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Патент USA US3040071

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United States Patent 0 ice
2
1
' Also included within the scope of this invention are the
3,040,061
acid addition salts of the basic nitrogen compounds
described.
The alkylene radicals of which Z is representative are
derived from aliphatic groups containing two unoccupied
N-SUBSTITUTED AMIDES 0F OMEGA-HYDRA
ZINO ALKANOIC ACIDS
Barry M. Bloom, Lyme, Conn., and Robert E. Carnahan,
Evansville, Ind., assignors to ‘Chas. P?zer & Co., Inc.,
New York, N.Y., a corporation of Delaware
No Drawing Continuation of application Ser. No.
808,921, Apr. 27, 1959. This application June 1, 1961,
Ser. No. 114,002
'
3,040,061
Patented June 19, 1962
8 Claims. (Cl. 260—347.3)
This invention relates to new and useful compounds
which are valuable therapeutic agents. More particularly,
it is an object of this invention to provide new and useful
compounds which are chemotherapeutic agents valuable
in the treatment of mental disease, commonly referred to
as psychic energizers. Other objects of the present inven
tion will become obvious from the following disclosure.
The new compounds of the present invention may be
represented by the following formula:
R1
A——NHNH Z 0 ON/
a, .
valences which permit them to be further connected as
indicated for Z in the structural formula. Such radicals
may be straight or branched and contain from 1 to 4
carbon atoms in their principal chain, that is, in the carbon
chain between the two unoccupied valences. The carbon
content of the various hydrocarbon substituents described
above represents preferred substituents. These are pre
ferred since compounds containing them are readily pre
parable and economical. Of course, substituents of higher
15 carbon content may be employed.
The various hydrocarbon radicals described may be
further substituted by the various substituents previously
mentioned. Further, the aryl and heterocyclic radicals
may be replaced by the corresponding benz-type com
20 pounds, that is, those containing a fused benzene ring, such
as naphthalene, benzofuran, benzothiophene and the like,
with no appreciable advantage being realized. Particularly
valuable are compounds of the formula:
in which Z is an alkylene radical containing. 1 to 5 carbon 25
atoms
R1
/
RC ONENHZ C 0N
R2
1,
R1 is hydrogen or lower alkyl;
especially those in which R2 is an aralkyl group.v Addi
R2 is selected from the group consisting of alkyl and
tionally, those compounds in which RC0 is derived from
alkenyl preferably containing up to 5 carbon atoms;
cycloalkyl containing 3 to 6 carbon atoms, pyridyl, 30 an amino acid possess desirable therapeutic properties.
The new compounds of this invention may be prepared‘
,pyridylalkyl, furylalkyl and thienylalkyl in which the
by reaction of an amine of the formula, R1(R2)NH, in
akyl group is lower alkyl, and ring-substituted deriva
which R1 and R2 are as described above, with correspond
tives thereof in‘ which said ring-substituent is a lower
ing lower alkyl esters of the formula:
alkyl group; aryl and aralkyl represented by the formula:
35
I X? (0112):;
ANHNHZCOOR,
wherein R4 is alkyl preferably containing 1 to 3 carbon
YJ
atoms and A and Z are as described above. It is obvious
that those compounds in which A is an acyl group (RCO)
wherein X is hydrogen, lower alkyl or halogen; Y is hy
drogen, lower alkyl, lower alkoxy, halogen, tri?uoro
methyl, cyano or alkanoyl containing 2 to 4 carbon atoms;
and n is an integer from 0 to 4.
A is ‘hydrogen or an acyl group of the formula
40
may also be prepared by the acylation of the compounds
in which A is hydrogen. Although the reaction may be
brought about by simply mixing the selected amine with
the alkyl ester and allowing the mixture to stand at room
temperature (about 20° C.) for from about 1 to about 3
45 days, it is generally preferred to heat the reaction mixture
to a temperature of from about 60° to about 200° C. since
RC
ll
shorter reaction time is realized in so doing. For example,
wherein R is selected from the group consistingof
[Z
when the reaction is carried out at about 130° C., a reac
tion time of 2 to 4 hours is found to give excellent yield of
50 product. Generally, an equal molar ratio of reactants is
employed although slight molar excesses (up to 10%) of
amine may be advantageously used in the present, process.
The use of a larger excess provides no appreciable ad
vantage and is not preferred. After the reaction is com
55 plete, the cooled reaction mass is recrystallized from a
x
(0112)“
Y
suitable solvent, such as ethyl acetate, lower alkanols, for
example, methanol, ethanol, propanol etc. and the like.
The above mentioned alkyl esters which are used in the
preparation of the instant therapeutic agents may be pre
wherein D is selected from the group consisting of alkyl 60 pared by procedures known in the art. One such pro
cedure involves two steps, the ?rst, the formation of the
and alkenyl containing up to 20 carbon atoms; a and b
are substituents each selected from the group consisting
hydrazone of a suitable carbonyl compound, and the sec—
which the alkanoyl group contains 2 to 4 carbon atoms.
a lower alkanol, such as methanol, ethanol or propanol, or
end, the reduction of the hydrazone to the desired ester.
of hydrogen, amino, lower valkylamino, hydroxy, lower
The ?rst of these reactions is brought about by re?ux
alkoxy, mercapto, lower alkylrnercapto, halogen and
alkanoylamino, alkanoyloxy and alkanoylmercapto, in 65 ing the carbonyl compound with the selected hydrazine in
E is selected from the group consisting of cycloalkyl con
taining 3 to 6 carbon atoms, pyridyl, furyl, thienyl, thi
aromatic hydrocarbon such as benzene, toluene, etc. Ex
cellent yields are obtained after heating for periods of
from about 1 to 4 hours. Many of the products separate
‘azolyl, oxazolyl, isoxazolyl and ring-substituted derivatives
thereof in which said ring-substituent is a lower alkyl group 70 almost instantaneously on initiating reaction. After the
reaction is complete, the hydrazone is obtained by cooling
m is an integer ham 0 to 4, and X, Y and n are as
the reaction mixture and ?ltering. The product may be
previously described.
3,040,061
3
.
further treated by standard procedures of recrystalliza
tion. The second step, viz. hydrogenation of the hydra
zone, may be accomplished by reaction with hydrogen
over a platinum oxide catalyst. The hydrogenation is con
veniently e?ected at pressures slightly higher than atmos
pheric pressure, for example, 30 to 50 pounds of hydro
gen gas per square inch.
4
7
,
alkanoyloxy, in which the alkanoyl group contains 2 to 4
carbon atoms.
.
.
For example, a lower alkyf-‘ester of acrylic acid is con
densed with RCONHNH2, in ,which R is as above de
scribed to produce
’-
.
The use of higher pressures
provides no appreciable’ advantage and is therefore, not
preferred. Theselected condensation product is dissolved
The reaction is carried out by heating a mixture of the
two reactants in at least an equimolar ratio in an inert
in a lower alkanol and reacted with hydrogen gas over 10 organic solvent and in the presence of a lower alkanoic
the above-described catalyst, employed at 1% to 5%
acid which is generally employed in catalytic amounts.
by weight of the substrate. The mixture is shaken in a
At least 1% of alkanoic acid by volume of the total re
standard shaker apparatus until the theoretical quantity
action mixture should be employed. Generally, it is found
of hydrogen gas is taken up. The desired product is then
that the optimum level of alkanoic acid is from 1% to 5%
obtained by the usual procedures of ?ltration of catalyst
by volume of the total reaction mixture. Larger amounts
and concentration of the ?ltrate. Alternatively, a hydra
of catalyst may be used but reduced yield of product may
zinoalkanoic acid ester of hydrazinoalkanoamide may be
be realized in so doing. Although it is preferred to em
acylated to form those compounds in which A is an acyl
ploy acetic acid as catalyst, other lower alkanoic acids
group employing standard procedures, such as a suitable
may be used, viz. formic, propionic, butyric and the like.
acid chloride (RCOCl) in the presence of pyridine. Addi 20 By inert organic solvents as employed herein is meant an
tional preparative methods are obvious to one skilled
organic solvent which dissolves the reactants but does.
in the art. For example, the selected hydrazine compound
not react with same under the reaction conditions de
may be reacted with a suitable amide, such as
scribed. Such solvents may be readily determined by
R1
to form ANHN=CHCHgC ON
/R1
‘ routine experimentation in the laboratory.
Although a
25 number of other solvents may be employed, excellent re
sults are obtained when using tertiary alcohols. Tertiary
alcohols, as is well known, are alcohols in which there is
followed by hydrogenation of the resulting hydrazone to
Y; no hydrogen on the carbon atom to which the hydroxy
group is attached, each of the valences of this carbon
It has been surprisingly found that a class of the alkyl 30 atom are involved in carbon to carbon linkage.’ Exem
plary of these alcohols are tertiary butyl alcohol, 1,1-di
esters from the group represented by the formula
methylpropanol, 1,1-dimethylbutanol, -1-methyl-l ethyl
RCONHNHZCOOR, as well as the corresponding amides
; butanol, 1,1-dimethylpentanol and the like. The mixture
of the formula
'
is conveniently heated at the re?ux temperature of the
R1
35 solvent, although lower temperatures may also be em
/
ployed, for example, a temperature of 50° C. The reac
tion is completed in as little as 6 hours although generally,
B:
~; time periods of from 6 to 18 hours at the above speci?ed
may be prepared by the condensation of a hydrazine,
temperatures are employed. In many cases, the use of
RCONHNHZ with a,B-unsaturated esters or amides of the 40 excess 01,}9-11I1S3t111'?t6d acid ester is found to appreciably .
' formula: R3CH=CHCOG, wherein G is selected from
improve the yield of the product. Up to 40% molar ex
the group consisting of a
cess of unsaturated ester is found to enhance the yield of
, product. After the reaction is complete, the product is
.
Rx
obtained by standard procedures, such as concentration,
-0R4 and -N/
obtain the desired product.
'
RooNnNHzcoN\
45 crystallization and ?ltration procedures. The product may
be puri?ed by standard procedures of recrystallization
R2
from solvents such as lower alkanols .for example, meth~
, anol, ethanol, propanol, etc., ethyl acetate, acetone and
the like.
>RCONHNHCH(R3)CH2COG. Interfering groups such 50 The new therapeutic agents of the present invention
possess a considerably higher activity in the treatment of
as amino, hydroxy and mercapto should notrbe present in
'in which R4, R1 and R2 are as‘ described above and R3 is
hydrogen or lower alkyl containing 1 to 3 carbon atoms.
This class of compounds is represented by the formula
the acylhydrazide, RCONHNHZ, employed in this proc
ess. Such groups are known to react with a,}9~unsaturated
mental depression than prior art agents, Further, the
> instant agents possess a higher therapeutic index than
acids and may appreciably reduce the yield of desired
prior art agents. Therapeuticindex as employed herein
capto, ‘amino and hydroxy groups are best prepared by
protecting these free groups, for example, by acylation.
The reaction is best e?ected employing acylhydrazides,
RCONHNH2, in which R is E—'-(CH2)m— in which E
use of many prior art agents in the treatment of mental ‘
product. Those compounds in which R contains free mer 55 refers to the ratio of therapeutic activity to toxicity. The
and m are as previously described;
' '
in which X, Y and n are as previously described; and
depression is attended by considerable toxic reactions in
the patient. The ratio of activity to toxicity of a thera
peutic agent is obviously most important in selecting such
60 an agent.
Although many agents are quite active thera~
peutically, their use is seriously curtailed by excessive
toxicity. The present therapeutic agents, due to their high
therapeutic index, are more desirable for treatment of
mental depression than prior art agents. The new thera
65 peutic agents of this invention in which R is a 4-pyridyl
radical additionally possess appreciable antitubercular
activity, while those in which R is phenyl, Z-pyridyl,
3-pyridyl, thienyl, or'furyl radicals do not.
.
a‘D)
.
d/
in which D is as previously described and c and d are sub
stituents each selected from the group consisting of hy_
_
The physician will indicate daily dosage of vthe thera
70 peutic agents of this invention. The dosage will be de
pendent upon the extent of mental depression, whether
mild or severe. In cases of mild depression, dosage of
from 10 to 50 milligrams per day may be indicated. In
drogen, lower alkylamino, halogen, lower alkoxy, lower
severe depression, considerably higher daily dosage may
alkylmercapto and alkanoylamino, alkanoylmercapto and 75 be required, for example, up to 150 milligrams and higher,
q
3,040,001
5
Tablets or capsules containing 10, 2'5, 50 and 150 milli
N-phenylethyl - beta - (isonicotinylhydrazino)propion
grams of the instant therapeutic agents are convenient
unit dosage forms for daily administration. Such tablets
or capsules may be prepared from mixtures of the present
N-(3,4-dimethoxyphenylethyl) - beta - (isonicotinylhy
amide (M.P. 145-l47° C.)
drazino)propionamide (M.P. 110-114° C.)
N-(3-methylbenzyl) - beta - (isonicotinylhydrazino)pro
compounds with well known pharmaceutical excipients,
pionamide (M.P. 114-116? C.)
such as starch, sugar, tapioca, certain forms of clay and
N-(4-methy1benzyl) - beta - (isonicotinylhydrazino)pro
the like. Alternatively, liquid preparations may bepre
pared from mixtures of the present therapeutic agents and
pharmaceutically acceptable liquid media, such as water,
pionamide (M.P. 133-135“ C.)
N-(Z-chlorobenzyl) - beta - (isonicotinylhydrazino)pro
pionamide (M.P. l48-149° C.)
aqueous glycols, sugar solutions and the like which may 10
N-(Z-methylbenzyl) - beta - isonic0tiny1hydrazino)pro—
contain conventional ?avoring and coloring agents.
pionamide (M.P. 148-149° C.)
Since many of the compounds of the present invention
N-(3,4-dichlorobenzyl) - beta --(isonicotinylhydrazino)
are basic, advantage may be taken of the water solubility
of salts of these compounds formed with acids in the isola
propionamide (M.P. 139-140" C.)
tion and/or puri?cation of the above compounds and in
N-(2,4-dichlorobenzyl) - beta - (isonicotinylhydrazino)
the preparation of aqueous solutions of these new com
pounds for oral or parenteral :adminstration. Of course,
N-benzyl - beta-(nicotinylhydrazino)propionamide (M.P.
only salts formed with pharmaceutically-acceptable acids
should be employed in therapeutic applications. Par
N-benzyl - beta- (cyclohexylcarbohydrazino) propionamide
tiuularly effective salts are those formed with pharma 20
ceutically-acceptable acids having a pK value of 3 or
lower. Such acids are well-known in the art, for example,
N - methyl - beta - (isonicotinylhydrazino)propionamide
propionarnide (M.P. l37—139° C.)
125-126" c.)
(M.P. ISO-152° C.)
(M.P. 119° c.)
.
N-ethyl-beta- (isonicotinylhydrazino) propionamide (M.P.
hydrochloric, hydrobromic, sulfuric, nitric, phosphoric,
benzenesulfonic, toluenesulfonic, methylsulfonic, ethyl
l3l-l32° C.)
'
N-n-propyl - beta - (isonicotinylhydrazino)propionamide
sulfonic acids and the like. These salts may be prepared 25
by procedures commonly employed in the art, for ex
ample, reacting the compound with an equivalent of the
selected acid in aqueous solution and concentration of the
solution. Other known procedures may ‘also be employed.
The following examples are given by way of illustration
(M.P. 118-120° C.)
>
'
_
N-i-propyl - beta - (isonicotinylhydrazino)propionamide
(M.P. 163-165" C.)
N-n-butyl - beta - (isonicotinylhydrazino)propionamide.
(M.P. 120-122“ C.)
N-i-butyl - beta - (isonicotinylhydrazino) propionamide
and ‘are not ‘to be construed as limitations of this inven
(M.P. 146—147° C.)
tion many variations of which are possible within the scope
N-cy'clohexyl - beta- (isonicotinylhydrazino)propionamide
and spirit thereof.
(M.P. 166-167” C.)
EXAMPLE I
N -BenzyI-Beta(Isonicotinylhydrazino) Propionnm idea
N-allyl-beta-(isonicotinylhydrazino)jpropionamide (M.P.
35
117-1199 c.)
.
.
N-phenethyl - beta - (isonicotinylhydrazino)propionamide
A slurry of 7.5 g. (0.034 mole) of l-isOnicotinyl-Z
(carbomethoxyethyl) -hydrazine and 5 ml. of benzylamine
‘(M.P. 145-147° C.)
N-benzyl-beta-(3 - chlorobenzoylhydrazino)propionamide
is heated with stirring at 130° for three hours. The cooled
(M.P. 151-153“ C.)
mass is then recrystallized from ethyl acetate to yield 40
N-benzyl-beta-(4 - ?uoroben'zoylhydrazino)propionamide
white needles melting at 151.1°-152.1° C. Elemental
analysis gives the following results:
Calcd. for C16H18N4O: C, 64.43; H, 6.07; N, 18.77.
Found: C, 64.43; H, 6.27; N, 19.17.
EXAMPLE II
(M.P.214—216° C.)
This compound is prepared by the procedure of Ex- ‘
N-Benzyl-Beta-(Benzoylhydrazino) Propionamide
ample ‘I employing benzylamine and methyl a-hydrazino
~ acetate.
Similarly, 7 additional jN-substituted hydrazinoalkanm
ample I employing 1-benzoyl-2-(carboethoxyethyDhydra
amides are prepared employing suitable amines:
zine in place of the corresponding isonicotinyl compound.
The product melts at 164°-165°'C. Elemental analysis
N-rnetihyl-‘N-benzyl-tz-hydrazino acetamide
.
55
'
N-(4-Pic0lyl) -Beta-(Benzoylhydrazino)Propiomzmia‘e
65
bomethoxyethyl)hydrazine. The product melts at 125 °
koxyethyDhydrazines and appropriate amines are:
N-4-chlorobenzyl-p-hydrazinopropionamide
N-4-?uorobenzy1- u-hydrazinopropionamide
N-4-methyl'benzyl-whydrazinopropionamide
N-3,4-dichlorobenzyl-whydrazinopropionamide
N-2,4-dibromobenzyl-u-hydrazinopropionarnide
127 ° C.
Additional N-substituted-beta-(acylhydrazino)propion
amides prepared employing suitable 1-acyl-2-(carboal
N- (2~furfuryl) -a-hydrazinoacetamide
N-benZyl-B~hydrazinopropionamide
N-allyle?-hydrazinopropionamide
N-n-propyl-e-hydrazinohexanoamide
N-cyclobutyl-u-hydrazinoacetamide
N-pentyl-u-hydrazinopropionamicle
N-cyclohexyhN-methyl-?éhydrazinobutyramide
N-phenethyl-a-hydrazinobutyramide
uct melts at 162°-163° C.
EXAMPLE IV
This compound is prepared by the procedure of Ex
ample I employing 4-picolylamine and l-benzoyl-Z-(car
N-(p-chlorobenzyl)-a-hydrazinoacetamide
N-(allyD-d-hydrazinoacetamide
The procedure of Example I is repeated employing
p.ch1orobenzylamine in place of benzylamine. The prod
70
N-benzyl-beta - (2 - furoylhydrazino) propionamide (M.P.
183-184° C. )
.
N-furfuryl - beta - (isonicotinylhydrazino)propionamide
(M.P.- 129-131° C.)
N-pyridyl-a-hydrazinoacetamide
1N-n~propyl-a-hydrazinoacetamide
N-( p.Ch lorobenzyl ) - (Beta-Isonicotinylhydrazin0 )
Propionamide
'
N-Benzy l-a-Hydrazinoacetam'ide
45
This compound is prepared by the procedure of Ex
agrees with the calculated values.
EXAMPLE III
a
EXAMPLE v
75
N-4-io dobenzyl-?-hydrazinoproprionamide
N-3 -methylbenzyl-?-hydrazinopropionamide
N-4-propylphenyl-?-hydrazinopropionamide
N-phenyl-,B~hydrazinopropionamide
N-furfuryl-?-hydrazinopropionamide
N-tbienylmethyl-?-hydrazinopropionamide
3,040,061
(b) REDUCTION OF‘ HYDRAZONES
In the above table C5H4N stands ‘for pyridyl; C4H3O,
Hydrogenation is conducted in 1a Parr apparatus at
C4H3S, C3H2NS, C3H2NO, and isoC3H2NO stand for
furyl’ thienyl, thiazolyl, oxazolyl and isoxaiolyl féspec' 40 three atmospheres. The method consists in shaking 10 g.
of the acylhydrazone with 0.5 g. of platinum oxide in
tively.
150 m1. of ethanol. Hydrogen absorption generally
stops when one equivalent of hydrogen is absorbed. The
EXAMPLE VII
Preparation of 1-Acyl-2-(Carboalkoxyalkyl)hydrazines
(Method 1)
(a) PREPARATION OF HYDRAZONES
reduced product is isolated by ?ltering o? catalyst, con
45 centrating the solution at reduced pressure and recrystal
lizing the product from acetone, ethylacetate, pentane
Equimolar proportions of the acylhydrazine and the
acetone, pentane-ethyl acetate and the like.
‘The above described hydrazones are respectively
carbonyl compound are re?uxed in ethanol for from 1-4
hours. In some cases, the crude product crystallizes out
of this solution, while in others, concentration of the
solution is necessary. The recovered hydrazone is then
puri?ed by recrystallization from solvent such as methanol,
hydrogenated to the following 1-acyl-2-(carboalkoxy
alkyl)hydnazine.
ethanol, ethyl acetate, isopropanol, hexane-ethyl acetate,
pentane-methanol and the like. A number of acylhydra
zones are prepared employing this procedure and are 55
listed in Table 11 together with the'carbonyl compounds
reacted with RCONHNH2.
l-benzoyl-Z-(?-carbomethoxyethyl)hydrazine
l-picolinoyl-Z-(,B-carbomethoxypropyl)hydradine
1-nicotinyl-2—(e-carboethoxypentyDhydrazine
lJbenzoy1-2-( ?-carboethoxybutyl) hydrazine
1-isonicotiny1-2-('y-carbopropoxypropyl)hydrazine
l-benzoyl-Z-(a-methyl, ?-carbomethoxypropynhydrazine
l-isonicotinyl-Z-(or-methyl, B-carboethoxybutyhhydrazine
l-benzoyl-2-(a~propyl, B-carboethoxyethyDhydrazine
60
1-isonicotinyl-2~(?-carbomethoxyethybhydrazine
l-isonicotinyl-Z-(/3-carboethoxyethyl)hydrazine
14(3-furoyl) Z-(a-methyl, ?-carboethoxypropyDhydr-azine
l-benzoy1-2~(B-carbopropoxypropyl)hydrazine
'l-picolinoyl-2-(,B-carbomethoxybutyhhydrazine
l-(2-thenoyl)-2-(,B-carbomethoxyethyl)hydrazine
i1- ( Z-furoyl) 2- ( B-carbomethoxyethyl) hydrazine
l-(3-thenoyl)-2-(,8-carbomethoxyethyl)hydrazine
Other I-acyl-Z-(carbalkoxyalkyl)hydrazines employed in
the previous examples are prepared employing this
procedure.
EXAMPLE VIII
R:
l
Preparation of compounds of the formula RC ONHNHCHC H|C 0 G
75 These compounds [are prepared by heating a selected
3,040,061
11
12
acylhydrazine with an a,?-unsaturated acid ester or amide
with glacial acetic acid in an alkanol solvent.
are prepared by this same procedure employing sulfuric
acid, phosphoric acid, hydrobromic acid, nitric acid, ben
zenesulfonic acid and toluenesulfonic acid.
For example, methyl acrylate, 28.0 g. (0.4 mole) was
added dropwise during one hour to a solution containing
54.8 g. (0.4 mole) of isonicotinic acid hydrazide and
10 ml. of glacial acetic acid in 400 ml. of tertiary butyl
alcohol. The resulting solution then was heated for
EXAMPLE XI
A tablet base was prepared by blending the following
ingredients in the proportion by weight indicated.
18 hours on a steam bath. Concentration of the reaction
Sucrose U.S.P.
mixture to 100 1111. yielded 13.0 g. of unreacted iso
Tapioca starch
nicotinic acid hydrazide. The ?ltrate was concentrated 10
Magnesium stearate
to a thick syrup which was triturated with anhydrous
ether and recrystallized from isopropyl alcohol;'M.P.
87°-88.5° C. Elemental analysis of the product, vl-iso
.
13.2
_______________ __. _______ __
6.5
Into this base there was blended sul?cient N-benzyl-beta
isonicotinylhydrazinopropionamide to provide tablets each
containing 10, 25, 50 and 100mg. of active ingredient.
nicotinyl-2-(?-carbomethoxymethyl)hydrazine, gave the ,
following results:
80.3 .
,
15
Calcd. for C10H13H3O3: C, 53.81; N, 5.87. Found:
C, 54.08; N, 5.65.
Other therapeutic agents as exempli?ed in the above
examples were similarly blended into thistablet base.
EXAMPLE XII
Employing this procedure, the following hydrazines
are prepared from suitable anti-unsaturated acid deriva
Aqueous suspensions were prepared each containing
tives as listed in Table III and corresponding 'acylhydra-. 20 25 mg. per teaspoonful (5 ml.) of each of the above de
zines, in 10—20% yields.
scribed therapeutic agents in a vehicle composed of U.S.P.
Table III
.
If,
V
Hydrazine product RCONHNHCHCHgCOOlh’ ,
tap-unsaturated ester
l-benzoyl-Z-(843mbomethoxyethyDhydrazine _____________________ __
Methylacrylate.
1-picolinoyl-2-(?~carbomethoxypropyl)hydrazine___
_ Methyl butenoate.
l-benzoyl-Z-(B-carboethoxybutybhydrazine ______ __
_
1-benzoyl-2-(B-carboethoxypentyDhydtazine____
1-isonieotinyl-2-(?-methyl, B'carbopropoxyethyDhydrazine
1-(3-furoyl)-2-(/3-carbomethoxybutyDhydrazine..__
1-(2-thenoyl)-2~( ~carbomethoxyethybhydrazine_-
Ethyl hexenoate.
Ethyl acrylate.
Propyl butenoate,
Methyl acrylate.
Do.
1-isonleotinyl~2-(,8-carboethoxyethyDhydrazine _________ --
1-(3-tl1enoyl)-2~
Ethyl pentenoate.
-carbomethoxyethybhydrazine __________________ .-
Do.
R:
/R1
Hydrazine product RCONH2~IH(JJHCH1C0N\
tad-unsaturated ester
R
N-benzyl-?-(benzoylhydrazino)propionamide ___________ __
N-benzylaerylamide_
N -phenethyl-?- (picolinylhyclrazino) butyramidm _.
N- (phenethyDaerylamide.
N-cyelohexyl-B-(benzoylhydrazlno)pentanoamide_
N-cyclohexylpentenoamide.
N-methyl-N-benzyl?-(benzoylhydrazino)propiona
N-methyl-N-benzylacrylamide.
N-allyl-B-(isonieotinylhydrazino)hexanoarnide.____
__ N-allylhexenoamlde.
N-n-propyl-?-(2-turoylhydrazino)propionamide ___________________ __
N-benzyl-?-(isoxazolylcarbohydrazino)proplonamide _____________ __
N-n-propylaeylamide.
N-benzylacrylamide.
' The hydrazines of the same general formulae men
simple syrup containing the following materials per 100
tioned in the previous examples are prepared in the same
manner ?om corresponding aye-unsaturated acid deriva
ml. of vehicle.
tives and acylhydrazines.
F.D. & C. Yellow No. 5 ________________ __ 5 mg.
The reactions are carried out using as solvents tertiary 50 Carboxymethylcellulose low-viscositiy type ___ v1 mg.
alcohols such as tertiary butanol, 1,1-dimethylpropanol,
Synthetic lemon ?avor (Freitsche) ________ __ 0.5 ml.
rl,1-dimethylbutanol and l-methyl-l-ethylbutanol.'
These suspensions are partly cloudy but well adapted for
oral administration of the active agent.
The starting materials for the above described reac
tions, viz. the carbonyl compounds and the a,,8-unsaturated
In addition to their use in the treatment of mental
esters, are‘ readily available in most cases or easily pre 55 disease, the compounds of the present invention are ef
parable by conventional procedures well known in the
fective monamine oxidase inhibitors especially in the
art. The acid hydrazides employed are well-known com
central nervous system and are also useful for the relief
pounds which are readily available or preparable by
standard procedures from acids such as benzoic acid, 2
of anginal pain. Many of these compounds possess anti
dine-3- and pyridine-4-carboxylic acids.
arthritis, etc.
convulsant properties. These compounds are addition
furoic acid, 3-furoic acid, Z-thenoic acid, pyridine-Z-pyri 60 ally useful for the amelioration of mood in rheumatoid
The procedure of Example VIII is repeated employing
.
No. 808,921, ?led April 27, 1959, now abandoned, which
in turn is a division of application Serial No. 784,083, ?led
The yield of 65 December 31, 1958 and now US. Letters Patent No.
a 40% molar excess of methyl acrylate.
product is 40%.
.
This application is a continuation of application Serial
EXAMPLE IX
'
'
EXAMPLE X
The ‘hydrochloride salt of N-benzyl-beta-isonicotinyl
hydrazino propionamide is prepared ‘by dissolving the com 70
pound in an aqueous solution containing an equivalent
amount of hydrochloric acid and evaporating the resultant
solution.
Other acid addition salts of the new pyridine compounds
of the present invention described in the above examples 75
2,894,972 of July 14, 1959, which in turn is a continuation
in-part of application Serial No. 749,061, ?led July 17,
1958, and now abandoned.
'
What is claimed is:
1. A compound selected from the group consisting of
compounds represented by the formula:
R1
3,040,061
13
14
two halo substituents on the phenyl moiety and up to four
carbon atoms in the alkyl moiety.
4. The compound of the formula:
wherein
Z is alkylene containing 1 to 5 carbon atoms;
R1 is selected from the group consisting of hydrogen
and lower alkyl; and
R2 is selected from the group consisting of alkyl and
alkenyl each containing up to 5 ‘carbon atoms; cyclo
alkyl containing 3 to 6 carbon atoms, pyridyl, pyridyl
alkyl, furylalkyl and thienylalkyl in which the alkyl
group is lower alkyl, and ring-substituted derivatives
thereof in which each ring-substituent is lower alkyl;
*aryl and aralkyl each represented by the formula:
NHgNH-Z-C ON
/
R1
R2
wherein Z is alkylene containing two carbon atoms in
the principal chain and a total of up to 5 carbon atoms,
R1 is hydrogen and R2 is phenylalkyl containing up to 4
carbon atoms in the alkyl moiety.
5. The compound of the formula:
R1
15
wherein X is selected from the group consisting of
hydrogen, lower alkyl and halogen, Y is selected from
the group consisting of hydrogen, lower alkyl, lower
R:
wherein Z is alkylene containing two carbon atoms in
the principal chain and a total of up to 5 carbon atoms,
R1 is hydrogen and R2 is furfuryl.
alkox'y, halogen, tri?uoromethyl, cyano and alkanoyl
6. The compound of the formula:
containing 2 to 4 carbon atoms, and n is an integer
from O to 4; and the acid addition salts thereof.
2. The compound of the formula:
NHgNH-—Z—C ON
/R1
\
Rn
25
wherein Z is alkylene containing two carbon atoms in
the principal chain and a total of up to 5 carbon atoms,
n is an interger from 0 to 4 and X is lower alkyl.
wherein Z is alkylene containing two carbon atoms in the
7. The compound of the formula:
principal chain and a total of up to 5 carbon atoms, R1
is hydrogen and R2 is alkyl containing up to 5 carbon 30
atoms.
3. The compound of the formula:
wherein Z is alkylene containing two carbon atoms in the
35 principal chain and a total of up to 5 carbon atoms, R1
R:
wherein Z is alkylene containing two carbon atoms in the
principal chain and a total of up to 5 carbon atoms, R1
is hydrogen and R2 is halophenylalkyl containing up to
is hydrogen and R2 is alkenyl containing up to 5 carbon
atoms.
8. N-benzyl-a-hydrazionacetamide.
No references cited.
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