 times wi~h tetra-
hydrofuran). The mixture was stirred for one hour and
filtered. The filtrate was concentrated under vacuum and
the residue was recrystallized from 95~ ethyl alcohol to
give 14.8 g(78~/O~of yellow needles melting at 184-186 C.
Analysis: calculated for C15Hl3Nz02F: C,66.17; H,4.81;
N,10.29
Found : C,66.32; ~,4.81;
~,10.48
Example 8
In the same manner as given in Example 2,
2-amino-3-(2-fluorobenzoyl)phenylacetamide,
2-amino-3-(2,4-dichlorobenzoyl)phenylacetamide,
2-amino-3-(2,4-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)-~-(phenylthio)phenyl-
acetamide, and
2-amino-3-(4-trifluoromethylbenzoyl)-~-(phenylthio)-
phenylacetamide.
19
Example 9
2-Amino-3-~4-methylthiobenzoYl)phenylacetamide.
The title compound is prepared by refluxing 2-amino-
3-(4-fluorobenzoyl)phenylacetamide with excess sodium methyl
mercaptide in ethanol and isolated by suitable means.
Example 10
2-Amino-3-(4-oxymethylthiobenzoyl)phenylacetamide.
The title compound is prepared by reacting one mole of
2-amino-3-(4-methylthiobenzoyl)phenylacetamide with one mole
of sodium metaperiodate and isolated by suitable means.
Example 11
2-Amino-3-(4-dioxYmethylthiobenzoyl)~henylacetamide.
The title compound is prepared by reacting one mole of
2-amino-3-(4~methylthiobenzoyl)phenylacetamide with two
moles of sodium metaperiodate and isolated by suitable means.
Example 12
2-Amino-3-benzoyl-5-chloro-N-methylphenylacetamide.
A solution of 28.33 g (0.081 mole) of 2-amino-3-benzoyl-
5-chloro~x-(methylthio)-N-methylacetamide in one liter of
tetrahydrofuran was treated with excess Raney nickel at room
temperature for 2 hr. The solution was filtered through
celite. The Raney nickel residue was washed with acetone
and the wash filtered. The combined organic filtrates were
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 solid collected and dried weighed
20.94 g (85.68O and melted at 179-180 C.
Analysis: calculated for Cl6Hl5N202Cl: C,63.48; H,4.99;
N,9-25
Found : C,63.44; H~4.99;
~9.27
~ , '
.
.oL
Example 1~
3-BenzoyI-2-(N-methylamino)-phenylacetamide.
When in the procedure of Example 2, 3-benzoyl-2-
(N-methylamino)~x-(methylthio)phenylacetamide is substituted
for 2-amino-3-benzoyl-~-(methylthio)phenylacetamide, the
title compound is obtained.
Example 14
3-Benzoyl-2-(N,N-dimethylamino)-phenylacetamide.
A solution of 12.7 g (0.05 mol) of 2-amino-3-benzoyl-
phenylacetamide in 150 ml of acetonitrile i5 treated four
times with 16 ml (0.2 mole) of 37~ 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 diethylether. The ether
extracts are combined, dried over magnesium sulfate and
concentrated. The product is isolated by column chroma-
tography.
!;~
38
2 ~ ~ 2
21
Formulation and Administration
;~ The present invention also cont~emplates novel
compositions containing the compounds oP the invention as
active ingredients. Effective quantities o~ any of the
foregoing pharmacologically active compounds may be
administered 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 solutions or suspensions,
and in some cases intravenously in khe 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
starch, gelatin, glucose, magnesium carbonate, lactose,
malt and the like. Liquid compositions are also within the
purview o~ 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 9.1 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 500-1000 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 the 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 lik_, for administration and the proportion
38
22
,' .
of the active agent in the compositions may be varied
widely.
The followinq are examples of compositions formed in
accordance with this invention.
l. Capsules
Capsules of 5 mg., 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 m~.
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.~
Total4~5.0 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.
~ 30 of active ingredient per tablet follows. The formulation may-
;~ be used for other strengths of active ingredient by adjust-
~: ment of weight of dicalcium phosphate.
.
,~
:' '
'
~84
2~
Per tabletJ m~.
1) Active ingredient 5.0
2) Corn starch 1~.6
~) 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 blend with starch
paste and pass the wet mass through an eight mesh screen.
The wet granulation is dried and sized through a twelve
mesh screen. The dried granules are blended with the
calcium stearate and pressed.
~. Injectable - 2~ sterile solutions.
Per cc.
Active ingredient ............ 20 mg.
Preservative, e.g.,
cholorobutanol ...........Ø5~ wèight/volume
Water for injection .......... q.s.
-~ 20 Prepare solution, clarify 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~
compositionsJ 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.
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