U.S. patent number 3,691,178 [Application Number 05/020,126] was granted by the patent office on 1972-09-12 for substituted imidazoles.
Invention is credited to Frederick C. Novello, 786 Bair Road, John J. Baldwin, 1680 Wagon Wheel Lane.
United States Patent |
3,691,178 |
|
September 12, 1972 |
SUBSTITUTED IMIDAZOLES
Abstract
Imidazoles substituted at the 2 and 4(5) positions having an
optional substituent in the 1 position are provided. Methods of
preparing the novel substituted imidazoles are described. The
substituted imidazoles are useful as anti-gout and
anti-hyperuricemic agents. Compositions useful in the treatment of
gout and hyperuricemia containing a substituted imidazole as the
active ingredient are provided. 11 Claims, No Drawings
Inventors: |
John J. Baldwin, 1680 Wagon Wheel
Lane (Lansdale, PA 19446), Frederick C. Novello, 786 Bair
Road (Berwyn, PA 19312) |
Family
ID: |
21796910 |
Appl.
No.: |
05/020,126 |
Filed: |
March 16, 1970 |
Current U.S.
Class: |
546/274.1;
514/825; 546/167; 548/183; 548/185; 548/189; 548/195; 548/198;
548/202; 548/311.7; 548/333.5; 548/336.5; 544/235; 548/153;
548/184; 548/186; 548/191; 548/197; 548/204; 548/315.1;
548/334.5 |
Current CPC
Class: |
C07D
233/64 (20130101); C07D 233/90 (20130101); Y10S
514/825 (20130101) |
Current International
Class: |
C07D
233/90 (20060101); C07D 233/54 (20060101); C07D
233/00 (20060101); C07d 049/36 () |
Field of
Search: |
;260/294.8F,294.9,295R,295K,297R,309,250A,287R,289R,302H,294.8C |
Other References
lawson, J. Chem. Soc. 1957, 4,225-8..
|
Primary Examiner: Henry R. Jiles
Assistant Examiner: G. Thomas Todd
Attorney, Agent or Firm: J. Jerome Behan I. Louis Wolk
Claims
1. A compound of the formula ##SPC4## and non-toxic salts thereof,
wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is naphthyl,
pyridyl, quinolyl, cinnolyl, indanyl, thienyl or thiazolyl,
substituted phenyl wherein the substituent is halogen, lower alkyl
wherein the alkyl group is a straight or branched chain group
containing one to five carbon atoms, sulfamoyl, lower alkoxy
wherein the alkoxy group contains from one to five carbons, nitro
or amino R.sub.5 is carboxy, carbamoyl, substituted carbamoyl
wherein the substituent is lower alkyl, cyano, benzoyl, or lower
alkanoyl, provided that where R.sub.5 is carboxy, R.sub.2 is not
p-nitrophenyl or
2. A compound of the formula ##SPC5## and non-toxic salts thereof,
wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is naphthyl,
halophenyl, dihalophenyl, pyridyl, quinolyl, cinnolyl, thienyl or
thiazolyl, and R.sub.5 is carboxy, carbamoyl, lower alkylcarbamoyl,
cyano, benzoyl, and
3. A compound of claim 1 wherein R.sub.1 is hydrogen, R.sub.2 is
halophenyl
4. A compound of claim 1 wherein R.sub.1 is hydrogen, R.sub.2 is
halophenyl
5. A compound of claim 1, which compound is
6. A compound of the formula: ##SPC6## and the non-toxic salts
thereof, wherein R.sub.2 is pyridyl or halophenyl
Description
The invention relates to a class of imidazoles which are
substituted in the 2 and 4(5) positions and bear optional
substituents in the 1 position. The substituent in the 1 position
is an alkyl group. The substituents in the 2 position are aryl or
heteroaryl groups, while the substituents in the 4(5) positions are
carboxy or carbamoyl groups, or a group derived therefrom.
The herein-described substituted imidazoles have utility as
anti-gout and anti-hyperuricemic agents.
Gout is a condition affecting humans and lower animals,
particularly birds and reptiles, which is characterized by
perversion of the purine metabolism resulting in an excess of uric
acid in the blood, by attacks of acute arthritis, and by formation
of chalky deposits in the cartilages of the joints. These deposits
are made up chiefly of urates, or uric acid. Hyperuricemia is a
condition characterized by an excess of uric acid in the blood.
Uric acid serves no biochemical function in the body and is merely
an end product of purine metabolism. It is well known in the art
that the purine bases adenine and guanine, which play key roles in
a wide variety of chemical processes, both give rise to uric acid
in the body. Adenylic acid and guanylic acid are converted to the
free purine bases by destructive metabolic enzymes. A portion of
the free purine bases is converted to purine ribonucleotides and
the remainder is degraded to the free bases xanthine and
hypoxanthine. A single enzyme, xanthine oxidase, converts both
xanthine and hypoxanthine to uric acid for excretion.
Although human purine biosynthesis can be inhibited at the stage of
formyl glycinimide ribotide by the glutamine antagonists azaserine
and 6-diazo-5-oxo-1-norleucine, a high incidence of undesirable
side effects precludes their being used clinically for this
purpose. In recent years, substantial progress has been made in
attempting to control the excessive levels of uric acid in patients
afflicted with gout through the use of pharmaceutical agents. Uric
acid synthesis has been effectively blocked by the use of
allopurinol, 4-hydroxypyrazolo-[3,4-d]-pyrimidine, a compound which
is a structural isomer of hypoxanthine. Allopurinol acts as a
specific inhibitor of the enzyme xanthine oxidase, which is
responsible for the conversion of both hypoxanthine and xanthine to
uric acid. As a direct result of the administration of this
compound to patients afflicted with gout, part of the uric acid
which would normally end up in the urine is replaced instead by the
oxypurines, hypoxanthine and xanthine, thus greatly reducing the
content of uric acid in serum and urine. Azathioprine has also been
employed in patients afflicted by gout to inhibit the excessive
purine synthesis, which tends to produce abnormal amounts of uric
acid. Other compounds, such as acetylsalicylic acid,
thiophenylpyrazolidine, and phenylbutazone have been employed in
the treatment of gout. Many of the existing compounds used in the
treatment of gout, however, relieve the inflammation and other
symptoms connected therewith but have no effect on the conditions
which give rise to gouty arthritis or hyperuricemia. Thus, there is
still a need for compounds which can be employed in the
prophylactic treatment of gout as well as for the treatment of
other abnormal conditions associated with hyperuricemia.
The substituted imidazoles which are the subject of this invention
have been found to be effective anti-gout and anti-hyperuricemic
agents in that they will inhibit the action of the enzyme xanthine
oxidase and thus reduce the content of uric acid in serum and
urine.
An object of this invention is to provide novel substituted
imidazoles which are useful as anti-gout and anti-hyperuricemic
agents. Methods of preparing the novel substituted imidazoles are
described. Also within the scope of the invention are the non-toxic
pharmaceutically acceptable quaternary salts, alkali metal and
alkaline earth metal salts of the imidazoles, and those acid salts
wherein the substituent in the 2-position is a heterocyclic ring
containing at least one nitrogen atom.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The novel imidazoles which are the subject of the present invention
can be structurally depicted as follows: ##SPC1## wherein R.sub.1
is hydrogen or loweralkyl wherein the alkyl group contains from one
to five carbons, such as methyl, ethyl, butyl and the like, R.sub.2
is naphthyl or heteroaryl such as quinolyl or cinnolyl, or a 5 or 6
membered heteroaryl ring system containing 1-3 hetero atoms wherein
the hetero atom is selected from the group oxygen, nitrogen, and
sulfur, such as a pyrazinyl, thienyl, thiazolyl, or pyridiyl ring,
substituted heteroaryl containing 1-3 substituents wherein the
substituent is loweralkyl or a loweralkoxy group wherein the alkyl
and alkoxy groups contain one to five carbons, substituted phenyl
wherein the substituent is halogen, such as fluorine, bromine,
chlorine or iodine, loweralkyl wherein the alkyl group is a
straight or branched chain group containing one to five carbons,
such as methyl, ethyl, propyl, butyl, isopropyl, and pentyl,
sulfamoyl, loweralkylsulfamoyl wherein the alkyl group contains
from one to five carbons, such as dimethylsulfamoyl,
ethylsulfamoyl, butylsulfamoyl, and the like, loweralkoxy wherein
the alkoxy group contains from one to five carbons, such as
methoxy, ethoxy, butoxy and the like, loweralkanoylamino wherein
the alkyl group contains from two to five carbons such as
acetylamino, propionylamino, butyrylamino, and the like, nitro,
amino, lowermonoalkylamino and lowerdialkylamino wherein the alkyl
group contains from one to five carbons, such as methylamino,
diethylamino, dibutylamino, and the like, methylenedioxy, or a
fused loweralkylene bridge containing from three to six carbons
such as a propylene, butylene, or pentylene bridge, and R.sub.5 is
carboxy, loweralkoxycarbonyl wherein the alkoxy group contains one
to five carbons, such as methoxycarbonyl, ethoxycarbonyl, or
butoxycarbonyl, carbamoyl, substituted carbamoyl wherein the
substituent is loweralkyl having one to three carbons, cyano,
loweralkanoyl wherein the alkanoyl group contains from one to five
carbons, such as acetyl, propionyl, butyryl, and the like, or
benzoyl, provided that where R.sub.5 is carboxy, R.sub.2 is not
p-nitrophenyl or m-nitrophenyl.
Where the substituent on the imidazole ring is a substituted phenyl
group, the phenyl ring may contain from 1-3 substituents. Where the
substituent on the phenyl ring is a loweralkylene bridge, the
bridge is joined to the phenyl ring on adjacent carbons such as,
for example, a 3,4-propylene bridge. Where R.sub.2 is a naphthyl
group, the naphthyl group is joined to the imidazole ring at the 1
or 2 position of the naphthyl group. Where the substituent on the
phenyl ring is a methylenedioxy group, the oxygen atoms are joined
to the phenyl ring on adjacent carbons such as, for example, a
3,4-methylenedioxy substituent.
Also within the scope of the present invention are the non-toxic
pharmaceuticallly acceptable quaternary salts such as the
methiodides and ethiodides where the heterocyclic group in the
2-position contains a nitrogen atom, alkali metal and alkaline
earth metal salts, such as the sodium, potassium, and calcium
salts, and those mineral acid salts such as the hydrochloride
salts, wherein the substituent in the 2-position is a heterocyclic
ring containing at least one nitrogen atom, such as a pyridine
ring. Also included are the disalts, which are formed in those
cases where R.sub.5 is carboxy.
Those compounds wherein R.sub.1 in Formula I is hydrogen, R.sub.2
is pyridyl or halophenyl, and R.sub.5 is carboxy,
loweralkoxycarbonyl, carbamoyl, cyano, loweralkanoyl or benzoyl
represent a preferred sub-class of compounds falling within the
scope of the present invention.
It should be understood that the 1-unsubstituted imidazoles
discussed herein are compounds in which the R.sub.5 substituent is
at either the 4or 5 position on the imidazole ring. The hydrogen
atom on a nitrogen in the imidazole ring is in a state of
tautomeric equilibrium, with the result that the 4 and 5 positions
are equivalent.
Typical of the compounds falling within the definition of Formula I
are: ethyl 2-(p-chlorophenyl)imidazole-4(5)-carboxylate methyl
2-(4-pyridyl)imidazole-4(5)-carboxylate
4(5)-acetyl-2-(p-bromophenyl)-imidazole
2-(p-bromophenyl)imidazole-4(5)-carboxylic acid methyl
2-(p-nitrophenyl)imidazole-4(5)-carboxylate
2-(p-bromophenyl)imidazole-4-(5)-carboxamide
2-(4-pyridyl)imidazole-4(5)-carboxamide
2-(p-chlorophenyl)imidazole-4(5)-carboxylic acid methyl
2-(6-quinolyl)imidazole-4(5)-carboxylate
2-(p-aminophenyl)imidazole--4(5)-carboxylic acid
4(5)-propionyl-2-(4-pyridyl)imidazole
1-ethyl-4-acetyl-2-(p-chlorophenyl)imidazole
2-(p-chlorophenyl)-4(5)-cyanoimidazole
1-methyl-2-(2-thienyl)imidazole-4-carboxylate
1-butyl-2-(p-chlorophenyl)-4-cyanoimidazole
2-(1-naphthyl)imidazole-4(5)-carboxylic acid methyl
2-(p-chlorophenyl)imidazole-4(5-carboxylate
4(5)-acetyl-2-(p-chlorophenyl)imidazole
2-(p-chlorophenyl)-imidazole-4(5)-carboxamide, and
2-(4-pyridyl)-4(5)-cyanoimidazole.
The compounds of the present invention having the structural
formula ##SPC2## wherein R.sub.1 is hydrogen or loweralkyl, R.sub.2
is naphthyl, substituted phenyl, heteroaryl, substituted
heteroaryl, and R.sub.5 is carboxy, loweralkoxycarbonyl, carbamoyl,
cyano, or loweralkanoyl, can be prepared by a series of reactions
from a substituted imidazole compound such as a
4(5)-trifluoromethylimidazole compound. For example, those
compounds where the substituent at the 4(5)-position is carboxy,
i.e., compounds having the formula ##SPC3## where R.sub.1 and
R.sub.2 are as defined above, can be prepared by treating a
substituted 4(5)-trifluoromethylimidazole with excess aqueous
alkali, such as sodium hydroxide or potassium hydroxide. Generally,
the substituted trifluoromethylimidazole compound is suspended in
the alkali solution and the reaction mixture is maintained at room
temperature for about 1-5 hours. It is preferred, however, to carry
out the reaction at about 80.degree.-120.degree. C. The resulting
carboxy-2-substituted imidazole is then obtained by acidifying the
alkaline solution with a mineral acid such as, for example,
hydrochloric acid, and is purified by recrystallization or other
techniques known in the art.
Those compounds of Formula I wherein R.sub.5 is alkoxycarbonyl are
prepared by converting the compounds where R.sub.5 is carboxy to
the desired ester by reaction with the appropriate alcohol in the
presence of a mineral acid such as hydrochloric acid or sulfuric
acid. For example, where the alkoxy carbonyl group is
methoxycarbonyl, the ester is prepared by heating the
4(5)-carboxyimidazole in methanol in the presence of dry hydrogen
chloride or concentrated sulfuric acid. Loweralkanols having 1-6
carbons may be employed as the alcohol. The reaction may be carried
out at room temperature or at the reflux temperature of the
solvent. Generally, temperatures between room temperature and
160.degree. C. may be employed. The alcohol reactant may also be
employed as the solvent, although hydrocarbons such as benzene and
toluene may also be employed as solvents. The
4(5)-alkoxycarbonylimidazole is then obtained by concentrating the
reaction mixture. The residual acid is neutralized by the addition
of base, such as sodium hydroxide, and the alkoxycarbonylimidazole
is purified by recrystallization from a suitable solvent, such as
acetonitrile, or alcohol, or by other techniques known in the
art.
Those compounds of Formula I wherein R.sub.5 is carbamoyl or
substituted carbamoyl are prepared by reacting a
4(5)-loweralkoxycarbonylimidazole with an amine, such as
methylamine or ethylamine, or ammonia, in a suitable solvent.
Generally, the starting 4(5)-carboxylate is reacted with an excess
of the amine in a closed reaction system at a temperature from
about 80.degree.-150.degree. C. for from about 10-25 hours.
Solvents such as methanol or ethanol may be employed. The
4(5)-carbamoylimidazole is obtained from the reaction mixture by
techniques known in the art. For example, the solvent is removed in
vacuo and the residue is crystallized from a suitable solvent, such
as methanol in water.
Alternatively, the imidazole 4(5)-carboxamides can be prepared by
reacting an imidazole-4(5)-carboxylic acid with a halogenating
agent such as thionyl chloride or phosphorous oxychloride to form
the corresponding acid halide, and the acid halide formed is then
reacted with an excess of a primary or secondary amine or ammonia
in a suitable solvent, such as benzene or toluene. The reaction
with the halogenating agent is generally carried out at a
temperature between about 0.degree.-50.degree. C. Where the
halogenating agent is employed as the solvent, a convenient
temperature for the reaction is the reflux temperature of the
solvent. Hydrocarbons such as benzene, toluene and ether may also
be employed as solvents. Where the amine reactant is ammonia,
aqueous solutions of ammonia may be employed. The reaction with the
amine is carried out at a temperature between 0.degree.-50.degree.
C. The excess amine is neutralized with dilute mineral acid such as
dilute hydrochloric acid, and the product is collected and purified
by techniques known in the art. For example, the imidazole
4(5)-carboxamide can be collected by filtration and purified by
recrystallization.
Those compounds of Formula I wherein R.sub.5 is cyano can be
prepared by reacting an imidazole 4(5)-carboxamide with an excess
of a dehydrating agent, such as phosphorous oxychloride. The
reaction is generally carried out at a temperature between
75.degree.-150.degree. C. for about 1-5 hours. The excess
phosphorous oxychloride is removed by conventional means, for
example, under reduced pressure, and the residue is neutralized
with dilute alkali, such as sodium bicarbonate. The
4(5)-cyanoimidazole compound is collected by filtration, and
purified by techniques known in the art.
Those compounds of Formula I wherein R.sub.5 is loweralkanoyl can
be prepared by reacting a 4(5)-cyanoimidazole with about a 2-4
molar excess of a loweralkyl metal halide such as, for example,
methyl magnesium iodide, in a suitable solvent, such as ether or
tetrahydrofuran. The reaction mixture is then heated, generally at
the reflux temperature of the solvent, for about 1-5 hours, after
which it is heated at about room temperature for about 20 hours.
The reaction mixture is then poured into dilute acid, such as
dilute hydrochloric acid or aqueous ammonium chloride, and the
mixture is extracted with a suitable solvent such as, for example,
ether. The loweralkanoylimidazole is obtained by concentration of
the extract. To obtain those compounds where R.sub.5 is benzoyl, an
aryl metal halide, such as phenyl magnesium halide, is employed.
Those compounds wherein the substituent in the 2- position is
nitrophenyl are not prepared in this manner. The 2-phenyl-4(5)-
alkanoylimidazole compound is prepared first and is then nitrated
to form the corresponding 2-nitrophenyl compounds. The nitrophenyl
compounds can also be reduced by known techniques to the
corresponding amino compound; the alkanoylamino compounds can be
prepared from the amino compounds by well known methods used to
acylate amines.
The trifluoromethylimidazole compounds can be prepared by first
reacting 1,1-dibromo-3,3,3-trifluoroacetone with mild base, such as
sodium acetate or potassium carbonate, at a temperature between
room temperature and 150.degree. C., and then reacting the mixture
with the appropriate carboxaldehyde and ammonia at room
temperature. The carboxaldehyde may be a substituted
arylcarboxaldehyde, such as o-chlorobenzenecarboxaldehyde,
p-nitrobenzenecarboxaldehyde, p-sulfamoylbenzenecarboxaldehyde, and
p-methoxybenzenecarboxaldehyde, or a heteroarylcarboxaldehyde, such
as pyridinecarboxaldehyde, quinolinecarboxaldehyde,
thiazolecarboxaldehyde, thiophenecarboxaldehyde, or
cinnolinecarboxaldehyde.
The starting materials used to prepare those compounds of Formula I
wherein R.sub.1 is loweralkyl can be prepared by reacting a
4(5)-trifluoromethylimidazole such as, for example,
2-(p-fluorophenyl)- 4(5)-trifluoromethylimidazole, with an
alkylating agent such as diazomethane in ether or with a
loweralkylsulfate such as dimethylsulfate in a suitable solvent.
Dimethylsulfate itself may be employed as the solvent;
loweralkanoic acids such as formic acid and acetic acid may also be
employed as the solvent. The alkylation may be carried out at room
temperature, but in the case of dimethylsulfate, it is preferred to
carry out the reaction at elevated temperatures from about
50.degree.- 150.degree. C. for from about 1-3 hours. The reflux
temperature of the solvent is a convenient temperature for the
alkylation step. The alkylated trifluoromethylimidazole compound is
then isolated by techniques known in the art. One isolation method,
for example, is to remove the solvent and triturate the residue
with dilute alkali, such as ammonium hydroxide, and take up the
product in a suitable solvent, such as hexane. The alkylated
trifluoromethylimidazole compound is then obtained upon removal of
the solvent.
The metal salts of the 2-substituted-4(5)-substituted imidazoles,
that is, those compounds where R.sub.1 in Formula I is hydrogen,
can be prepared by methods known in the art. For example, the
sodium or potassium salt can be prepared by addition of an
equivalent amount of sodium or potassium hydroxide to a solution of
the substituted imidazole compound. The salt is then obtained by
concentrating the reaction mixture.
The acid addition salts of the substituted imidazoles having in the
2- position a heterocyclic ring containing at least one nitrogen
atom can be prepared by any of the known methods for preparing acid
addition salts of amines.
The substituted imidazoles which are the subject of this invention
inhibit the action of the enzyme xanthine oxidase resulting in a
significant decrease in the concentration of uric acid in the blood
and urine and are, therefore, capable of aborting attacks of
gout.
For testing purposes, xanthine oxidase obtained from milk may be
employed to demonstrate the ability of the
2-substituted-4(5)-substituted imidazoles to inhibit the enzyme.
The general procedure is to employ a 5-10 unit suspension of the
enzyme per milliliter of 60 percent saturated ammonium sulfate of
the enzyme; 1 unit of such a suspension converts 1.mu. mole of
xanthine to uric acid per minute. Generally, for a 1-day assay,
about 0.05 ml. of enzyme is diluted with about 3 ml. of buffer. As
the buffer, tris buffer (0.05 mole) pH 7.4 may be employed. The
inhibitor to be tested is dissolved in buffer or a suitable
solvent, such as dimethylsulfoxide; the same solvent is used to
dilute the solution. The buffer, hypoxanthine and solvent are
placed in a cell, and the resulting solution is shaken to absorb
air. The diluted enzyme solution is then added, and the rate of
increase in absorbance at 290m.mu. is noted with a recording
spectrophotometer. Generally, sufficient enzyme is employed to give
about 0.1 absorbance units change per minute, and sufficient
inhibitor is used to give 30-70 percent inhibition. The .mu.M
concentration of inhibitor necessary for 50 percent inhibition
(V.sub.0 /V.sub.1 = 2) is determined by plotting V.sub.0 /V.sub.1
against I, where V.sub.0 = velocity without inhibitor, V.sub.1 =
velocity with inhibitor, and I = inhibitor concentration.
The therapeutically active substituted imidazoles can be
administered as the active ingredient in association with a
pharmaceutically acceptable carrier in the form of tablets,
elixirs, capsules, and the like. These preparations may be made by
any of the known pharmaceutical methods. For example, in tablet
form, they are compounded with an inert pharmaceutical carrier
which may contain a suitable binder such as, for example, gums,
starches, and sugars. They may also be incorporated into a gelatin
capsule or formulated into elixirs which have the advantage of
being susceptible to manipulations in flavor by the addition of
standard natural or synthetic flavoring materials. The compound is
generally administered in compositions which are so proportioned as
to afford a unit dosage of about 30 mg. to 1.5 gm. per day. The
preferred dosage level, however, is about 100-800 mg. per day.
The following examples serve to illustrate typical tablet, capsule,
and elixir formulations incorporating the therapeutically active
2-substituted-4(5)-substituted imidazoles of this invention:
Formulation I -- Compressed Tablet Comprising 0.5 gm. of Active
Ingredient Ingredient Amt.--Mg.
_________________________________________________________________________
_ Methyl 2-(p-chlorophenyl)imidazole- 4(5)-carboxylate 500.0 Starch
paste - 121/2%, 100 cc. allow. 12.5 512.5 Starch, U.S.P. Corn 25.0
Magnesium stearate 5.5 543.0
_________________________________________________________________________
_ The methyl 2-(p-chlorophenyl)imidazole-4(5)-carboxylate is
granulated with the starch paste and while moist passed through a
No. 14 screen, dried at 45.degree. C. for 20 hours, and then passed
3 times through a No. 14 screen. The starch is then passed through
a No. 90 bolting cloth onto the granulation, and all ingredients
are blended thoroughly The magnesium stearate is passed through a
No. 90 bolting cloth onto the granulation, and these ingredients
are blended, after which the granulation is compressed into tablets
using a fourteen thirty-seconds of an inch flat, bevelled, scored
punch having a thickness of 0.205.+-. 0.005 inch yielding 1,000
tablets each weighing 0.543 grams.
Formulation II: Encapsulation -- for 250 mg. Capsule Ingredient
Amt.-- Mg.
_________________________________________________________________________
_ 2-(3,4-dichlorophenyl)imidazole- 4(5)-carboxylic acid 250 Lactose
93 Talc 7
_________________________________________________________________________
_ Blend lactose, talc and the 2-(3,4-dichlorophenyl)imidazole-4(5)-
carboxylic acid in suitable blending equipment, and encapsulate
into a No. 2 capsule at a target weight of 350 mg.
Formulation III: Liquid Suspension -- Formula Ingredient Amt.--
g./l.
_________________________________________________________________________
_ Veegum H.V. 3.0 Water 150.0 Methyl paraben 1.0
2-(4-pyridyl)-4(5)-cyanoimidazole 50.0 Kaolin 10.0 Flavor 1.0
Glycerin, 9.5 to 1 liter
_________________________________________________________________________
_ Suspend Veegum in water with vigorous agitation, add methyl
paraben and allow to stand overnight to ensure complete hydration
of Veegum. In separate vessel suspend
2-(4-pyridyl)-4(5)-cyanoimidazole in about 750 cc. of glycerin. Add
kaolin and stir until homogeneous. Slowly add aqueous dispersion of
Veegum and methyl paraben. Add flavor and continue agitation for 1
hour to ensure homogeneity. Q.S. with remaining glycerin to 1:1.
Stir until homogeneous. 1 Teaspoonful contains 250 mg. of
2-(4-pyridyl)-4(5)-cyanoimidazole. The following examples are given
for purposes of illustration and not by way of limitation:
EXAMPLE 1
METHYL 2-(p-CHLOROPHENYL)IMIDAZOLE-4(5)-CARBOXYLATE
Dry hydrogen chloride is introduced into a solution of
2-(p-chlorophenyl)imidazole-4(5)-carboxylic acid (3.5 grams) in
methanol (150 ml.) at reflux for one hour. The reaction mixture is
then allowed to cool to room temperature and is concentrated under
reduced pressure to a solid residue. Upon recrystallization from
acetonitrile-water, 3 grams of
methyl-2-(p-chlorophenylimidazole-4(5)-carboxylate, m.p.
237.degree.-238.degree. C., is obtained.
When in the above procedure
2-(p-bromophenyl)-imidazole-4(5)-carboxylic acid,
2-(1-naphthyl)imidazole-4-(5)-carboxylic acid and
2-(2-thienyl)imidazole-4(5)-carboxylic acid are employed in place
of 2-(p-chlorophenyl)imidazole-4(5)-carboxylic acid, there are
obtained methyl 2-(bromophenyl)imidazole-4(5)-carboxylate, methyl
2-(1-naphthyl)-imidazole-4(5)-carboxylate and methyl 2-(2-
thienyl)imidazole-4(5)-carboxylate, respectively.
EXAMPLE 2
METHYL 2-(4-PYRIDYL)IMIDAZOLE-4(5)-CARBOXYLATE
Dry hydrogen chloride is introduced into a solution of
2-(4-pyridyl)imidazole-4(5)-carboxylic acid (3.5 grams) in methanol
(150 ml.) at reflux for one hour. The reaction mixture is then
cooled to room temperature and is concentrated under reduced
pressure until a solid residue is obtained. Upon recrystallization
from acetonitrile-water, methyl
2-(4-pyridyl)-imidazole-4(5)-carboxylate, m.p.
218.5.degree.-220.degree. C. is obtained.
When in the above procedure ethanol is employed in place of
methanol, there is obtained ethyl
2-(4-pyridyl)-imidazole-4(5)-carboxylate.
When in the above procedure 2-(5-indanyl)imidazole-4(5)-carboxylic
acid and 2-(6-quinolyl)imidazole-4(5)-carboxylic acid are employed
in place of 2-(4-pyridyl)-imidazole-4(5)-carboxylic acid, there are
obtained methyl-2-(5-indanyl)imidazole-4(5)-carboxylate and methyl
2-(6-quinolyl)imidazole-4(5)-carboxylate, respectively.
EXAMPLE 3
4(5)-ACETYL-2(p-CHLOROPHENYL)IMIDAZOLE
2-(p-Chlorophenyl)-4(5)-cyanoimidazole (2 grams, 0.01 mole) is
dissolved in tetrahydrofuran (100 ml.), and the resulting solution
is added dropwise to methyl magnesium iodide (0.03 mole) in ether
(30 ml.). The reaction mixture is refluxed for 3 hours, after which
it is cooled to room temperature and maintained at this temperature
for 20 hours. The reaction mixture is then concentrated to 30 ml.
and poured with cooling onto dilute hydrochloric acid (about 100
ml.). The mixture is then extracted with ether, and the ether
extract is dried over sodium sulfate. The ether extract is then
concentrated until a solid residue is obtained. Upon
recrystallization of the solid residue from acetonitrile, 4(5)
-acetyl-2(p-chlorophenyl)imidazole, m.p.
244.5.degree.-246.5.degree. C. is obtained.
When in the above procedure ethyl magnesium iodide and phenyl
magnesium iodide are employed in place of methyl magnesium iodide,
there are obtained 4(5)-propionyl-2-(p-chlorophenyl)imidazole and
4(5)-benzoyl-2-(p-chloro-phenyl)imidazole, respectively.
EXAMPLE 4
2-(p-CHLOROPHENYL)IMIDAZOLE-4(5)-CARBOXYLIC ACID
A suspension of 2-(p-chlorophenyl-)-4(5)-trifluoromethylimidazole
(17 grams) in 1 N aqueous sodium hydroxide (1 liter) is heated at
100.degree. C. for 1-1/2 hours. The resulting solution is filtered,
and the filtrate is acidified with hydrochloric acid. A solid
separates from the acid solution and is collected by filtration.
Upon recrystallization of the solid product from
acetonitrile-water, 2-(p-chlorophenyl)imidazole-4(5)- carboxylic
acid, m.p. 261.degree. C., is obtained.
When in the above procedure
2-(4-pyridyl)-4(5)-trifluoromethylimidazole is employed in place of
2-(p-chlorophenyl)-4(5)-trifluoromethylimidazole,
2-(4-pyridyl)-imidazole-4(5)-carboxylic acid, m.p. 300.degree. C.,
is obtained.
When in the above procedure 2-(3,4-dichlorophenyl)-4(5)-
trifluoromethylimidazole is employed in place of a
(p-chlorophenyl)-4(5)- trifluoromethylimidazole,
2-(3,4-dichlorophenyl)imidazole-4(5)-carboxylic acid, m.p.
249.degree.-250.degree. C., is obtained.
When in the above procedure 2-(4-thiazolyl)-4(5)-
trifluoromethylimidazole is employed in place of
2-(p-chlorophenyl)-4(5)- trifluoromethylimidazole, there is
obtained 2-(4-thiazobyl)-imidazole- 4(5)-carboxylic acid.
EXAMPLE 5
2-(p-CHLOROPHENYL)IMIDAZOLE-4(5)-CARBOXAMIDE
Methyl 2-(p-chlorophenyl)-imidazole-4(5)-carboxylate (2.36 grams,
0.01 mole) is reacted with ammonia (9 grams) in methanol (50 ml.)
at 120.degree. C. for 18 hours. The reaction mixture is then
concentrated until a solid residue is obtained. Upon
recrystallization of the residue from methanol-water,
2-(p-chlorophenyl)imidazole-4(5)-carboxamide, m.p.
272.degree.-274.degree. C., is obtained.
When in the above procedure methyl 2-(2-quinolyl)-imidazole-4(5)-
carboxylate, ethyl 2-(3-cinnolyl)imidazole-4(5)-carboxylate and
methyl 2-(p-sulfamoylphenyl)imidazole-4(5)-carboxylate are employed
in place of methyl 2-(p-chlorophenyl)imidazole-4(5)-carboxylate,
there are obtained 2-(2-quinolyl)imidazole-4(5)-carboxamide,
2-(3-cinnolyl)imidazole-4(5)- carboxamide and
2-(p-sulfamoylphenyl)imidazole-4(5)-carboxamide, respectively.
EXAMPLE 6
2-(4-PYRIDYL)IMIDAZOLE-4(5)-CARBOXAMIDE
Methyl 2-(4-pyridyl)imidazole-4(5)-carboxylate (0.01 mole) is
reacted with ammonia (.52 mole) in methanol (50 ml.) at 120.degree.
C. for 18 hours. The reaction mixture is the concentrated until a
solid residue is obtained. Upon recrystallization of the residue
from methanol-water, 2-(4-pyridyl)imidazole-4(5)-carboxamide, m.p.
273.degree.-276.degree. C., is obtained.
When in the above procedure ethyl 2-(p-methylphenyl)
imidazole-4(5)-carboxylate and methyl 2-(p-methoxyphenyl)
imidazole-4(5)-carboxylate are employed in place of methyl
2-(4-pyridyl)imidazole-4(5)-carboxylate, there are obtained
2-(p-methylphenyl)imidazole-4(5)-carboxamide and 2-(p-
methoxyphenyl)imidazole-4(5)-carboxamide, respectively.
EXAMPLE 7
2-(p-CHLOROPHENYL)IMIDAZOLE-4(5)-CARBOXAMIDE
2-(p-Chlorophenyl)imidazole-4(5)-carboxylic acid (2grams) is
dissolved in thionyl chloride (40 ml.), and the resulting solution
is heated at reflux for 30 minutes. The thionyl chloride is removed
under reduced pressure, and the solid residue is added with cooling
to concentrated aqueous ammonia (40 ml.). The reaction mixture is
then stirred for 45 minutes at room temperature, diluted with water
(40 ml.), and concentrated under reduced pressure to 40 ml. The
concentrated solution is neutralized with dilute hydrochloric acid
and the solid which precipitates is collected by filtration. Upon
recrystallization of the solid from methanol-water,
2-(p-chlorophenyl)imidazole-4(5)-carboxamide, m.p.
272.5.degree.-275.degree. C., is obtained.
EXAMPLE 8
2-(p-CHLOROPHENYL)-4(5)-CYANOIMIDAZOLE
A suspension of 2-(p-chlorophenyl)imidazole-4(5)-carboxamide (1
gram) in phosphorous oxychloride (10 ml.) is heated at 100.degree.
C. for 3-1/2 hours. The phosphorous oxychloride is removed under a
stream of air until a solid residue is obtained. Dilute sodium
bicarbonate solution is added to neutralize the residual acid, and
the solid is collected by filtration. Upon recrystallization of the
solid residue from benzene-hexane,
2-(-p-chlorophenyl)-4(5)-cyanoimidazole, m.p.
210.degree.-213.degree. C., is obtained.
When in the above procedure
2-(2-quinolyl)imidazole-4(5)-carboxamide and
2-(2-naphthyl)imidazole-4(5)-carboxamide are employed in place of
2-(p-chlorophenyl)imidazole-4(5)-carboxamide there are obtained
2-(2-quinolyl)-4(5)-cyanoimidazole and 2-(2-naphthyl)-4(5)-
cyanoimidazole.
EXAMPLE 9
2-(4-PYRIDYL)-4(5)-CYANOIMIDAZOLE
A suspension of 2-(4-pyridyl)imidazole-4(5)-carboxamide (1 gram) in
phosphorous oxychloride (10 ml.) is heated at 100.degree. C. for
3-1/2 hours. The phosphorous oxychloride is removed under a stream
of air until a solid residue is obtained. Dilute sodium bicarbonate
solution is added to neutralize the residual acid, and the solid
precipitate is collected by filtration. Upon recrystallization from
benzene-hexane, 2-(4-pyridyl)-4(5)-cyanoimidazole, m.p.
295.degree.-297.degree. C., is obtained.
When in the above procedure 2-(3,4-dichlorophenyl)imidazole-4(5)-
carboxamide and 2-(5-indanyl)imidazole-4(5)-carboxamide are
employed in place of 2-(4-pyridyl)imidazole-4(5)-carboxamide, there
are obtained 2-(3,4-dichlorophenyl)-4(5)-cyanoimidazole and
2-(5-indanyl)-4(5)- cyanoimidazole, respectively.
PREPARATION A
2-(4-PYRIDYL)-4(5)-TRIFLUOROMETHYLIMIDAZOLE
The trifluoromethylimidazoles used as the starting materials are
prepared as follows:
Sodium acetate trihydrate (11.6 grams, 0.084 mole) is dissolved in
40 ml. of water, and 1,1-dibromo-3,3,3-trifluoroacetone (11.6
grams, 0.042 mole) is added to the resulting aqueous solution. The
solution is heated for 30 minutes at 100.degree. C. and is then
cooled in an ice bath. The cooled solution is added to a solution
of 4-pyridinecarboxaldehyde (4.7 grams, 0.044 mole) in methanol
(200 ml.). Concentrated aqueous ammonia (50 ml.) is added to the
alcoholic solution, and the reaction mixture is allowed to stand
for 5 hours at room temperature. The mixture is then concentrated
to about 75 ml., and the product separates from the solution as an
oil which solidifies on standing. Upon recrystallization from
water, there is obtained
2-(4-pyridyl)-4(5)-trifluoromethylimidazole, m.p.
156.degree.-157.5.degree. C.
When in the above procedure 3-pyridinecarboxaldehyde is employed in
place of 4-pyridinecarboxaldehyde, there is obtained
2-(3-pyridyl)-4(5)- trifluoromethylimidazole, m.p.
228.degree.-228.5.degree. C.
When in the above procedure 2-pyridinecarboxaldehyde is employed in
place of 4-pyridinecarboxaldehyde, there is obtained
2-(2-pyridyl)-4(5)- trifluoromethylimidazole, m.p.
156.degree.-157.5.degree. C.
PREPARATION B
2-(p-FLUOROPHENYL)-1-METHYL-4(AND 5)-TRIFLUOROMETHYLIMIDAZOLE
Dimethylsulfate (0.63 grams, 0.005 mole) is added to a solution of
2-(p-fluorophenyl)-4(5)-trifluoromethylimidazole (1.1 grams, 0.005
mole) in acetic acid (10 ml.), and the reaction mixture is refluxed
overnight. After 17 hours at reflux, additional dimethylsulfate
(0.63 grams, 0.005 mole) is added, and the solution is heated at
reflux for an additional 5 hours. The acetic acid is removed in
vacuo, and the resulting residue is triturated with dilute ammonium
hydroxide, water, and then with hexane. The hexane extract is
concentrated to a solid residue and is sublimed to yield 200 mg. of
product. Upon recrystallization from hexane,
2-(p-fluorophenyl)-1-methyl-4(and 5 )-trifluoromethylimidazole are
obtained, m.p. 81.degree.-84.5.degree. C. Thin layer chromatography
and VPC indicate the presence of two isomeric components.
When in the above procedure diethylsulfate is employed in place of
dimethylsulfate, 2-(p-fluorophenyl)-1-ethyl-4(and 5)-
trifluoromethylimidazole are obtained.
It should be understood that although this invention has been
described with reference to particular embodiments thereof, changes
and modifications may be made which are within its intended scope,
and it should be limited only by the language of the appended
claims.
* * * * *