Note: Descriptions are shown in the official language in which they were submitted.
1~55~20
27, 767 -1-
SUBSTITUTED lH - 1,2,4-TRIAZOLES
BRIEF SUMM~R~ OF THE INVENTION
This invention relates to new organic compounds
and, more particularly, is concerned with novel substituted
l-phenyl-lH-1,2,4-triazoles which may be represented by the
following structural formula:
Rl
~ R2 (I)
N
N4
wherein Rl and R2 are each individually selected from the
group consisting of hydrogen, fluoro, chloro, bromo, nitro,
~amino and dimethylaminomethyleneamino; R3 is selected
from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyri-
dyl, 2-pyrazinyl, 3,4,5-trimethoxyphenyl and moieties of
the formula: ~
wherein R is hydrogen, fluoro, chloro, bromo, nitro, amino
or dimethylaminomethyleneamino with the proviso that when R
is hydrogen then Rl and R2 may not both be hydrogen; and R4
i5 hydrogen or methyl.
The organic bases of this invention form non-toxic
3~
55~20
-- 2 --
acid-addition salts with a variety of pharmacologically
acceptable organic and inorganic salt-forming reagents.
Thus, acid-addition salts, formed by a mixture of the organic
free base with one or more equivalents of an acid, suitably
in a neutral solvent, are formed with such acids as sulfuric,
phosphoric, hydrochloric, hydrobromic, sulfamic, citric,
lactic, malic, succinic, tartaric, acetic, benzoic,
gluconic, ascorbic, and the like. For purposes of this
invention the free bases are equivalent to their non-toxic
acid-addition salts. The acid-addition salts of the organic
bases of the persent invention are, in general, crystalline
solids, relatively soluble in water, methanol and ethanol but
relatively insoluble in non-polar organic solvents such as
diethyl ether, benzene, toluene, and the like.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention may be
readily prepared as set forth in the following reaction
scheme:
5:~lZV
--3--
o 1 4
3 2 ( 3)2 C (o alkyl)2
(II) (III) /
/
1 o f
N=C- ~(CH3)2 (IV)
Rl ~ ~HNH2 (V)
R2
,~
I~L R2
R ~ N ~ (I)
wherein alkyl is methyl or ethyl and R1, R2, R3 and R4 are as
hereinabove defined. In accordance with the above reaction
scheme, an amide (II) such as picolinamide, nicotinamide,
isonicotinamide, pyrazinamide or an appropriately substituted
benzamide is condensed with the dimethylaretal or diethyl-
acetal of either dimethylformamide or dimethylacetamide (III).This condensation is best carried out in an inert solvent
such as dimethylformamide or dimethylacetamide at 100-120C.
' . : '
~20
for a period of 1-3 hours to provide the corresponding sub-
stituted ~-dimethylaminomethylene-amide (IV). Treatment of
(IV) witll an appropriately substituted phenylhydrazine (IV)
in a solvent such as glacial acetic acid at 75-100~.
for a period of 1-3 hours then provides the novel
compounds (I) of the present invention. Compounds having a
nitrophenyl substituent may be converted to the aminophenyl
derivative by treatment with sodium sulfide in aqueous
dioxane at 80-100C. for a period of 1-4 hours followed by
precipitation with water and recrystallization .rom an or-
ganic solvent. Treatment of the aminophenyl derivative with
excess dimethylformamide dimethylacetal at the reflux temper-
ature for 1-3 hours then provides the corresponding dimethyl-
aminomethyleneamino derivative.
The novel compounds of the present invention have
been found to be highly useful for meliorating inflammation
and inhibiting joint deterioration in mammals when administered
in amounts ranging from about one milligram to about 250 mg./kg.
of body weight per day. A preferred dosage regimen for optimum
results would be from about 5 mg. to about 100 mg./kg. of body
weight per day, and such dosage units are employed that a total
of from about 0.35 g. to about 7.0 g. of the active ingredient
for a subject of about 70 kg. of body weight are administered
in a 24 hour period. This dosage regimen may be adjusted to
provide the optimum therapeutic response. For example, sev-
eral divided doses may be administered daily or the dose may
be proportionally reduced as indicated by the exigencies of
the therapeutic situation. A decided practical advantage of
this invention is that the active ingredient may be adminis-
tered by the oral route or by intravenous, intramuscular,topical or subcutaneous routes.
Compounds according to the present invention may be
orally administered, for example, with an inert diluent or with
an assimila~le edible carrier, or they may be enclosed in hard
or soft gelatin capsules, or they may be compressed into tab-
lets, or they may be incorporated directly with the food of
the diet. For oral therapeutic administration, the active
,
~55~2
--5--
compounds may be incorporated with excipients and used in the
form of tablets, troches, capsules, suspensions and the like.
Such compositions and preparations should contain at least
0.1~ of active compound. The percentage of the compositions
and preparations may, of course, be varied and may conveniently
be between about 2 to about 60~ of the weight of the unit. Tne
amount of active ingredient in such therapeutically useful
compositions is such that a suitable dosage wili be obtained.
Preferred compositions or preparations according to the pres-
ent invention are prepared so that an oral dosa~e unit formcontains between about 50 to 250 mg. of active compound.
The tablets, troches, pills, capsules and the like
may also contain the following: a binder such as gum traga-
canth, acacia, corn starch or gelatin; excipients such as di-
calcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid and the like; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose,
lactose or saccharin may be added or a flavoring agent such as
peppermint, oil of wintergreen, or cherry flavoring. When the
dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier such as a fatty
oil. Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For
instance, tablets, pills or capsules may be coated with shel-
lac, sugar or both. A suspension may contain the active ingre-
dient, sucrose as a sweetening agent, methyl and propyl para-
bens as preservatives, a dye and flavoring such as cherry or
orange flavor. Of course, any material used in preparing any
dosage unit form should be pharmaceutically pure and substan-
tially non-toxic in the amount~ employed.
Compositions according to the present invention hav-
ing the desired clarity, stability and adaptability for parent-
eral use are obtained by dissolveing from 0.10% to 10.0~ by
weight of active compound in a vehicle consisting of a poly-
hydric aliphatic alcohol or mixtures thereof. Especially sat-
isfactory are glycerin, propylene glycol and polyethylene gly-
cols. The polyethylene glycols consist of a mixture of non-
l~SS120
-6--
-volatile, normally liquid, polyethylene glycols which are
soluble in both water and organic liquids and which have mol-
e~ular weiqhts of from about 200 to l5no. Although the amount
of active compound dissolved in the above vehicle may vary
from 0.10 to 10.0% by weight, it is preferred that the amount
of active compound employed be from about 3.0 to about 9~o% by
weight. Although various mixtures of the aforementioned non-
-volatile polyethylene glycols may be employed, it is preferred
to use a mixture having an average molecular weight of from
about 200 to about 400.
In addition to the active compound, the parenteral
solutions may contain various preservatives which may be used
to prevent bacterial and fungal contamination. Such preserva-
tives are, for example, myristyl-gamma picolinium chloride,
phenyl mercuric nitrate, benzalkonium chloride, phenethyl al-
cohol, ~-chlorophenyl- -glycerol ether, methyl and propyl para-
bens and thimerosal. As a practical matter, it is alxo con-
venient to employ antioxidants. Suitable antioxidants include,
for example, sodium bisulfite, sodium metabisulfite and sodium
formaldehyde sulfoxylate. Generally, from about 0.05 to about
0.2% concentrations of antioxidant are employed.
Adjuvant induced experimentaI polyarthritis is a
specif~ic systemic disease of the rat which shares interesting
similarities with rheumatoid arthritis. Specifically, the
histology of the two diseases bears a remarkable resemblence
as shown by C. M. Pearson, et al, Am. J. Path., 42, 73 (1963).
E. M. Glenn, Am. J. Vet. Res., 27, (il6), 339 (1966) has clas-
sified adjuvant induced polyarthritis as a crippling and perm-
anent deformity resulting from diffuse connective tissue in-
volvement around certain susceptible joints in the rat.Zahiri, et al., Can. Med. Ass. J., 101, 269 (1969) have shown
that the fusiform swelling of the distal joints is associated
with edema, congestion and synovitis including pannus forma-
tion, all of which precede the ultimate destruction of bone
and cartilage. Furthermore, Zahiri, et al., indicate that the
cartilage destruction in the joint is due to an invasive pan-
nus which originates in the marginal synovium and extends
,
~5
--7--
across the articular surface to erode it. When non-steroidal,
anti-inflammatory agents such as indomethacin inhibit arthritic
paw swelling, which is composed of inflammatory cell infil-
trates, they have also been shown to prevent joint and bone
deterioration [see S. Wong, et al., J. Pharm. & Exp. Ther.,
185, 127 (1973) and G. R. Bobalic, et aI., Agents and Actions,
4, 364 (1974)]. The most pointed reference showing the rela-
tionship between arthritis and joint deterioration is "An
X-Ray Analysis of Adjuvant Arthritis in the Rat; the Effect of
Prednisolone and Indomethacin", Blackham, et al., Agents and
Action, _ (No. 1), 145-151 (1977). In a similar manner,
inhibition of the progress of arhtritis in paws of rats treat-
ed with the compounds of this invention also lessens associa-
ted joint deterioration.
The novel compounds of the present invention are ac-
tive anti-inflammatory agents as established in the follow-
ing tests:
Adjuvant Arthritis Assay
Groups of three Royal Hart Wistar strain rats,
weighing 200 + 10 g. each were injected intradermally in the
right hind paw with Freund's adjuvant (dried human tubercle
bacilli in a mineral oil vehicle) at a dose of 2 mg./kg. of
body weight. Test compounds were administered orally in a
1.5% starch vehicle at 50 mg./kg. of body weight once daily on
days 0 through 13 post-challenge. Control rats were treated
in a similar manner, buty given only starch vehicle. On the
14th day post-challenge the diameter of the injected paw
(primary lesion) was measured by micrometer caliper. From
these measurements of inflamed paws a determination was made
of the relative surface area ~RSA). This i8 a ratio of the
mean surface area of the paws of 3 treated rats/mean surface
area of the paws of 60 control rats. If the R5A is equal to
or less than 0.76, the compound is retested. After the second
test, the mean RSA for the rat paws from both tests is calcu-
lated and if it is equal to or less than 0.736 the compound istested a third time. If the mean RSA of all three tests is
less than 0.753, the compound is considered active. The re-
'
.
ssl2b
--8--sults of this test with typical compounds of this invention
appear in Table I below.
TABLE I
Compound Resuit
l-Phenyl-5-(o-nitrophenyl)-lH-1,2,4- Active
-triazole
l-(P-Fluorophenyl)-S-(~-nitrophenvl)- Active
-lH-1,2,4-triazole
I (r Bromophenyl)-5-(~-nitrophenyl)- Active
--lH-1,2,4-triazole
5~ Aminophenyl)-l-(~-bromophenyl)- Active
-lH-1,2,4-triazole
5-(~-Aminophenyl)-i-(~-fluorophenyl)- Active
-lH-1,2,4-triazole
5-lp-(Dimethylaminomethylene)amino]-l- Active
~` -(p-fluorophenyl)-lH-I~2~4-triazole
; 20 5-(~-Aminophenyl)-l-(~-chlorophenyli- Active
-lH-1,2,4-triazole
-~ 5-~-Fluorophenyl)-l-(~-nitrophenyl)- Active
-lH-1~,2,4-triazole
l-(g~minophenyl)-5-(~-fluorophenyl)- Active
-lH-1,2,4-triazole
5-(~-Aminophenyl)-l-(o-fluorophenyl)- Active
-lH-1,2,4-triazole
2-Cyano-4'-11-(p-fluorophenvl)-lH- Active
-1,3,4-triazol-~-yI]acetaniiide
. ... _.
Carrageenin Edema A~say
~ Royal Hart, ~istar strain rats ranging in weight
; 35 from 80 to 90 grams were used. The rats were fasted overnight
prior to dosing but had free access to water. The test com-
pounds were administered in aqueous suspension, by gavage, in
:.,.-
~, ' . ~,, . -
, ~ -
l~S5i~V
_g_
a volume of 1.7 ml. per 50 grams of rat [corresponds to hydra-
tion volume used by winter, et al., Proc. Soc. Exp. Biol. &
Med., 111, 544-547 (1962)]. The dose of all compounds was
250 mg./kq. The phlogistic agent used was carrageenin pre-
pared as a sterile 1~ suspension in 0.9% aqueous sodium chlor-
ide for routine testing. A volume of 0.05 ml. was injected
into the plantar tissue of the right hind paw. Measurements
were made 5 hours after drug administration (4 hours after
carrageenin challenge). The paw of the unanesthetized rat
was immersed in mercury exactly to an ink mark on the skin
over the lateral malleolus. The mercury was contained in a
glass cylinder 25 x 60 mm. The mercury column was connected
with a Statham pressure transducer (model P23BB), range 0-5
cm. mercury. The output from the transducer was led through
a model 260BLH signal conditioning unit and visualized by
digital indicator. Volumes of both the normal and carrageenin
inflamed feet were determined. The difference between the
two measurements was considered to be the increased edema due
to the carrageenin administration. Results were expressed
as a control (C)/treated (T) efficacy ratio. (The ratio of
mean edema volume of 8 control rats over the mean edema vol-
ume of 2 treated rats.) If the C/T ratio is equal to or
greater than 1.41, the test is repeated. If the mean ratio
of test 1 and 2 is equal to or greater than 1.43, the com-
pound is considered active. The results of this test withtypical compounds of this invention are recorded in Table
II below.
~15~120
--10--
TABLE II
Compound ~ _ R-esult
3-(4E~-l,2,4-Triazol-3-yl)-pyridine Active
2-[1-(~-Chlorophenyl)-lH-1,2,4-tria- Active
zol-S-yl]-pyrazine
4-(1-Phenyl-lH-1,2,4-triazol-5-yl)- Active
-pyridine
{l-[~-(Difluoromethylsulfonyl)-phenyl~- Active
-lH-1,2,4-triazol-S-yl}-pyrazine
1,5-Diphenyl-lH-1,2,4-triazole Active
1-(p-Bromophenyl)-3-methyl-5-(3,4,5- Active
-trlmethox~phenyl)-lH-1,2,4-triazole
[i-(p-Nitrophenyl)-lH-1,2,4-triazol- Active
-5-yll-pyrazine
4-[1-(~-Fluorophenyl)-lH-1,2,4-triazol- Active
-S-yl]-pyridine
.. . ~ .
Migratory Inhibition Test
Rheumatoid arthritis i5 a chronic inflammatory
disease that is characterized by the migration of lymphocytes,
macrophages and polymorphonuclear leukocytes to the sites of
inflammation. The mi~ration of lymphocytes and macrophages
and their multiplication ln situ is one reason for the very
large increase in size of the normally thin synovial membrane
which encloses the joint space. This transformed synovial
membrane slowly grows over the articular surfaces and causes
the destruction of the articular cartilage and other connec-
tive tissue structures of the joint. One of the mechanismsfor the destruction of articular cartilage by the synovium is
through the release of various hydrolytic enzymes by the resi-
1~51~0
--11--
dent macrophages which have been immobilized and activated bymiqration inhibitory factor (MIF). Macrophages stimulated by
MIF are termed "activated macrophages" and undergo the follow-
ing changes: (a) increased glucose oxidation, ~b) increased
ruffling of plasma membrane and increased spreading of cells,
(c) synthesis and secretion of neutral proteases, (d) release
of preformed lysosomal enzymes, (e) decreased migration from
a capillary tube. All these effects are associated with an
inflammatory situation and it has been demonstrated that MIF
is present in the synovial fluid from patients with rheumatoid
arthritis. The mechanism of cartilage destruction can be
pictured as follows:
~
Antigen > ~ymphocyt~ > MIF
\ /
Enzvmes< ¦Macrophage~
¦ Cartilage ¦ ~ Breakdown Products
Althou~h the postulated antigen initiating these
destructive event8 in rheumatoid arthritis has not been dis-
covered, the ~ecretion of MIF by lymphocytes and the secretion
of enzymes by macrophages as well as the breakdown of cartilage
by macrophage enzymes has been demonstrated. Drugs that can
therefore block the release of MIF by lymphocytes or the acti-
vation of macrophages by MIF may be clinically effective inretarding the destructive joint damage which occurs in rheuma-
toid arthritis. Drugs can be tested as MIF inhibitors by using
11S51ZO
--12--
the capillary tube migration assay as follows: Male Hartley
~uinea pigs, weiqhinq between 3~0 and 600 grams, were injected
intraperitoneally with 25 ml. of Marcal 52 Oil~ (Humble Oil
Co.). Three to four days later the guinea pigs were decapi-
S tated, the peritoneum opened and 50 ml. of cold Hank's solu-
tion added to the peritoneum. The Hank's solution containing
the cell suspension was then aspirated into a separatory funnel.
This procedure was repeated twice. The oil phase was discard-
ed and the cell suspension was centrifuged at 1200 r.p.m. for
10 minutes. The cells were resuspended in cold Hank's sol-
ution and centrifuged at 900 r.p.m. for 5 minutes. This
procedure was repeated twice. Viability of the cells was
then determined using trypan blue. Viability must be greater
than 90~. The cell concentration was then adjusted to give
a 10% packed cell volume by the addition of the appropriate
amount of Minimal Essential Medium (Earle's salts) plus 15~
guinea pig serum. To the medium was added L-glutamine (2mM),
penicillin (100 U./ml.) and streptomycin (100 mcg./ml.).
Capillary tubes (1.1-1.5 x 75 mm., Clay Adams) were filled
with cells by capillary action and selaed at one end with a
small plug of paraffin. These capillary tubes were centri-
fuged at 700-800 r.p.m. for 5 minutes to get approximately
4-5 mm. of packed cells at the closed end. The tubes were
cut at the cell-fluid interface. Two packed capillary tubes
were then trans,erred to each chamber of a Lexy culture
dish (Mini-Lab Co., LLC-4002, Quebec, Canada). The capillar-
ies were held in place using a small amount of silicone
grease (Dow Corning) and a cover glass was then placed on top
of the chamber, making a seal between the cover glass and the
chamber using paraffin wax.
The test compound solutLon (c) Ls prepared by dis-
solving 10 mg. of the test compound in one ml. of absolute
ethanol. A 10 ~1. portion of this i8 transferred to 10 ml.
of complete medium containing antigen. The antigen control
(b) is prepared by adding 10 ~1. of absolute ethanol to 10
ml. of complete medium containing antigen. The non-antigen
control ~a) is prepared by adding 10 ~1. of absolute ethanol
. : ,
~.
~55~20
-13-
to 10 ml. of complete medium without antigen. Therefore, (a)
contains medium + 0.1~ absolute ethanol; (b) contains medium
+ 0.1~ absolute ethanol + antigen; and (c) contains medium +
0.1~ absolute ethanol + antigen + test compound. The chamber
was then filled through the passages with either (a), (b) or
(c). The passages were then sealed off using silicone. The
cell~ were then incubated at 37C. for 24 hours. To deter-
mine the area of cell migration out of the capillary tube
onto the chamber surface, the chamber was projected onto a
microscope screen, the area traced onto paper and then meas-
ured using a planimeter. The antigen inhibits the migration
of macrophages by approximately 50%. Test compounds that
reverse this inhibition by greater than 15~ are considered
active. The results of this test with typical compounds of
this invention appear in Table III below.
TA~ LE I I 1
Compound Dose mcg./ml. Result*
l-(p-Bromophenvl)-5-( - 10 Active
-nitrophenyl)-lH-l, 2 ,~-
-triazole
4-(1-Phenyl- lH-1, 2, 4- 10 Active
-triazol-5-yl)pyridine
5 (~-A~inophenyl)-l-(E~ 10 Active
-bromophenyl)-lH-1,2,4-
-triazole
... _ _.. , .. . _ ~
*Greater than 15% reversal of inhibition, c-b,
a-b
where a = cells with no addition, b = cells +
antigen and c = cells + anti~en + test compound.
~55~ZO
-14-
A preferred embodiment of the present invention
may be represented by the following structural formula:
X
~3
~ ll H
wherein X and Y are each individually selected from the group
consisting of hydrogen, fluoro, chloro, bromo, nitro and amino
with the proviso that X and Y may not both be hydrogen.
The invention will be described in greater detail
in conjunction with the following specific examples.
Example 1
201-Phenyl-5-(p-nitrophenyl)-lH-1,2,4-triazole
A mixture of S0.0 g. of p-nitrobenzamide, 50 ml. of
N,N-dimethyl,ormamide and 100 ml. of N,N-dimethylformamide
;
diethylacetal is heated at 120C. for l.S hours, during which
time some ethanol forms and is collected through a reflux con-
denser. Cooling the solution produces 54.1 g. of N-(dimethyl-
aminomethylenel-p-nitrobenzamide as colorless crystals.
To a solution of 5.4 g. of phenylhydrazine in 70 ml.
of 30% aqueous acetic acid is added 10.0 g. of N-(dimethyl-
aminomethylene)-~-nitrobenzamide. The reaction mixture i~
stirred at 90C. for one hour and ~hen cooled. The solid is
collected and recrystallized from ethanol giving 9.1 g. of
the desired product as colorless crystals, mp. 130-132C.
Example 2
1-~p-Fluorophenyl)-5-(p-nitrophenyl)-lH-1,2,4-triazole
35To a solution of 8.80 g. of 4-fluorophenylhydrazine
hydrochloride in a mixture of 10.9 ml. of 5N sodium hydroxide,
100 ml. of 30% aqueous acetic acid and S0 ml. of ~-dioxane is
' -:
~, ;~ . '
-15-
added 10.0 g~ of N-(dimethylaminomethylene)-p-nitrobenzamide.
The reaction mixture is stirred and heated at 90C. for 1.5
hours, then poured into 200 ml. of water. The solid is col-
lected and recrystallized from ethanol, giving 10.4 g. of the
desired product as yellow crystals, mp. 132-134C~
Example 3
l-(p-Bromophenyl)-5-(p-nitrophenyl)-lH-1,2,4-triazole
To a solution of 12.1 g. of 4-bromophenylhydrazine
hydrochloride in a mixture of lQ.9 ml. of 5N sodium hydroxide,
100 ml. of 30~ aqueous acetic acid and 50 ml. of p-dioxane is
added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide.
The procedure of Example 2 is followed, giving 12.7 g. of the
desired product as tan crystals, mp. 142-144C.
Example 4
3-(4H-1,2,4-Triazol-3-yl)-pyridine
A solution of 75.0 g. of nicotinamide in 150 ml. of
N,N-dimethylformamide diethylacetal is heated at 120C. for
1.5 hours during which time some ethanol is forms and is col-
lected through a reflux condenser. Cooling the solution pro-
duces 88.0 g. of N-(dimethylaminomethylene)nicotinamide as
colorless crystals.
To a solution of 3.1 g. of hydrazine hydrate in
100 ml. of acetic acid is added 10.0 g. of N-(dimethylamino-
~- methylene)nicotinamide. The reaction mixture is stirred at
; 25 90C. for 1.5 hours, then concentrated in vacuo to about 15 ml.
The addition of 50 ml. of ether causes the desired product to
precipitate as 7.8 g. of colorless crystals, mp. 169-172C.
Example 5
2-[1-(p-Chlorophenyl)-lH-1,2,4-triazol-5-yllpyrazine
A solution of 15.0 g. of pyrazinamide in 40 ml. of
N,N-dimethylformamide diethylacetal i~ heated at 120C. for
2 hours with collection of ethanol. Cooling gives 9.9 g. of
N-(dimethylaminomethylene)pyrazinecarboxamide as tan crystals.
To a solution of 12.1 g. of 4-chlorophenylhydrazine
hydrochloride in a mixture of 13.5 ml. of 5N sodium hydroxide,
100 ml~ of 30~ aqueous acetic acid and 50 ml. of ~-dioxane is
added 10.0 g~ of N-(dimethylaminomethylene)pyrazinecarboxamide.
'' : " :.
~Ls~o
-16-
The procedure of Exampl~ 2 is then f~llowed giving 3.8 g. of
the desired product as tan crystals, mp. 129-131C.
Example 6
4-(1-Phenyl-lH-1,2,4-triazol-5-yl)pyridine
A 75~0 g. portion of isonicotinamide is reacted as
described in Example 4 for nicotinamide, giving 86.6 g. of
N-(dimethylamlnomethylene)isonicotinamide as tan crystals.
To a solution of 6.9 g. of phenylhydrazine in 100 ml.
of acetic acid is added 10.0 g. of N-(dimethylaminomethylene)-
isonicotinamide. me reaction mixture is stirred at 90C. for1.5 hours and then evaporated in vacuo to an orange oil. This
oil is dissolved in 250 ml. of chloroform, washed with 60 ml.
of saturated sodium bicarbonate solution, then with 60 ml. of
water, dried over sodium sulfate and filtered. The ch}oroform
is removed and the residue is dissolved in 60 ml. of ether.
Cooling produces 8.8 g. of the desired product as tan crystals,
mp. 92-94C.
Example 7
~ -(Difluoromethylsulfonyl)phenyl]-lH-1,2,4-
-triazol-S-yl}pyrazine
A reaction mixture comprising 100 g. of pyrazina-
mide in 270 ml. of dimethylformamide diethylacetal is heated
at 120C. for 2 hours with collection of ethanol The mixture
is cooled, the solid is collected by filtration ;nd washed
with ether giving 40.6 g. of N-(dimethylaminomethylene)pyrazine
carboxamide.
A reaction mixture comprising 10.0 g. of the above
product and 15.0 g. of p-(difluoromethylsulfonyl)phenylhydra-
zine in 100 ml. of acetic acid is stirred at 90C. for 3 hours
and concentrated in vacuo to an oil. The oil i8 di~solved in
250 ml. of chloroform, washed with two 100 ml. portions of
water, dried over sodium sulfate and filtered. The solvent is
removed and the residue is dissolved in hot ethanol. Cooling
produces 7.8 g. of the desired product as tan crystals,
mp. 152-154C.
' ' '' ~ ~' ', :
llS5~ZO
--17--
Example 8
1,5-Diphenyl-lH-1,2,4-triazole
A reaction mixture comprising 150 g. of benzamide in
300 ml. of dimethylformamide dimethylacetal is heated at 120C.
for 3 hours with collection of methanol. The mixture is cooled
and the solid is collected and washed with ether giving
173.2 g. of N-(dimethylaminomethylene)benzamide.
A reaction mixture comprising 10.0 g. of the above
product, 7.36 g. of phenylhydrazine and 100 ml. of acetic acid
is reacted as described in Example 7, giving 7.1 g. of the
desired product as colorless crystals, mp. 85-87C.
Example 9
l-(p-Bromophenyl)-3-methy1-5-(3,4,5-
-trimethoxyphenyl)-lH-1,2,4-triazole
A reaction mixture comprising 100 g. of 3, 4,5-tri-
methoxybenzamide in 200 ml. of 85% dimethylacetamide is heated
at 120C. for 2 hours with collection of methanol. The mixture
is cooled, the solid is collected by filtration and recrystal-
lized from dimethylformamide giving 88.1 g. of N-(dimethyla-
minoethylidene)-3,4,5-trimethoxybenzamide as light yellow
crystals.
A 10.0 g. portion of the above product is added to a
mixture of 9.60 g. of 4-bromophenylhydrazine hydrochloride,
8.58 ml. of 5N sodium hydroxide, 100 ml. of 30% aqueous acetic
acid and 100 ml. of ~-dioxane. The reaction mixture is stir-
red at 90C. for 3 hours and then evaporated in vacuo to
a~out 30 ml. The residue is poured into 250 ml. of water and
extracted with two 250 ml. portions of chloroform. The chloro-
form extracts are combined, washed with two 100 ml. portions
of water, dried over sodium sulfate and filtered. The chloro-
form is removed and the re9idue i9 triturated with ether giving
colorless crystals which are recrystzllized from ethanol giving
8.1 g. of the desired product as colorless crystals, mp. 132-
133C.
Example 10
~l-(p-Nitrophenyl)-lH-1,2,4-triazol-5-yl]pyrazine
~ . ~
A 10.0 g. portion of N-(dimethylaminomethylene)-
,,
.'`:. , , ~ ' ~' - '. .
:
:
~55
-18-
pyrazine carboxamide is added to a mixture of 10.3 g. of 4-
-nitrophenylhydrazine, 200 ml. of acetic acid and 50 ml~ of
p-dioxane. The mixture is heated at 90C. for 5 hours and
evaporated to dryness in vacuo. The residue is recrystallized
from ethanol giving 9.0 g. of the desired product as tan crys-
tals, mp. 188-189C.
Example 11
5-(p-Aminophenyl)-l-(_-bromophenyl)-lH-1,2,4-triazole
A mixture of 9.0 g. of 1-(p-bromophenyl)-5-(p-nitro-
phenyl)-lH-1,2,4-triazole, 18.0 g. of sodium hydrosulfite,
40 ml. of water and 150 ml. of acetone is stirred at room
temperature overnight. The acetone is removed in vacuo and
the residue is extracted with hot chloroform. Cooling produces
2.1 g. of the desired product as pale yellow crystals, mp. 128-
-130C.
- Example 12
4-[1-(p-Fluorophenyl)-lH-1,2,4-triazol-5-yl~pyridine
A 6.0 g. portion of N-(dimethylaminomethylene)iso-
nicotinamide is added to a mixture prepared by adding 6.05 g.
of p-fluorophenylhydrazine hydrochloride to 80 ml. of 30~
aqueous acetic acid, 40 ml. of p= dioxane and 7.5 ml. of 5N
sodium hydroxide. The mixture is heated to reflux for 1.5
hours, poured into water and allowed to stand overnight. Ex-
traction with ether gives a dark solid which is recrystallized
from acetone-hexane giving 1.7 g. of the desired product,
mp. 114-115C.
Example 13
5-(p-Aminopheny~ -fluoropheny~ 2~4-triazole
A mixture of 9.0 ~. of 1-~ luorophenyl)-5~ nitro-
phenyl)-lH-1,2,4-triazole, 18~0 g. of sodium hydrosulfite,
40 ml. of water and 150 ml. of acetone is stirred at room tem-
perature for 1/2 hour. The acetone is removed in vacuo and
the residue extracted with hot chloroform. Cooling produces
1.1 g. of the desired product as off-white crystals, mp. 128-
-130C.
~S51120
--19--
Example 14
l-(p-Fluorophenyl)-5- ~p-[(dimethylaminomethylene)-
amino]phenyll-lH-l~2~4-triazole
A solution of 5.0 g. of 5-(p-aminophenyl)-1-(p-
S -fluorophenyl)-lH-1,2,4-triazole in 20 ml. of dimethylformamide
dimethylacetal is heated to reflux for 1.5 hours while the
methanol formed is collected by distillation. The reaction
mixture is cooled, lS ml. of ether is added and the mixture is
cooled further, giving 5.5 g. of the desired product, mp. 159-
-161C.
Example 15
2-Cyano-4'- [1-(~-fluorophenyl)-lH-1,3,4-
-triazol-S-yl]acetanilide
A solution of 3.5 ml. of phosphorus trichloride in
15 25 ml. of acetonitrile is added dropwise to a stirred suspen-
sion of 19.0 g. of 5-(p-aminophenyl)-1-(e-fluorophenyl)-lH-
-1,2,4-triazole in a mixture of 15.6 ml. of triethylamine,
6.35 g. of cyanoacetic acid and 200 ml. of acetonitrile at
room temperature over a period of one hour. The mixture is
20 heated to boiling, giving a clear solution and kept at 90C.
for 2.5 hours. The suspension is filtered hot through diato-
maceous earth. The filtrate is heated to boiling, 250 ml. of
hot water is added and the solution is slowly cooled to 5C.
A 400 ml. portion of water is added and the solid is collected
25 and recrystallized from ethanol giving the desired product as
~; 19.0 g. of cream crystals, mp. 223-225C.
Example 16
5-(p-Aminophenyl)-l-(~-chlorophenyl)-lH-1,2,4-triazole
To a solution of 38.9 g. of 4-chlorophenylhydrazine
~`~ 30 hydrochloride in a mixture of 400 ml. of 30% aqueous acetic
acid, 43.6 ml. of 5N sodium hydroxide and 200 ml. of ~-dioxane
is added 40.0 g. of N-(dimethylaminomethylene)-p-nitrobenza-
mide. The mixture is stirred and heated at 90C. for 1.5
hours, concentrated in vacuo to about 350 ml. and 350 ml. of
35 water is added. The mixture is refrigerated overnight and the
solid is collected, washed with water and recrystallized from
600 ml. of ethanol giving 48.6 g. of 1-(p-chlorophenyl)-5- (p-
:".
-. -
1~S5~ZO
--20--
-nitrophenyl)-lH-1,2,4-triazole as cream crystals.
To a solution of 40.0 g. of the above product in
320 ml. of p-dioxane at 80C. is added a hot (70C.) solution
of 74.4 g. of sodium sulfide nonahydrate in 320 ml. of water.
The mixture is stirred at 80C. for 45 minutes, cooled and
poured into one liter of ice-water. The solid is collected by
filtration and recrystallized from chloroform-hexane giving
23.7 g. of the desired product as colorless crystals, mp. lS0-
-152C.
Example 17
5-(p-Fluorophenyl)-l-(p-nitrophenyl)-lH-1, 2, 4-triazole
A mixture comprising 116 ml. of dimethylformamide
dimethylacetal, 62.0 ml. of dimethylformamide and 60.0 g. of
p-fluorobenzamide is stirred and heated at 90-120C. for 3
hours with collection of methanol. The mixture is cooled in
an ice bath giving a solid which is collected by filtration,
washed with three 75 ml. portions of ether and dried, giving
-53.0 g. of N-(dimethylaminomethylene)-p-fluorobenzamide.
A 12.4 g. portion of the above product in 50 ml. of
~-dioxane is added to a mixture of 16.7 g. of 4-nitrophenyl-
hydrazine in 75 ml. of p-dioxane, lOS ml. of water and 45 ml.
of glacial acetic acid. This mixture is heated to 90C.,
250 ml. of dimethylformamide is added and the solution is
heated at 90C. for }.5 hours. The solution is concentrated
in vacuo at 80C. to 300 ml. and poured into 1200 ml. of water
with, stirring. The solid is collected by filtration, washed
with water, then two 50 ml. portions of ether and recrystal-
lized twice from ethanol giving the desired product as 6.7 g.
of brown crystals, mp. 151-154C.
Example 18
l-(p-Aminophenyl)-5-(p-1uorophenyl)-lH-1,2,4-triazole
A 5.0 g. portion of S-(~-fluorophenyl)-l-(p-nitro-
phenyl)-lH-1,2,4-triazole in 42 ml. of dioxane is added to
9.9 g. of sodium sulfide nonahydrate in 42 ml. of water and
the mixture is stirred and heated at reflux (90CC.) for 1.5
hours. The solution is cooled and poured into 300 ml. of`ice
and water with stirring. The solid is collected by filtration,
.: . . ~,
- l~S~
--21--
dried, recrystallized from 30 ml. of acetonitrile, washed with
ether and dried giving 2.6 g. of the desired product as tan
crystals, mp. 147-150C.
Example 19
N'-[p-[5-(p-Fluorophenyl)-lH-1,2,4-triazol-1-yl]-
phenyl]-N,N-dimethylformamidine
A 1.7 g. portion of 1-(p-aminophenyl)-5-(p-fluoro-
phenyl)-lH-1,2,4-triazole is gently refluxed in a mixture of
5.0 ml. of dimethylformamide dimethylacetal and 2.5 ml. of
dimethylformamide. Heatiny is continued for 1.5 hours, then
the mixture is evaporated under high vacuum (70C.) to a brown
oil. This oil is triturated with S0 ml. of ether. The solid
is collected by filtration, dried and recrystallized from
25 ml. of hot cyclohexane, giving 1.1 g. of the desired pro-
duct as a light tan solid, mp. 90-93C.
Example 20
N'-[p-5-(p-Bromophenyl)-lH-1,2,4-triazol-1-yl]-
-N,N-dimethylformamidine
A 24.8 g. portion of p-bromobenzamide in 33.0 ml.
of dimethylformamide dimethylacetal and 200 ml. of dimethyl-
formamide is heated at 120C. until evolution of methanol
ceases (2 hours). The mixture is cooled and then evaporated
under high vacuum to a gum which is triturated with ether.
The resulting crystals are collected, washed with ether, dried
and then recrystallized from 150 ml. of ethanol at 0C. giving
21.8 g. of N-(dimethylaminomethylene)-_-bromobenzamide as yel-
low crystals.
A 12.7 g. portion of the above product in 50 ml. of
p-dioxane is added to a mixture of 11.7 g. of ~-nitrophenyl-
hydrazine, 75 ml. of p-dioxane, 45 ml. of acetic acid and
105 ml. of water and heated at 90C. for 2 hours. A 50 ml.
portion of p-dioxane and 100 ml. of dimethylformamide are
added to effect solution. ~he mixture is cooled and poured
into 1200 ml. of water. The precipitate is collected by fil-
traticn, washed with water, dried and recrystallized fromethanol giving 6.75 g. of 5-(p-bromophenyl)-1-(p-nitrophenyl)-
-lH-1,2,4-triazole as orange crystals.
~155~1!ZO
--22--
An 8.1 g. portion of sodium sulfide nonahydrate in
35 ml. of water is heated to 60C. and added to a solution of
5.5 g. of the above triazole in 35 ml. of p-dioxane at 90C.
The mixture is cooled and poured into 300 ml. of water with
stirring. The solid is collected by filtration, washed with
water, dried and recrystallized from chloroform:cyclohexane
(1:1) giving 1.9 g. of 1-(p-aminophenyl)-5-(p-bromophenyl)-
-lH-1,2,4-triazole as a brown solid.
A 1.6 g. portion of the above amine in 5 ml. of
dimethylformamide dimethylacetal and 2.5 ml. of dimethylfor-
mamide is heated at 90C. for 1.5 hours, cooled and evaporated
under high vacuum to a brown oil. This oil is triturated with
30 ml. of ether. The resulting solid is collected by filtra-
tion, dried and recrystallized from 25 ml. of chloroform:cyclo-
hexane (1:1), giving 1.30 g. of the desired product as a tan
solid, mp. 140-144C.
Example 21
l-(p-Aminophenyl)-5-phenyl-lH-1,2,4-triazole
A reaction mixture comprising 22.4 g. of N-(dimethyl-
aminomethylene)benzamide in 100 ml. of p-dioxane is added to a
mixture of 23.5 g. of p-nitrophenylhydrazine in 150 ml. of p-
-dioxane, 80 ml. of acetic acid and 210 ml. of water. The mix-
ture is stirred and heated at 90-95C. for 2 hours with the
addition of 250 ml. of dimethylformamide to effect solution.
The mixture is cooled and poured into one liter of ice-water
producing a brown oil. This oil solidifies, is collected,
dried and recrystallized from ethanol giving 6.7 g. of l-(p-
-nitrophenyl)-5-phenyl-lH-1,2,4-triazole.
A 6.0 g. portion of the above triazole in 55 ml. of
~-dioxane is stirred and boiled at 90-95C. together with a
mixture of 12.7 g. of sodium sulfide nonahydrate in 55 ml. of
water. After 2 hours, the mixture is cooled and poured into
400 ml. of water. The solid is collected by filtration, washed
with water, dried and recrystallized from chloroform-hexane,
giving 750 mg. of the desired product as cream colored crys-
tals, mp. 161-163C.
5120
-23-
Example 22
N,N-Dim~thy]-N'-[p-(5-phenyl-lH-1,2,4-triazol-
-l-yl)phenyl]formamidine
. . .
A 1.5 g. portion of 1-(p-aminophenyl)-5-phenyl-lH-
-1,2,4-triazole in I0.0 ml. of dimethylformamide dimethyl-
acetal and 4.0 ml. of dimethylformamide is heated at 90-95C.
for 1.5 hours. The solution is concentrated to 10 ml., cooled
and then evaporated at 60C. to an oil. This oil is tritur-
ated with 50 ml. of ether. The solid is collected by filtra-
tion and recrystallized from chloroform-hexane giving 670 mg.
of the desired product as yellow plates, mp. 109-111C.
Example 23
1-(o-Fluorophenyl)-5-(p-nitrophenyl)-lH-1,2,4-triazole
A 25.0 g. portion of o-fluorophenylhydrazine hydro-
chloride is dissolved in 150 ml. of p-dioxane with warming and
31.0 ml. of SN sodium hydroxide is added. After solution is
complete, 80 ml. of glacial acetic acid and 210 ml. of water
are added followed by 28.1 g. of N- (dimethylaminomethylene)-
-~nitrobenzamide in 100 ml. of warm ~-dioxane. This reaction
mixture is heated at 90-95C. for 1.5 hours, then cooled and
poured into 1500 ml. of water. The solid is collected by
filtration, washed with water, dried and crystallized from
200 ml. of ethanol, giving 13.9 g. of the desired product as a
tan solid, mp. 143-145C.
- 25 Example 24
5-(p-Aminophenyl)-1-(o-fluorophenyl)-lH-1,2,4-triazole
An 11.9 g. portion of 1-(o-fluorophenyl)-5-(p-
-nitrophenyl)-lH-1,2,4-triazole and 25.4 g. of sodium sulfide
nonahydrate in a mixture of 110 ml. of ~-dioxane and 110 ml.
of water is heated at 90-95C. for 1~5 hours. The solution is
cooled, poured into one liter of water and allowed to stand
overnight. The solid is collected by filtration, washed with
water and dried. This solid is taken up in the minimum amount
of warm chloroform, cooled, dried over magnesiwm sulfate and
filtered through diatomaceous earth. Hexane is added until
the mixture becomes cloudy and deposits crystals. After 2
hours, the solid is collected by filtration, washed with ether,
:
.
.. ~, ,. ,: ,
..
: . : . . . .
. : :.
s~
-24-
dried and recrystallized from chloroform-hexane giving the
desired product as yellow crystals, mp. 139-141C.
