Note: Descriptions are shown in the official language in which they were submitted.
!8~30
BACKGROIJND OF THE INVENTION
1. FIELD OF INVENTION
Our Canadlan Patent Application Serial No. 3O9J651 is concerned with
heterocyclic compounds possessing anti-emetic and gastric emptying properties
and is particularly concerned with certain N-(4-pyrazolidinyl)benzamides which
are useful for controlling emesis and which display gastric emptying proper-
ties in warm blooded animals with minimal side effects. This application,
which is divided out of Application Serial No. 309,6Sl, is concerned with
certain 4-aminopyrazolidines which are useful intermediates in the preparation
of the N-(4-pyrazolidinyl~benzamides.
2. DESCRIPTION OF THE PRIOR ART
The prior art discloses various benzamido derivatives wherein one
of the substituents attached to the benzamido nitrogen can be a pyrrolidinyl
or a piperidinyl radical. United States Patent 3,342,826 discloses hetero-
cyclic aminoalkyl benæamides having anti-emetic properties. United States
Patent 3,577,440 describes 1-substituted-3-amidopyrrolidines having analgetic
and anti~depressant properties. United States Patents 3,966,957 and 3,963,745
describe N-(l-substituted-3-pyrrolidinyl)benzamides and thiobenzamides as
particularly useful in controlling emesis.
SUMMARY OF THE INVENTION
The novel compounds of Application Serial No. 309,651 are
N-(1,2-hydrocarbyl-4-pyrazolidinyl)benzamides (I) which have the formula:
¦ O ~ (R )n
~ N _ C
R - N ~N
Il I
wherein;
- 2 -
~J
8~1~
R is low~r alkyl, lower cycloalkyl or phenyllower alkyl,
Rl is lower alkyl,lower cycloalkyl or phenyllower alkyl,
R2 is hydrogen, lower alkyl or phenyl,
R3 is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoro-
methyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido, R3 can be the same
radical or different radicals, and
n is an integer from zero to three inclusive.
The non-toxic pharmaceutically acceptable acid addition salts of
the basic compounds of Formula I are also included within the scope of the
invention, since such salts can likewise be used as anti-emetics or ~astric
emptying compounds. Both organic and inorganic acids can be employed to form
the pharmaceutically acceptable acid addition salts, illustrative acids being
sulfuric, nitric, phosphoric, citric, acetic, lactic, tartaric, sulfamic,
succinic, fumaric, maleic, hydrochloric, hydrobromic, benzoic, and the like.
The salts are prepared by methods well known to the art.
The anti-emetic properties were determined using a modification of
the methods of Chen and Enxor, J. Pharmac. Exp. Ther. 98, 245-250 ~1950) and
of Leonard et al., J. Pharmac. Exp. Ther. 154, 339-345 (1966).
The gastric emptying activity was determined using the following
procedure. Female Sprague-Dawley rats weighing 117-221 g. were starved 24
hours in individual screen-bottom cages with water ad libitum. Animals were
arranged in groups of eight. At time 0, 9 mg/kg of a test compound is adminis-
tered intraperitoneally to the rats in 5% acacia (0.4 ml/100 g. body weight).
The control group is dosed with acacia alone, 4 ml/kg intraperitoneally.
Thirty minutes following dosing, the rats are given orally, by stomach tube,
3 ml. of a test meal consisting of methylcellulose base to which had been
added beef bouillon, casein, powdered sugar and corn starch to yield a semi-
solid homogenous paste. Sixty minutes following the test meal (ninety minutes
total time), the rats are sacrificed by cervical dislocation, laparotomized
and the stomachs removed. The full stomachs are weighed on an analytical
8~
balance after which they are cut open, rinsed and the empty stomach weighed.
The difference between full and empty stomach weights represents the amount
of meal remaining in the stomach and is substracted from the weight of 3.0
ml. of test meal to yield the amount of meal emptied from the stomach during
the test period.
The preferred compound of Example 6 reduced emesis 87% when adminis-
tered at a dose level of 5 mg/kg ~s.c.) and increased the gastric emptying
time significantly when administered at doses from 0.33 to 9.0 mg/kg.
The lower alkyl moiety has 1 - ~ carbon atoms.
The term "lower cycloalkyl" as used herein includes primarily cyclic
alkyl radicals containing from four up to twelve carbon atoms inclusive and
includes such groups as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
methylcyclopentyl, ethylcyclohexyl and the like.
The term "phenyl" as used herein includes the unsubstituted phenyl
radical and phenyl radicals substituted by any radical or radicals which are
not reactive or otherwise interfering under the conditions of reaction de-
scribed herein such as lower-alkyl, lower-alkoxy, trifluoromethyl, bromo,
chloro, fluoro, and the like. The substituted phenyl radicals have preferably
no more than three substituents such as those given above and, furthermore,
these substituents can be in various available positions of the phenyl nucleus
~ and when more than one substituent is present, can be the same or different
- and can be in various position combinations relative to each other. The lower-
alkyl and lower-alkoxy substituents each have preferably from one to four
carbon atoms which can be arranged as straight or branched chains. Examples
of the preferred substituents are methyl, ethyl, propyl, butyl, fluoro, bromo,
chloro, iodo, amino, hydroxy, cyano, acetamido, sulfamoxyl, methoxy, ethoxy,
propoxy, butoxy and trifluoromethyl radicals.
The term "lower-alkyl" includes straight and branched chain radicals
containing 1 to 8 carbon atoms as, for example, methyl, ethyl, propyl, iso-
propyl, n-butyl, tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl, and n-octyl
8~
radicals. A "lower-alkoxy" radical has the formula -O-lower alkyl.
Included in the term "phenyllower-alkyl" are such groups as benzyl,
phenethyl, phenpropyl, ~-methylbenzyl, and the like.
This present application relates to novel 4-amino-1,2-hydrocarbyl-
pyrazolidines of formula II
lR2
l l N H
R - N J ~II)
~ Rl
wherein R is lower alkyl, lower cycloalkyl or phenyllower alkyl; R is lower
alkyl, lower cycloalkyl or phenyllower alkyl; R is hydrogen, lower alkyl or
phenyl.
The compounds of formula II are prepared by:
(a) reacting a compound of formula
X (V)
R
wherein X is halogen, preferably chlorine, and R and Rl are as defined above,
with ammonia or a lower alkylamine under pressure at an elevated temperature
to provide a compound of formula II wherein R is hydrogen or lower alkyl
and R and R are as defined above; or
(b) reacting a compound of formula
R6 (VI)
N ~ N
R
. - 5 -
wherein R and Rl are as defined above and R6 is an arylsulfonyloxy radical
with an aniline whic}l may be substituted, to prepare a compound of formula
II above wherein R2 is a phenyl group, or
(c) hydrolysing a 1,2-hydrocarbyl-4-phthalimidopyrazolidine which
is substituted in the 1- and 2-position by substituents R and R as defined
above.
The compounds of Formula II wherein R2 is hydrogen can be prepared
by heating a mixture of a 4-halo-1,2-hydrocarbylpyrazolldine and concentrated
ammonium hydroxide in a steel bomb at a temperature of from about 125C to
about 200~C for a period of several hours. The procedure is also applicable
to prepare compounds wherein R2 is lower alkyl such as methyl, ethyl, o-r pro-
pyl. In the latter case a solution of the appropriate lower alkylamine in a
lower alkanol is preferably used.
The compounds of Formula II wherein R is phenyl can be prepared
by reacting a 1,2-hydrocarbyl-4-arylsulfonyloxypyrazolidine and aniline or a
substituted aniline together in a suitable solvent. The 1,2-hydrocarbyl-4-
arylsulfonyloxypyrazolidine is generally prepared by reacting the sodium salt
of a 1,2-hydrocarbyl-4-pyrazolidinol with benzenesulfonyl chloride or p-tolyl-
sulfonyl chloride in a dry aprotic solvent such as toluene.
The 1,2~hydrocarbyl-4-pyrazolidinols from which the respective 4-
aminopyrazolidinols are prepared are either disclosed in or they can be pre-
pared by the procedures disclosed in United States Patent No. 3,660,426.
s ~ f~ ~r~
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~1~ hydrc~a~ pllt.h~l t lmldo~lyr.azo.lit.l1rl~ ar:s~ u~;~cl a~ a
r~acî,ant. Th~ l.at.tt3r ar~ prt~pf~.r oli ~y t~ eelc~ inll
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pot~a~ n l)llt.hal:lml.(.ls~, Tht~ 1,2-hy(ll:i)cat~t~yl
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;2r~ at~ Z I~ x~ e ~ .t.~Zr~Z~(1 arl~l k~ Z ac~.ld fi~lt.~ t.
.fit~Ztl t.c. ~ t~l.at:~Z tll~? :~rt~ 4 alll.Lr~o~
}~yc~ ar~y.ll?~,)rAz~ .ic~ Zc~k~Z~l w:it.~l a ~lnt~t~c.
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3 4 6 - C I P -1
., I
Another alternate method which can be used in
preparing th~ novel compounds of Formula I utilizes an
appropriately substituted benzoic acid which is contacted
with ethylchlorocarbonate in the presence of triethylamine
5 in methylene chloride at 0-5C to form the mixed anhydride
of the benzoic acid. After approximately one hour at
the lower temperature, a solution of the 4-amino-1,2-
; hydrocarbylpyrazolidine is added. Subsequent to an
additional period of stirring, an aqueous sodium
10 bicarbonate solution is added to the reaction mixture,
the organic phase is separated and the benzamide
compound is isolated therefrom by suitable means.
~ The substituted benzoyl chlorides III useful in
I practicing the present invention are either known
' 7 15 compounds or they can be prepared by procedures well
,' ~ known to the art and include but are not limited to the
-' following:
: 2-fluorobenzoyl chloride
' 3-bromobenzoyl chloride
; 20 4-bromobenzoyl chloride
; 3,5-dinitrobenzoyl chloride
. 3,4-dichlorobenzoyl chloride
3,4-diethoxybenzoyl chloride
3-trifluoromethylbenzoyl chloride
, 25 4-tertiarybutylbenzoyl chloride
4-butoxybenzoyl chloride
2,4-dimethoxybenzoyl chloxide
; 4-methylbenzoyl chloride
3 4-cyanobenzoyl chloride
2-methoxy-5-sulfamoylbenzoyl chloride
~ 2-methoxy-4-dimethylaminobenzoyl chloride
.~ 2-methoxy-4~nitrobenzoyl chloride
2-methoxy-3-fluoro-5-chlorobenzoyl chloride
2-ethoxy-4-bromobenzoyl chloride
2-methoxy-3-acetamido-5-trifluoromethylbenzoyl
chloride
,~
^ .
f
346-CIP-l
'
. In Formula I centers of asymmetry are present. The
- ~ compounds can be resolved Lnto their optically active
.~ forms by combining the compounds with optically active
; organic acids and separating the optically active forms
~ 5 by fractional crystallization. The optically active
- . forms are included within the scope of the present
invention.
!
P
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~ '' , .
'.,' ' ' .
,~ ~
. ~
1109880 346-CIP-1
~;
!
' Prepara~ion 1
, ,
4-Chloro-1,2-diethylpvrazolidine.
A solution of triphenyl phosphine (52 g.; 0.2 mole)
in 150 ml. of chloroform was treated with chlorine gas
- 5 which was accompanied by a rise in the temperature of
the mixture to 60C. until excess chlorine gas appeared
over the surface of the mixture. Air was passed into
- the mixture until the greenish yellow gas disappeared.
To the cooled (30C.) stirred mixture was added dropwise
28.8 g. (0.2 mole) of 1,2-diethyl-4-pyrazolidinol at a
rate which caused the reaction mixture to rise to 40C.
Subsequent to the addition, the stirred solution was
refluxed two hours, cooled to room tempera~ure and
extracted with water. The combined aqueous extracts
; 15 were basified with concentrated sodium hydroxide solution
, and the basic mixture extract~d with chloroform. The
Ç, : dried chloroform extract (sodium sulfate) was concentrated
. at reduced pressure and the residual material distilled
at 92-94C./30 mm. to give 24.5 g. (75%) of product.
Analysis: Calculated for C7X15N2Cl: C,51.68; H,9.29; H,17.22
Found : C,51.45; H,9.30; H,17.29
s Preparation 2
4-Amino-1,2-diethylp~razolidine.
A mixture of 100 g. (0.615 mole) of 4-chloro-1,2-diethyl-
25 pyrazolidine and 200 ml. of concentrated ammonium hydroxide
; in a closed steel chamber was heated at 150C. for
. approximately 36 hours. The cooled reaction mixture was
extracted with isopropyl ether, the aqueous layer saturated
with potassium carbonate and continuously extracted with
30 chloroform for six hours. The dried chloroform extract
(sodium sulfate~ was concentrated at reduced pressure
~` and the residue distilled at 113-115C./40 mm. to give
40.5 g. (45.5%) of product.
~ t~
:
. ~
. .
. ~
~ _ _ _ . _ _ _ _ . . _ _ . _ _ _ . _ . _ _ . _ _ _ _ . . . . . .. _ . _ _ _ _ _ _ ., . _ , _ . _ , .
f
11 346-CIP-1
,, j
Pre~aration 3
4-Amino~1,2-dimethvl~vrazolidine.
A mixture of 300 g. ~2.22 mole) of 4-chloro-1,2-
dimethylpyrazolidine and 600 ml. of conc. ammonium
hydroxide was heated at 150C. for 18 hrs. in a steel
bomb. The cooled mixture was saturated with potassium
carbonate and continuously extracted for 18 hrs. with
chloroform. The residual material after concentration
of the chloroform e~tract was distilled at 9o-100C./40
mm. to give 73 g. of product.
Preparation 4
4-Anilino-1,2-dimethYlpYrazolidine.
A stirred suspension of 40 g. (1.02 mole) of
sodamide in dry toluene was treated dropwise with 116 g.
15 (1.0 mole) of 1,2-dimethyl-4-pyr~zolidinol at 80C.
` After 4.5 hrs. at reflux the mixture was cooled and
maintained below 20C. while 161.0 g. (1.0 mole) of
benzenesulfonyl chloride was added dropwise. After
stirring 1.0 hr. the reaction mixture was shaken with
dilute sodium hydroxide, the separated toluene layer
dried over sodium sulfate and concentrated at reduced
pressure. The residue was dissolved in 300 ml. of
aniline, the mixture heated 2.5 hrs. on the steam bath
and refluxed for 3.0 hrs. The cooled mixture was
extracted with dilute sodium hydroxide solution and the
separated aqueous layer extracted with isopropyl ether.
The combined organic layers after drying over sodium
sulfate were concentrated and the residue distilled to a
pot temperature of 140C./80 mm. The residue which
30 would not crystallize was distilled at 110-125C./0.1
mm. to give 86 g. of product.
Preparation 5
4-Anilino-1,2-diethvlpYrazolidine.
~ To a stirred suspension of 7.9 g. (0.2 mole) of
_ 35 sodamide in 100 ml. of dry toluene was added 28.8 g.
~ (0.2 mole) of 1,2-diethyl-4-pyrazolidinol at a rate so
,~
- - .
8~ (-
346-CIP 1
12
that a pot temperature of 30-35C. was maintained.
After stirring 2.0 hrs. at room temperature, the solu-
tion was added dropwise to a solution of 38.0 g. (0.2
mole) of p-toluenesulfon~l chloride in 200 ml. of dry
toluene with the pot temperature maintained below 30C.
After stirring for about one hr. at room temperature,
the reaction mi~ture was washed twice with water and
dried over sodium sulfate. The dried filtered solution
, was concentrated to a volume of about loo ml., aniline
(loO ml.) was added, the solution refluxed for 3.0 hrs.
~` and then concentrated. The residue was partitioned
between chloroform and dilute sodium hydroxide. The
dried chloroform layer was concentrated and the residue
I distilled at 120C./0.1 mm. to give 4.0 ~. of product.
Pre~aration 6
1,2-Diethyl-4-~hthalimido-~vrazolidine Maleate.
To.100 ml. of dimethyl sulfoxide was added 32.4 g.
(.2 mole) of 4-chloro-1,2-diethylpyrazolidine and 37 g.
(.2 mole) of potassium phthalimide. The solution was
stirred at 115C. for 48 hours., cooled and filtered.
The filtrate was treated with an equal volume of water
and extracted 2 times with 150 ml. of ethyl acetate.
The extracts were combined and concentrated. The resi-
due was partitioned between dilute hydrochloric acid and
ethyl acetate. The acid layer was made basic with
potassium carbonate and extracted with chloroform. The
chloroform was dried (sodium sulfate) and concentrated.
The residue (22 g.) was treated with 22 g. of maleic
acid and 75 ml. of isopropyl alcohol and 7S ml. of
isopropyl ether. The maleate salt was recrystallized
twice from the same solvent system to give ll.S g. (15%)
of product which ~elted at 144-147~C.
Analysis: Calculated for ClgH23N3O6 C,58.60; H,5.95; N,10.79
Found : C,58.64; H,6.03; n,10.73
. .
` ~ 1~l~9~30
346-CIP-l
13
Preparation 7
4-Amino-l-benzYl-2-methylpyrazolidine.
4-Amino-l-benzyl-2-methylpyrazolidine, b.p. 115-
125C./l.0 mm., was prepared from 1-benzyl-2-methyl-4-
pyrazolidinol according to preparations 1 and 2.
Pre~aration 8
4-Amino-l-cyclohexyl-2-methylpyrazolidine Fumarate.
4-Amino-1-cyclohexyl-2-methylpyrazolidine, b.p.
90-100C./0.5-1.0 mm., was prepared from 1-cyclohexyl-2-
methylpyrazolidinol according to preparations 1 and 2.
The fumarate salt melted at 149-151C.
Preparation 9
4-Amino-l-iso~ropvl-2-methYlpyrazolidine.
4-Amino-l-isopropyl-2-methylpyrazolidine, b.p.
110-115C./50 mm., was prepared from 1-isopropyl-2-
methylpyrazolidinol according to preparations 1 and 2.
PreParation 10
^ When in the procedure of Preparation 2, concentrated
- ammonium hydroxide is replaced by an e~ual molar amount
of methylamine in methanol, there is obtained 4-
- methylamino-1,2-diethylpyrazolidine.
j,
'~
.~
346-CIP-1
14
E;~ am ~i 1 e
4-Chloro-N-phenyl-N-(1,2-dimethyl-4-p~razolidlnyl)-
benzamide.
To a solution of 10 g. (0.0525 mole) of 1,2-dimethyl-
4~anilinopyrazolidine in 50 ml. of chloroform was addedwith stirring 9.15 g. (O.0525 mo]e) of p-chlorobenzoyl
chloride with the temperature not exceeding 50C. On
completion of addition the solution was refluxed for one
hour, cooled to room t~mperature and extracted with
dilute sodium hydroxide. The chloroform layer was dried
over sodium sulfate and concentrated at reduced pressure
to give an oil which cr~stallized upon cooling. The
; solid was recrystallized twice from ligroin. Yield 13.1
! g. (76%); m.p. 104-108C.
Analysis: Calculated for C18H20ClN30: C,65.54; H,6.11; N,12.74
Found : C,65.77; H,6.08; N,12.86
Ex~n~le 2
4-Fluoro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide~
A solution of lO ~. (0.026 mole) of 1,2-diethyl-4-
phthalimidopyrazolidine maleate in 25 ml. of 6N hydrochloricacid was refluxed two hours, the resulting mixture was
cooled and filtered. The filter cake was washed with
; water which was combined with the acidic solution. The
acidic solution was made basic with dilute sodium
, 25 hydroxide and cooled with ice. To the resulting solu-
tion was added 8.2 g. ~0.052 mole) of p-fluorobenzoyl
chloride and the mixture shaken for lO minutes. The
resulting mixture was extracted with chloroform, the
chloroform diluted with an equal volume of isopropyl
ether and the resulting solution extracted with dilute
hydrochloric acid. The acid layer was made basic with
dilute sodium hydroxide and extracted with chloroform.
The chloroform was dried (sodium sulfate) and concen-
- trated. The residue was crystallized from isooctane-
isopropyl ether and recrystallized from isooctane-
isopropyl ether containing a few drops of ethyl acetate
f
9880
' 346-CIP-1
1~
and clarified hy charc~al tre~aLrr,erlt. The product (2.0
g; 29%) melted at 114-116C.
Analysis: Calc~llated for C~ 32o~l3~: C,63.38; H,7.60; N,15.84
Found : C,63.36; H,7.61; N,15.96
EXamD1e ~
3, 4, 5-Tr1methOX~-N- ( 1, 2 -d1methY1-4-PVraZO1idinY1 ~-
benzamide.
To 10 g (0.09 mole) of ~-~nino-1,2-
dimethylpyrazolidine in chlorofol~ was added with stirring
20.7 g. (0.09 mole) of 3,4,5-trimethoxybenzoyl chloride.
After 30 minutes of stirring the solution was extracted
with dilute sodium hydroxide. The chloroform solution
was dried (sodium sulfat~), filtered, and the filtrate
concentrated. The resulting crystalline material was
recrystallized from equal portions of ethyl acetate and
~ isopropyl ether. The product (12.1 g~; 44%) melted at
; 163-166~C.
Analysis: Calculated for Cl5H23N304: C,58.24; H,7.49; N,13.58
Found : C,58.20; H,7.45; N,13.19
Example 4
4-Nitro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide
'- - HYdrochloride.
To a solution of 40.5 g (0.28 mole) of 4-amino-1,2-
diethylpyra701idine in 200 ml of chloroform was added
; 25 with stirring 52 g (0.28 mole) of p-nitrobenzoyl chloride
- in 200 ml chloroform. The solution was allowed to stand
overnight and then extracted with dilute sodium hydroxide.
The chloroform was dried (sodium sulfate) and concentrated.
The residue was crystallized twice from isopropyl ether-
ethyl acetate to give 73 g. (80%) of the free base.
Analysis: Calculated for Cl~H20N~03: C,57.52i H,6.90; N,19.17
Found : C,57.56; H,6.94i N,18.99
~ The base was converted to the hydrochloride salt and
,~ crystallized from isopropyl alcohol which melted at
35 139-191C (dec.).
:~ .
:
,
0 346-CIP-l
16
Analysis: Calculated for Cl9H~lN.I03Cl: C,51.14; H,6.44; N,17.04
Found : C,50.96; H,6.59; N,16.58
. ExamDle 5
4-Amino-N-(1, 2-diethyl-4-pyrazolldinyl)benzamide.
A solution of 20 g. (0.069 mole) of 4-nitro-N-(1,2-
diethyl-4-pyrazolidinyl)benzamide in ethanol was treated
with Raney nickel and shaken in three atmospheres of
hydrogen in a Parr apparatus at room temperature for two
hours. The mixture was filtered, the filtrate concen-
trated and the residue crystallized from isopropyl
ether-ethyl acetate. The product (12.0 g.; 66.5%) melted
at 119-121C.
Analysis: Calculated for C14H22N40: C,64.09; H,8.45; N,21.36
! Found : C,63.98; H,8.55; N,21.37
; 15 Exam~le 6
. 4-Amino-5-chloro-2-methoxv-N-(1,2-diethyl-4-
;~ pyrazolidinyl~ben2amide.
To 75 ml. of thionyl chloride was added 12 g. (0.05
- mole) of 4-acetamido-5-chloro 2-methoxy-benzoic acid and
the stirred suspension refluxed one hour. The resulting
solution was concentrated and 100 ml. of chloroform added
to the residue which was concentrated to remove traces
of thionyl chloride. The residue was dissolved in 100
ml. of chloroform and the solution added at a rapid drop
to 7 g. (0.05 mole) of 4-amino-1,2-diethylpyrazolidine in
100 ml. of chloroform while stirring and cooling to
20-25C. with an ice bath. After 30 minutes the chloro-
form solution was extracted two times with 100 ml. of 3N
I hydrochloric acid and the chloroform solution retained.
The acid extract was boiled 10 minutes, cooled with ice,
'~ made basic with concentrated sodium hydroxide while
cooling and extracted with chloroform. The chloroform
was dried (sodium sulfate), concentrated and the residue
crystallized from isopropyl ether-isooctane to give 3 g.
; 35 of material which melted at 116-118C. The retained
chloroform solution was extracted with dilute sodium
,, .
.
.
- 346-CIP-1
17
hydroxide and concentrated. The residue was dissolved
in 3N hydrochloric acid and extracted with isopropyl
ether. The acid solution was refluxed for 10 minutes,
cooled with ice bath, made basic with sodium hydroxide
S whlle cooling and extracted with chloroform. The chloro-
form was dried (sodium sulfate) and concentrated. The
residue was crystallized three times from isopropyl
ether to give 0.7 g. of material which melted at 117-119C.
A mixture melting point of both materials gave no depres-
sion of the melting point. The combined yield was 3.7 g.
(23~).
Analysis: Calculated for C15H23ClN4O2: C,55.13; H,7.09; N,17.14
Found : C,55.23; H,7.10; N,17.17
~;i Exam~le 7
When in the procedure of Example 3 there is substituted
for 3,4,5-trimethoxybenzoyl chloride equal molar amounts
of:
4-cyanobenzoyl chloride,
3-trifluoromethylbenzoyl chloride,
20 4-methylbenzoyl chloride,
4-metho~ybenzoyl chloride,
4-acetamidobenzoyl chloride, and
2-methoxy-5-sulfamoylbenzoyl chloride,
there are obtained:
- 25 4-cyano-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide,
3-trifluoromethyl-N-(1,2-dimethyl-4-pyrazolidinyl)-
` benzamide,
4-methyl-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide,
1 4-methoxy-N-(1,2-dimethyl-4-pyrazolidinyl)-
benzamide,
4-acetamido~N-(1,2-dimethyl-4-pyrazolidinyl)-
benzamide, and
t 2-methoxy-5-sulfamoyl-N-(1,2-dimethyl- 4-
pyrazolidinyl)benzamide.
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~ 80 346-CIP-1
18
Exam~ e 8
4-Amino-5-chloro-2-methoxy-N-1,2-dimethyl-4-
.,
Yrazol-idinylbenzamid -e .
A stirred solution of equal molar amounts of 4-amino-
S-chloro-2-methoxybenzoic acid and triethylamine in
methylene chloride (0-5C) was treated dropwise with a
slight excess of ethylchlorocarbonate. After 1.0 hour a
solution of 4-amlno-1,2-dimethylpyrazolidine in methylene
chloride was added and the mixture stirred for about two
hours at room temperature. An agueous solution of
` sodium bicarbonate was added to the reaction mixture,
the organic phase separated and concentrated to give the
` ' product which melted at 169-171C.
Example 9
4-Amino-5-chloro-2-methoxY-N-(l-benzYl-2-methYl-4-
~yrazolidinYl)benzamide Fumarate.
; 4-Amino-5-chloro-2-methoxy-N-(1-benzyl-2-methyl-4-
' pyrazolidinyl)benzamide was prepared from 4-amino-5-
chloro-2-methoxybenzoic acid and 4-amino-1-benzyl-2-
~; 20 methylpyrazolidine according to the procedure of Example
8. The fumarate salt was prepared and it melted at
129-131~C.
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346-CIP-1
19
Example 10
4-Amino-5-chloro-2-methoxy-N-(l-cyclohexyl-2-
methyl-4-pyrazolidinyl)benzamide was prepared from
4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-
S 1-cyclohexyl-2-methylpyrazolidine according to the
procedure of Example 8. Melting point of the hydro-
chloride hydrate was 105-120C.
Example 11
4-Amino-5-chloro-2-methoxy-N-(l-isoPropyl-2
`. 10 methYl-4-~vrazolidinYl)benzamide Dihydrochloride.
4-Amino-5-chloro-2-methoxy-N-(l-isopropyl-2-methyl-
4-pyrazolidinyl~benzamide was prepared from 4-amino-5-
chloro-2-methoxybenzoic acid and 4-amino-1-isopropyl-2-
methylpyrazolidine according to the procedure of Example
8. The dihydrochloride salt was prepared and it melted
at 162-166C.
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11~39~80
The pharmaceutical compositions comprise compounds of Formula I
above in an amount to provide effective anti-emetic and gastric emptying ac-
tion. The compositions contain 1.0 mg. to 100 mg. active medicament per unit
dose. Preferably, the compositions contain from about 5 mg. to 100 mg. of
medicament, advantageously from about 5 mg. to about 50 mg. per unit dose.
The pharmaceutical carrier employed in the composition can be either
solid or liquid. Exemplary of solid carriers are lactose, magnesium stearate,
terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
Exemplary of liquid carriers are vegetable oils and water. Similarly, the
carrier or diluent may include a sustained release material such as glyceryl
monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed by methods
well known to the art. Thus, if a solid carrier is used the composition can
be tableted or prepared as a powder, a troche or a lozenge. Gelatin capsules
' containing the medicament can also be prepared. If a liquid carrier is used,
the composition can be in the form of a soft gelatin capsule, a liquid suspen-
sion or a syrup. Parenteral dosage forms are obtained-by dissolving a water-
soluble salt of the active agent in water or saline solution in a concentration
such that 1 cc. of the solution contains from 1.0 mg. to 25 mg. of active
. 20 agent. The solution can be filled into single or multiple dose ampules.
The method of use of the compounds comprises administering inter-
, nally to warm blooded animals including human beings certain N-~4-pyrazolidi-
nyl)benzamides or a non-toxic organic or inorganic acid addition salt thereof,
preferably with a non-toxic pharmaceutical carrier such as described above,
in an amount sufficient to control emesis and/or
- 20 -
8V
346-CIP-l
21
facilitate gastric emptying. The active agent is
administered orally or parenterally in repeated doses
until satisfactory response is obtained. The daily
dosage is from about 10 my. to about 300 mg. of active
S ~edicsment, advantageously from about 5 mg. to 50 mg.
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