U.S. patent number 3,899,508 [Application Number 05/460,646] was granted by the patent office on 1975-08-12 for 5-(2-aminophenyl)pyrazole-3-carboxylic acids and esters thereof.
This patent grant is currently assigned to Eli Lilly and Company. Invention is credited to James H. Wikel.
United States Patent |
3,899,508 |
Wikel |
August 12, 1975 |
5-(2-Aminophenyl)pyrazole-3-carboxylic acids and esters thereof
Abstract
5-(2-Aminophenyl)pyrazole-3-carboxylic acids, useful as
intermediates in the preparation of compounds useful as complement
inhibitors, are prepared by reacting a 2-nitroacetophenone with a
dialkyl oxalate in the presence of a strong base and in an inert
solvent to give the corresponding alkyl 2-nitrobenzoylpyruvate,
condensing the alkyl 2-nitrobenzoylpyruvate with hydrazine in an
inert solvent to give an alkyl
5-(2-nitrophenyl)-pyrazole-3-carboxylate, reducing the nitro group
catalytically to give the alkyl
5-(2-aminophenyl)pyrazole-3-carboxylate, and, if desired,
hydrolyzing the ester to the free acid.
Inventors: |
Wikel; James H. (Greenwood,
IN) |
Assignee: |
Eli Lilly and Company
(Indianapolis, IN)
|
Family
ID: |
23829525 |
Appl.
No.: |
05/460,646 |
Filed: |
April 12, 1974 |
Current U.S.
Class: |
548/374.1;
514/825; 544/250 |
Current CPC
Class: |
C07C
205/56 (20130101); C07D 231/14 (20130101); Y10S
514/825 (20130101) |
Current International
Class: |
C07D
231/00 (20060101); C07D 231/14 (20060101); C07C
205/56 (20060101); C07C 205/00 (20060101); C07d
047/02 () |
Field of
Search: |
;260/31R |
Foreign Patent Documents
Other References
Chemical Abstracts Vol. 59: 15214b (1963). .
Chemical Abstracts Vol. 52: 3784g (1956). .
Chemical Abstracts Vol. 66: 75947k (1967)..
|
Primary Examiner: Moyer; Donald B.
Attorney, Agent or Firm: Maycock; William E. Smith; Everet
F.
Claims
What is claimed is:
1. A compound of the formula, ##SPC4##
wherein R.sub.1 is hydrogen or C.sub.1 -C.sub.3 alkyl and R.sub.2
and R.sub.3 are monovalent groups independently selected from the
group consisting of hydrogen, methyl, methoxy, fluoro, chloro, and
bromo, with the limitation that R.sub.2 and R.sub.3 must be
different unless each of R.sub.2 and R.sub.3 is hydrogen.
2. The compound of claim 1, wherein R.sub.1 is C.sub.1 -C.sub.3
alkyl.
Description
BACKGROUND OF THE INVENTION
This invention relates to 5-(2-aminophenyl)pyrazole-3-carboxylic
acids and alkyl esters thereof. More particularly, this invention
relates to 5-(2-aminophenyl)pyrazole-3-carboxylic acids and alkyl
esters thereof which are useful as intermediates in the preparation
of compounds useful as complement inhibitors, and to a process for
preparing said 5-(2-aminophenyl)pyrazole-3-carboxylic acids and
esters.
Malfunction of the serum complement system is known to be involved
in glomerulonephritis and is believed to be involved in serum
sickness and in certain inflammatory diseases such as rheumatoid
arthritis. Consequently, an effective complement inhibitor would
substantially block the malfunction of the serum complement system
and hence would be useful in the treatment of such diseases.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel
5-(2-aminophenyl)pyrazole-3-carboxylic acids and alkyl esters
thereof are provided having the following general formula:
##SPC1##
Wherein R.sub.1 is hydrogen or C.sub.1 -C.sub.3 alkyl and R.sub.2
and R.sub.3 are monovalent groups independently selected from the
group consisting of hydrogen, methyl, methoxy, fluoro, chloro, and
bromo, with the limitation that R.sub.2 and R.sub.3 must be
different unless each of R.sub.2 and R.sub.3 is hydrogen.
The compounds of the present invention are prepared by the process
which comprises the steps of (1) reacting a 2-nitroacetophenone
with a C.sub.1 -C.sub.3 dialkyl oxalate in the presence of a strong
base, in an inert solvent, and at a temperature of from about
-40.degree.C to about 100.degree.C, and then acidifying the
reaction mixture to give the corresponding alkyl
2-nitrobenzoylpyruvate; (2) condensing the alkyl
2-nitrobenzoylpyruvate with hydrazine in an inert solvent and at a
temperature of from about 0.degree.C to about 100.degree.C to give
an alkyl 5-(2-nitrophenyl)pyrazole-3-carboxylate; (3) reducing
catalytically the nitro group of the alkyl
5-(2-nitrophenyl)pyrazole-3-carboxylate, in an inert solvent, at an
initial hydrogen pressure of from about 15 to about 100 psig, and
at a temperature of from about 0.degree.C to about 50.degree.C, to
give the alkyl 5-(2-aminophenyl)pyrazole-3-carboxylate; and, if
desired, (4) hydrolyzing the alkyl
5-(2-aminophenyl)-pyrazole-3-carboxylate to the free acid.
The compounds of the present invention are useful as intermediates
in the preparation of certain 5-[2-(N-substituted
amino)phenyl]pyrazole-3-carboxylic acids which are useful as
complement inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Examples of compounds coming within the foregoing general formula
include, among others,
5-(2-Aminophenyl)pyrazole-3-carboxylic acid,
Methyl 5-(2-aminophenyl)pyrazole-3-carboxylate,
Ethyl 5-(2-aminophenyl)pyrazole-3-carboxylate,
Propyl 5-(2-aminophenyl)pyrazole-3-carboxylate,
Isopropyl 5-(2-aminophenyl)pyrazole-3-carboxylate,
Methyl 5-(2-amino-3-methylphenyl)pyrazole-3-carboxylate,
Isopropyl 5-(2-amino-4-fluorophenyl)pyrazole-3-carboxylate,
Methyl 5-(2-amino-6-methoxyphenyl)pyrazole-3-carboxylate,
5-(2-Amino-3-methyl-6-methoxyphenyl)pyrazole-3-carboxylic acid,
Ethyl 5-(2-amino-3-methyl-5-bromophenyl)pyrazole-3-carboxylate,
and
Methyl
5-(2-amino-4-chloro-5-methoxyphenyl)pyrazole-3-carboxylate.
The referred compounds are the esters; i.e., R.sub.1 preferably is
C.sub.1 -C.sub.3 alkyl.
The process of the present invention can be represented by the
following reaction scheme: ##SPC2##
wherein R.sub.4 is C.sub.1 -C.sub.3 alkyl and R.sub.2 and R.sub.3
are as defined hereinbefore. Briefly, a 2-nitroacetophenone is
reacted with a dialkyl oxalate in the presence of a strong base and
in an inert solvent, then the reaction mixture is acidified to give
the corresponding alkyl 2-nitrobenzoylpyruvate. The alkyl
2-nitrobenzoylpyruvate then is condensed with hydrazine in an inert
solvent to give an alkyl 5-(2-nitrophenyl)pyrazole-3-carboxylate.
The nitro group of the alkyl
5-(2-nitrophenyl)pyrazole-3-carboxylate is reduced catalytically in
an inert solvent to give the alkyl
5-(2-aminophenyl)pyrazole-3-carboxylate. Optionally, but not
preferably, the alkyl 5-(2-aminophenyl)pyrazole-3-carboxylate can
be hydrolyzed by known methods to the
5-(2-aminophenyl)pyrazole-3-carboxylic acid.
The first step, which involves reacting a 2-nitroacetophenone with
a dialkyl oxalate, preferably with dimethyl oxalate, essentially is
a known procedure. See, for example, L. Musajo, et al., Gazz. chim.
ital., 80, 161 (1950) [C.A., 45, 624 (1951)], and K. Makino, et
al., Kumamoto Med. J., 6, 122 (1954) [C.A., 49, 6179 (1954)]. In
general, both starting materials are either commercially-available
or readily prepared by known procedures. Normally and preferably,
the molar ratio of the 2-nitroacetophenone to the dialkyl oxalate
will be about 1:1, although an excess of either reactant can be
employed, if desired. Thus, said molar ratio can vary from about
2:1 to about 1:2. The molar ratio of strong base to the dialkyl
oxalate can vary from about 1:1 to about 1.2:1, and preferably from
about 1:1 to about 1.1:1. Most preferably, the molar ratio of base
to oxalate will be about 1:1. Examples of suitable strong bases
include, among others, alkali metal hydroxides, such as lithium
hydroxide, sodium hydroxide, potassium hydroxide, rubidium
hydroxide, and cesium hydroxide; alkali metal C.sub.1 -C.sub.4
alkoxides, such as sodium methoxide, potassium ethoxide, lithium
isopropoxide, cesium propoxide, rubidium butoxide, sodium
sec-butoxide, lithium t-butoxide, and the like; C.sub.1 -C.sub.4
alkyl lithium compounds, such as methyl lithium, ethyl lithium,
propyl lithium, isopropyl lithium, butyl lithium, sec-butyl
lithium, isobutyl lithium, and t-butyl lithium; alkali metal
hydrides, such as lithium hydride, sodium hydride, potassium
hydride, rubidium hydride, and cesium hydride; and the like. The
preferred bases are the alkali metal alkoxides. Of course, the base
must be significantly soluble in the reaction solvent, and
preferably will be substantially, i.e., at least about 50 percent,
soluble. Most preferably, the base will be completely soluble in
the reaction solvent. Generally, the solvent must be inert.
Examples of such solvents include, among others, alkanols, such as
methanol, ethanol, propanol, and isopropanol; aromatic
hydrocarbons, such as benzene, toluene, the xylenes, and the like;
aliphatic hydrocarbons, such as pentane, hexane, octane, and the
like; ethers, such as diether ether, diisopropyl ether, methyl
butyl ether, tetrahydrofuran, 1,4-dioxane, and the like; and such
miscellaneous solvents as N,N-dimethylformamide,
N,N-dimethylacetamide, and dimethyl sulfoxide. The preferred
solvents are the alkanols. The choice of a particular preferred
solvent is important only when it is desired to isolate the alkyl
2-nitrobenzoylpyruvate in pure form. That is, when the alkyl moiety
of the alkanol solvent is different from the alkyl moiety of the
dialkyl oxalate, transesterification can result in the formation of
two alkyl 2-nitrobenzoylpyruvates having different alkyl moieties.
Consequently, when using an alkanol solvent, it is preferred that
the alkyl moieties of the alkanol and the dialkyl oxalate be the
same. The amount of solvent employed is not critical, provided
adequate agitation can be maintained during the reaction.
Typically, the amount of solvent employed will constitute about 50
percent by weight of the total reaction mixture. The reaction
temperature, which can vary from about -40.degree.C to about
100.degree.C, is to some extent dependent upon the base-solvent
combination employed. When both a preferred base and a preferred
solvent are used, the reaction temperature can vary from about
-20.degree.C to about 20.degree.C. The reaction time is not
critical and can vary from about 15 minutes to about 24 hours.
Typically, the reaction time will vary from about 1 to about 18
hours. When the reaction is complete, the alkyl
2-nitrobenzoyl-pyruvate normally has precipitated as the enolate.
The precipitate is isolated and dissolved in water. Acidification
of the resulting aqueous solution results in the precipitation of
the alkyl 2-nitrobenzoylpyruvate which can be purified, if desired,
by standard techniques. The acid used in said acidificatioon is not
critical and can be either organic or inorganic. Examples of
suitable acids include, among others, organic carboxylic acids,
such as acetic acid, propionic acid, chloroacetic acid,
trichloroacetic acid, benzoic acid, m-nitrobenzoic acid,
p-bromobenzoic acid, and the like; organic sulfonic acids, such as
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, and the like; and inorganic acids, such as
hydrochloric acid, sulfuric acid, phosphoric acid, and the like.
The organic acids are preferred, with the organic carboxylic acids
being most preferred.
The second step of the process of the present invention requires
condensing hydrazine with the alkyl 2-nitrobenzoyl-pyruvate
obtained above. In general, the molar ratio of hydrazine to the
alkyl 2-nitrobenzoylpyruvate can vary from about 1:1 to about 3:1
or even higher. Preferably, this molar ratio will vary from about
1:1 to about 1.1:1. In general, any inert solvent can be used.
Examples of such solvents include those listed as suitable in the
first step, and additionally, aliphatic carboxylic acid esters,
such as methyl acetate, ethyl acetate, butyl acetate, and the like;
and halogen-containing hydrocarbons, such as methylene chloride,
ethylene dichloride, chloroform, carbon tetrachloride,
chlorobenzene, bromobenzene, and the like. The preferred solvents
are the alkanols. The amount of solvent employed is not critical,
although the solvent normally will constitute at least about 50
percent by weight of the total reaction mixture. However, the
solvent often will constitute up to about 95 percent by weight of
the total reaction mixture when the alkyl 2-nitrobenzoylpyruvate
has but limited solubility in the solvent. The reaction temperature
can vary from about 0.degree.C to about 100.degree.C, preferably
from about 10.degree.C to about 40.degree.C, and most preferably
will be ambient temperature. The parameters discussed hereinabove
with respect to the reaction time in the first step apply here,
also. The alkyl 5-(2-nitrophenyl)pyrazole-3-carboxylate which is
obtained is isolated and, if desired, purified in accordance with
standard procedures. It should be noted that the alkyl
5-(2-nitrophenyl)pyrazole-3-carboxylate is light-sensitive; i.e.,
the compound turns to a lavender to purple color upon exposure to
light. Consequently, it is desirable to the appropriate precautions
while carrying out the second step, which precautions are well
known to those skilled in the art. However, the color change which
occurs upon exposure of the compound to light apparently has no
significant effect upon the chemical structure of the compound.
In the third step of the process of the present invention, the
nitro group of the alkyl 5-(2-nitrophenyl)pyrazole-3-carboxylate is
catalytically reduced to an amino group in accordance with known
procedures. Briefly, the compound is dissolved in an inert solvent,
examples of such solvents being those listed with respect to step
two above. Again, the preferred solvents are the alkanols. The
amount of solvent is not critical and typically will constitute
from about 50 to about 95 percent by weight of the total reaction
mixture. Suitable catalysts include, among others, 5 percent
rhodium on alumina, 5 percent rhodium on activated charcoal,
ruthenium oxide, platinum oxide, 5 percent palladium on activated
charcoal, and other like catalysts known to catalyze the reduction
of aromatic nitro groups. The amount of catalyst employed can vary
from about 0.1 percent to about 20 percent by weight, based on the
amount of alkyl 5-(2-nitrophenyl)pyrazole-3-carboxylate; about ten
percent by weight of catalyst has been found to give satisfactory
results. The initial hydrogen pressure can vary from about 15 to
about 100 psig, with from about 45 to about 60 psig being
preferred. The reduction temperature normally will vary from about
0.degree.C to about 50.degree.C. The reduction is exothermic;
hence, some care must be exercised to keep the reduction under
control. The reaction mixture is worked up according to standard
procedures in order to isolate the alkyl
5-(2-aminophenyl)pyrazole-3-carboxylate which can be purified, if
desired.
As indicated hereinbefore, an optional fourth step can be carried
out, if desired, which step comprises hydrolyzing by known
procedures the alkyl 5-(2-aminophenyl)pyrazole-3-carboxylate to the
corresponding 5-(2-aminophenyl)pyrazole-3-carboxylic acid. This
fourth step, however, is not preferred since the carboxylic acid
moiety of the compounds of the present invention must be blocked in
order to convert the compounds of the present invention to certain
5-[2-(N-substituted amino)phenyl]pyrazole-3-carboxylic acids which
are useful as complement inhibitors.
The compounds of the present invention are converted to the
complement inhibiting pyrazole-3-carboxylic acids in accordance
with the following reaction scheme: ##SPC3##
wherein R.sub.2, R.sub.3, and R.sub.4 are as defined hereinbefore;
R.sub.5 is a monovalent group selected from the group consisting of
methyl, benzyl, and monosubstituted benzyl in which the substituent
is methyl, trifluoromethyl, methoxy, methylsulfonyl, fluoro,
chloro, or bromo; and X is fluoro, chloro, or bromo. Thus, an alkyl
5-(2-aminophenyl)pyrazole-3-carboxylate is treated with phosgene in
a large excess of pyridine to give the corresponding alkyl
pyrazolo[1,5-c]quinazolin-5(6H)-one-2-carboxylate. The
pyrazoloquinazolinone then is N-alkylated at the 6-position with an
alkyl or aralkyl halide in the presence of a strong base, such as
sodium hydride, and in the presence of a suitable solvent, such as
N,N-dimethylformamide. The resulting 6-substituted
pyrazoloquinazolinone is hydrolyzed to the corresponding
5-[2-(N-substituted amino)phenyl]pyrazole-3-carboxylic acid,
typically by heating at reflux a mixture of the 6-substituted
pyrazoloquinazolinone, potassium hydroxide, and aqueous ethanol.
The reaction mixture then is cooled and made acidic with aqueous
hydrochloric acid. The solid which forms is isolated by filtration
and purified, if desired, according to known methods.
It will be apparent that in converting a compound of the present
invention to a complement-inhibiting pyrazole-3-carboxylic acid,
any carboxylic acid blocking group can be employed which is stable
during the conversion and yet capable of being readily removed.
The activity of a complement-inhibiting pyrazole-3-carboxylic acid
obtained as described above from a compound of the present
invention is determined by the test procedure of W. T. Jackson, et
al., reported at the 1971 Annual Meeting of the Federation of
American Societies of Experimental Biology and abstracted in
Federation Proceedings, Vol. 30, No. 2 (March-April), 1971.
The pyrazole-3-carboxylic acids obtained from compounds of the
present invention are useful in inhibiting complement-induced
hemolysis. Complement inhibitors find practical utility in the
treatment of such diseases as glomerulo-nephritis, serum sickness,
and certain inflammatory diseases such as rheumatoid arthritis.
Utilization of a complement inhibitor in general involves
administering to a mammal parenterally, preferably intravenously or
intraperitoneally, an effective amount of such a compound,
typically at a dosage level sufficient to provide a concentration
of the compound in the blood of from about 1 to about 400 .mu.g/ml.
Such a concentration on the average can be attained by the
administration of a dose of from about 0.05 to about 32 mg/kg. The
necessary concentration in the blood of complement inhibitor can be
achieved by administering a single dose or up to about six smaller
doses per day, depending upon the tolerance of the patient to the
compound, persistence of the compound in the blood stream, and
other factors. The complement inhibitor normally is formulated into
a suitable pharmaceutical composition comprising the active
ingredient in association with at least one
pharmaceutically-acceptable carrier therefor by procedures well
known in the art.
Suitable pharmaceutical carriers are described in E. W. Martin, et
al., "Remington's Pharmaceutical Sciences," 14th Ed., Mack
Publishing Company, Easton, Pa., 1965.
In addition to parenteral administration, the complement inhibitor
can be administered to a mammal enterally, preferably orally. For
enteral administration, the complement inhibitor normally is
administered at a level of from about 1 to about 200 mg/kg of
mammal body weight. Advantageously, the complement inhibitor is
formulated in a dosage unit form containing from about 5 to about
500 mg, preferably from about 10 to about 150 mg, of active
ingredient in association with suitable carriers, diluents, and the
like.
The present invention is more fully described, without intending to
limit it in any manner, by the following examples which illustrate
the preparation of a compound of the present invention by means of
the process of the present invention. In the examples, all
temperatures are in degrees centigrade, unless otherwise
specified.
EXAMPLE 1
Preparation of methyl 2-nitrobenzoylpyruvate
To a solution of 20 g of sodium methoxide and 43 g of dimethyl
oxalate in 150 ml of methanol, under nitrogen and at a temperature
of 0.degree., was added dropwise 60 g of 2-nitroacetophenone. The
reaction mixture was allowed to warm slowly to ambient temperature
and was stirred at ambient temperature overnight. To the solidified
reaction mixture was added 125 ml of diethyl ether. The resulting
slurry was filtered and the solid was washed thoroughly with
additional diethyl ether. The dried solid was dissolved in about
1200 ml of water. The resulting solution was filtered to remove
insoluble material. The filtrate was acidified with glacial acetic
acid and cooled, and the precipitated solid was isolated by
filtration to give, after drying, 77 g (84 percent) of methyl
2-nitrobenzoylpyruvate, mp 94.degree.-95.degree.. The following
elemental analysis was obtained.
Calculated for C.sub.11 H.sub.9 NO.sub.6 :
C, 52.60; h, 3.61; n, 5.58; o, 38.22
found:
C, 52,38; h, 3.56; n, 5.44; o, 38.44
example 2
preparation of methyl 5-(2-nitrophenyl)pyrazole-3-carboxylate.
To a slurry of 77 g of methyl 2-nitrobenzoylpyruvate in 1600 ml of
methanol at ambient temperature was added, in the dark, 11.5 ml of
85 percent hydrazine hydrate. The solution which resulted was
allowed to stand in the dark overnight at ambient temperature. The
reaction solution was distilled under reduced pressure, giving 56 g
(75 percent) of methyl 5-(2-nitrophenyl)pyrazole-3-carboxylate. The
following elemental analysis was obtained.
Calculated for C.sub.11 H.sub.9 N.sub.3 O.sub.4 :
C, 53.44; h, 3.67; n, 17.00; o, 25.89
found:
C, 53.42; h, 3.37; n, 17.26; o, 25.96
example 3
preparation of methyl 5-(2-aminophenyl)pyrazole-3-carboxylate.
Methyl 5-(2-nitrophenyl)pyrazole-3-carboxylate was reduced, using
25 g of the nitro compound, 570 ml of ethanol, 2.5 g of 5 percent
palladium on activated characoal, and an initial hydrogen pressure
of 55 psig. The reduction required 1.5 hours, during which time the
reaction temperature increased from ambient temperature to about
54.degree.. Hydrogen uptake was 92 percent of theory. The reaction
solution was treated with decolorizing carbon and filtered. The
filtrate was distilled under reduced pressure to give 15 g (69
percent) of crude product which upon recrystallization from
benzene/hexane gave 7.4 g of methyl
5-(2-aminophenyl)pyrazole-3-carboxylate, mp
131.degree.-132.degree.. The following elemental analysis was
obtained.
Calculated for C.sub.11 H.sub.11 N.sub.3 O.sub.2 :
C, 60.82; h, 5.10; n, 19.34; o, 14.73
found:
C, 60.87; h, 5.0l; N, 19.52; O, 14.98
* * * * *