U.S. patent application number 10/455220 was filed with the patent office on 2004-02-26 for pyrazolecarboxylic acid derivatives, their preparation and pharmaceutical compositions containing them.
Invention is credited to Barth, Francis, Camus, Philippe, Martinez, Serge, Rinaldi, Murielle.
Application Number | 20040039024 10/455220 |
Document ID | / |
Family ID | 26234792 |
Filed Date | 2004-02-26 |
United States Patent
Application |
20040039024 |
Kind Code |
A1 |
Barth, Francis ; et
al. |
February 26, 2004 |
Pyrazolecarboxylic acid derivatives, their preparation and
pharmaceutical compositions containing them
Abstract
N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-ca-
rboxamide and its salts and solvates are powerful antagonists of
the CB.sub.1 cannabinoid receptors. They are prepared by reacting a
functional derivative of
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-
pyrazole-3-carboxylic acid with 1-aminopiperidine, optionally
followed by salification.
Inventors: |
Barth, Francis; (Saint
Georges D'Orques, FR) ; Camus, Philippe; (Muret,
FR) ; Martinez, Serge; (Montpellier, FR) ;
Rinaldi, Murielle; (Saint Georges D'Orques, FR) |
Correspondence
Address: |
SANOFI-SYNTHELABO INC.
9 GREAT VALLEY PARKWAY
P.O. BOX 3026
MALVERN
PA
19355
US
|
Family ID: |
26234792 |
Appl. No.: |
10/455220 |
Filed: |
June 5, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10455220 |
Jun 5, 2003 |
|
|
|
10165140 |
Jun 7, 2002 |
|
|
|
6645985 |
|
|
|
|
10165140 |
Jun 7, 2002 |
|
|
|
09890242 |
Jul 27, 2001 |
|
|
|
6432984 |
|
|
|
|
09890242 |
Jul 27, 2001 |
|
|
|
PCT/FR00/00194 |
Jan 28, 2000 |
|
|
|
Current U.S.
Class: |
514/326 ;
546/211 |
Current CPC
Class: |
A61P 25/34 20180101;
C07D 231/14 20130101; A61P 25/32 20180101; C07C 251/80 20130101;
A61P 3/00 20180101; A61P 3/04 20180101; A61P 25/28 20180101; A61P
25/00 20180101; A61P 25/18 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/326 ;
546/211 |
International
Class: |
A61K 031/454; C07D
43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 1, 1999 |
FR |
99/01201 |
Aug 2, 1999 |
FR |
99/10166 |
Claims
1.
N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-
-carboxamide, of formula: 6its pharmaceutically acceptable salts
and the solvates thereof.
2. Process for preparing
N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophe-
nyl)-4-ethylpyrazole-3-carboxamide, its salts and the solvates
thereof, characterized in that a functional derivative of
5-(4-bromophenyl)-1-(2,4-
-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid, of formula: 7is
treated with 1-aminopiperidine, in an organic solvent and in the
presence of a base; and the compound thus obtained is optionally
converted into one of its salts or one of the solvates thereof.
3. Process according to claim 2, for preparing an alkyl ester of
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic
acid by cyclization of an alkyl ester of
3-(4-bromobenzoyl)-2-(2-(2,4-dic- hlorophenyl)hydrazono)pentanoic
acid (IX).
4. Process according to claim 3, for preparing an alkyl ester of
3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic
acid by the action of a 2,4-dichlorophenylhydrazine salt on an
alkyl ester of 4-bromobenzoyl-2-oxopentanoic acid (VIII).
5. Process according to claim 4, for preparing an alkyl ester of
4-bromobenzoyl-2-oxopentanoic acid by the action of LiHMDS and then
an alkyl ester of 2-(1-imidazolyl)-2-oxoacetic acid on
bromobutyrophenone.
6. Process according to claim 2, for preparing an alkyl ester of
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic
acid from 4-bromobenzoyl-2-oxopentanoic acid by the action of a
2,4-dichlorophenylhydrazine salt, followed by cyclization.
7. Compound of formula: 8in which Alk represents a
(C.sub.1-C.sub.6)alkyl.
8. Compound of formula 9in which Alk represents a
(C.sub.1-C.sub.6)alkyl.
9. Pharmaceutical composition containing, as active principle, a
compound according to claim 1.
10. Pharmaceutical composition according to claim 9, containing
from 0.1 to 1000 mg of active principle, in unit dosage form, in
which the active principle is mixed with at least one
pharmaceutical excipient.
11. Use of a compound according to claim 1 for the preparation of
medicinal products intended for treating diseases involving the
CB.sub.1 cannabinoid receptors.
12. Use of a compound according to claim 11 for the treatment of
psychotic disorders, for the treatment of appetite disorders and
obesity, for the treatment of memory and cognitive disorders; for
the treatment of alcohol dependency and for withdrawal from
tobacco.
Description
[0001] The present invention relates to a novel pyrazole
derivative, to its salts and to the solvates thereof, to a process
for their preparation and to pharmaceutical compositions containing
them.
[0002] Patent applications EP-A-576 357, EP-A-658 546 and
WO-97/19063 describe pyrazole derivatives with affinity for
cannabinoid receptors. More particularly, patent appliction
EP-A-656 354 describes
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-
-carboxamide, also known as SR 141 716, and the pharmaceutically
acceptable salts thereof which have very good affinity for the
central cannabinoid receptors.
[0003] Compounds similar to SR 141716 have been described in the
literature, in particular
N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorop-
henyl)-4-methylpyrazole-3-carboxamide, referred to hereinbelow as
compound A, which is described by B. F. Thomas et al. in J. Pharm.
Exp. Therap., 1998, 285, 285-292.
[0004] The effects of cannabinoids are due to an interaction with
specific high-affinity receptors present at the central level
(Devane et al., Mol. Pharmacol., 1988, 34, 605-613) and at the
peripheral level (Nye et al., Pharmacol. and Experimental Ther.,
1985, 234, 784-791; Kaminski et al., 1992, Mol. Pharmacol., 42,
736-742; Munro et al., Nature, 1993, 365, 61-65).
[0005] Characterization of the receptors was made possible by the
development of synthetic ligands specific for cannabinoid
receptors, such as the agonists WIN 55212-2 (J. Pharmacol. Exp.
Ther., 1993, 264, 1352-1363) or CP 55,940 (J. Pharmacol. Exp.
Ther., 1988, 247, 1046-1051). The pharmacology of the CB.sub.1 and
CB.sub.2 cannabinoid receptor subtypes is outlined in Pharmacol.
Ther., 1997, 74, 129-130.
[0006] A novel N-piperidino-3-pyrazolecarboxamide derivative has
now been found which has very good affinity for the CB.sub.1
subtype of cannabinoid receptors (CB.sub.1 receptors) with
long-lasting action, which is useful in the therapeutic fields in
which cannabinoids are known to be involved.
[0007] According to one of its aspects, the present invention
relates to
N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-c-
arboxamide, of formula: 1
[0008] to its pharmaceutically acceptable salts and to the solvates
thereof.
[0009] According to another of its aspects, the present invention
relates to a process for preparing compound (I) above, its salts
and the solvates thereof, characterized in that a functional
derivative of
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic
acid, of formula: 2
[0010] is treated with 1-aminopiperidine, in an organic solvent and
in the presence of a base; and the compound thus obtained is
optionally converted into one of its salts or one of the solvates
thereof.
[0011] The reaction is carried out in basic medium, for example in
the presence of triethylamine in an inert solvent such as
dichloromethane or tetrahydrofuran.
[0012] Functional derivatives of the acid (II) which may be used
are the acid chloride, the anhydride, a mixed anhydride, a
C.sub.1-C.sub.4 alkyl ester in which the alkyl is straight or
branched, an activated ester, for example the p-nitrophenyl ester,
or the suitably activated free acid, for example activated with
N,N-dicyclohexylcarbodiimide or with
benzotriazole-N-oxotris(dimethylamino)phosphonium (BOP)
hexafluorophosphate.
[0013] Thus, by means of the process according to the invention, it
is possible to react the acid chloride of formula (II) obtained by
reacting thionyl chloride with the acid of formula (II) in an inert
solvent, such as benzene or toluene, or a chlorinated solvent (for
example dichloromethane, dichloroethane or chloroform), an ether
(for example tetrahydrofuran or dioxane), or an amide (for example
N,N-dimethylformamide) under an inert atmosphere, at a temperature
of between 0.degree. C. and the reflux point of the solvent.
[0014] One variant of the procedure consists in preparing the mixed
anhydride of the acid of formula (II) by reacting ethyl
chloroformate with the acid of formula (II), in the presence of a
base such as triethylamine.
[0015] The acid of formula (II) can be prepared according to the
reaction scheme described below, in which:
[0016] LiHMDS=lithium hexamethyldisilazide
[0017] NBS=N-bromosuccinimide. 3
[0018] The first step is carried out according to J. Heterocyclic.
Chem., 1989, 26, 1389. In the penultimate step, the conversion of
the 4-bromomethyl substituent of the pyrazole into 4-ethyl is
carried out according to J. Am. Chem. Soc., 1968, 90, 5615.
[0019] The 1-aminopiperidine used is a commercial product.
[0020] The ester of formula (VII) and the acid of formula (II) can
be prepared according to another process which constitutes a
further subject of the present invention.
[0021] This process is illustrated by the reaction scheme below, in
which Alk represents a (C.sub.1-C.sub.6)alkyl and represents an
ethyl. 4
[0022] This process is characterized in that an alkyl ester,
preferably the ethyl ester, of
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyraz-
ole-3-carboxylic acid is prepared by cyclization of an alkyl ester,
preferably the ethyl ester, of
3-(4-bromobenzoyl)-2-(2-(2,4-dichloropheny- l)hydrazono)pentanoic
acid (IX).
[0023] This reaction is carried out in a protic solvent such as an
alcohol, for example a C.sub.1-C.sub.4 alcohol, preferably ethanol,
at a temperature of between room temperature and 80.degree. C.,
preferably in reluxing ethanol.
[0024] According to the invention, the alkyl ester, preferably the
ethyl ester, of
3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic
acid is prepared by the action of a 2,4-dichlbrophenylhydrazine
salt, preferably the hydrochloride, on an alkyl ester, preferably
the ethyl ester, of 4-bromobenzoyl-2-oxopentanoic acid (VIII).
[0025] The reaction is carried out in a protic solvent, for example
a C.sub.1-C.sub.4 alcohol, preferably ethanol.
[0026] According to the invention, the alkyl ester, preferably the
ethyl ester, of 4-bromobenzoyl-2-oxopentanoic acid is prepared by
the action of LiHMDS and then of an alkyl ester, preferably the
ethyl ester, of 2-(1-imidazolyl)-2-oxoacetic acid on
bromobutyrophenone.
[0027] The reaction is carried out in an organic solvent such as an
aromatic solvent or an ether, preferably methyl tert-butyl ether.
The first step of this reaction is carried out at low temperature,
for example at a temperature between 0.degree. C. and -60.degree.
C., preferably at a temperature in the region of -20.degree. C.;
the second step is carried out at a temperature of between room
temperature and -20.degree. C., preferably at room temperature.
[0028] Thus, according to Scheme 2, the preparation of an alkyl
ester of
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic
acid (VII) is carried out starting with
4-bromobenzoyl-2-oxopentanoic acid (VIII) by the action of a
2,4-dichlorophenylhydrazine salt, followed by cyclization.
[0029] Bromobutyrophenone is commercially available.
[0030] The ethyl ester of 2-(1-imidazolyl)-2-oxoacetic acid is
described and prepared according to J. Org. Chem., 1981, 46 (1),
211-213.
[0031] The present invention also comprises a process for preparing
an alkyl ester, preferably the ethyl ester, of
5-(4-bromophenyl)-1-(2,4-dich-
lorophenyl)-4-ethylpyrazole-3-carboxylic acid, from
4-bromobenzoyl-2-oxopentanoic acid, by the action of a
2,4-dichlorophenylhydrazine salt, preferably the hydrochloride, in
a protic solvent, for example a C.sub.1-C.sub.4 alcohol, preferably
ethanol. The reaction is carried out at a temperature of between
room temperature and 80.degree. C., preferably in reluxing
ethanol.
[0032] The compounds of formula: 5
[0033] in which Alk represents a (C.sub.1-C.sub.6)alkyl are novel
and form part of the invention. Preferably, Alk represents an
ethyl.
[0034] The compound of formula (I) obtained by the process
according to the invention is isolated, in the form of the free
base or of a salt or solvate, according to the conventional
techniques.
[0035] The pharmaceutically acceptable salts of the compound of
formula (I) comprise the addition salts with acids, such as the
hydrochloride, the hydrobromide, the sulphate, the hydrogen
sulphate, the dihydrogen phosphate, the methanesulphonate, the
methyl sulphate, the oxalate, the maleate, the fumarate, the
2-naphthalenesulphonate, the glyconate, the gluconate, the citrate,
the isethionate, the para-toluenesulphonate or the succinate.
[0036] The compound of formula (I) can be isolated in the form of
one of its salts, for example the hydrochloride or the oxalate; in
this case, the free base can be prepared by neutralizing the said
salt with an inorganic or organic base, such as sodium hydroxide or
ammonium hydroxide, triethylamine or an alkali metal carbonate or
bicarbonate such as sodium or potassium carbonate or bicarbonate,
and converted into another salt such as the methanesulphonate,
fumarate or 2-naphthalenesulphonate.
[0037] When the compound of formula (I) is obtained in the form of
the free base, the salification is carried out by treatment with
the acid chosen in an organic solvent. By treating the free base,
dissolved, for example, in an ether such as diethyl ether or in
acetone, with a solution of the acid in the same solvent, the
corresponding salt is obtained and is then isolated according to
the conventional techniques.
[0038] The compounds of formula (I) have very good in vitro
affinity for the CB.sub.1 cannabinoid receptors, under the
experimental conditions described by Devane et al., Mol.
Pharmacol., 1988, 34, 605-613.
[0039] Thus, the compound according to the invention has very
strong affinity for human CB.sub.1 cannabinoid receptors (Ki=5.4
nM) which compares favourably with that of SR 141716 for the same
receptors, determined under the same conditions (Ki=34 nM).
[0040] The compound according to the invention was also compared
with
N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3--
carboxamide, (compound A). The affinity of this compound for human
CB.sub.1 cannabinoid receptors, measured under the same conditions,
is reflected by a Ki value of 8 nM.
[0041] Moreover, the duration of occupation of the CB.sub.1
receptors present in the brain by the 3 compounds below was
compared:
[0042] the compound of formula (I) according to the invention,
[0043] SR 141716,
[0044] compound A.
[0045] The study was performed in vivo in mice, after oral
administration of each of the compounds at a dose of 10 mg/kg,
according to the technique described in M. Rinaldi-Carmona et al.,
Life Sciences, 1995, 56, 1941-1947. The results obtained are
collated in the table below.
1 TABLE 1 % of occupation of the receptors 1 hour 24 hours Compound
of 82% 44% formula (I) SR 141716 69% 4% Compound A 89% 4%
[0046] Surprisingly, it is observed that the compound of formula
(I) according to the invention is the only compound which shows
appreciable occupation (44%) 24 hours after its administration.
[0047] Moreover, the antagonist nature of the compound of formula
(I) was demonstrated by the results obtained in models of
adenylate-cyclase inhibition as described in M. Rinaldi-Carmona et
al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878.
[0048] More particularly, the compound of the present invention, in
its native form or in the form of one of its pharmaceutically
acceptable salts, is a powerful and selective antagonist of the
CB.sub.1 cannabinoid receptors.
[0049] The antagonist nature of the compound according to the
invention, as well as its good penetration into the central nervous
system, are confirmed by the results obtained in the model of
antagonism of the hypothermia induced with a cannabinoid receptor
agonist. Thus, the compound of formula (I) according to the
invention antagonizes the hypothermia induced with WIN 55212-2 in
mice, with an oral ED.sub.50 of 0.3 mg/kg in the test described by
Pertwee R. G. et al. in Marijuana, 84, Ed. Harvey, D. Y. Oxford IRL
Press, 1985, 263-277. In this test, the activity and the duration
of action of 3 compounds were compared. The results obtained are
collated in the table below:
2TABLE 2 Antagonism of the hypothermia induced Duration of action
oral ED.sub.50 oral dose 24 h Compound of formula (I) 0.3 mg/kg 1
mg/kg active SR 141716 0.4 mg/kg 1 mg/kg not active 10 mg/kg active
Compound A 0.3 mg/kg 1 mg/kg not active 10 mg/kg active
[0050] It is found that the compound of the present invention has
an ED.sub.50 which is comparable with those of the compounds of the
prior art, but its duration of action is markedly longer.
[0051] Thus, whereas 24 hours after their administration, SR 141716
and compound A are only active at a dose of 10 mg/kg/p.o., the
compound of formula (I) according to the invention is active 24
hours after its administration, at a dose 10 times lower (1
mg/kg/p.o.).
[0052] The long-lasting action of the compound of formula (I)
according to the invention is particularly noteworthy and
represents an important advantage for its use as a medicinal
product.
[0053] The toxicity of compounds (I) is compatible with their use
as medicinal products.
[0054] According to another of its aspects, the present invention
relates to the use of a compound of formula (I), or one of the
pharmaceutically acceptable salts or solvates thereof, for the
preparation of medicinal products intended for treating diseases
involving the CB.sub.1 cannabinoid receptors.
[0055] For example, and in a non-limiting manner, the compound of
formula (I) is useful as a psychotropic medicinal product, in
particular for the treatment of anxiety disorders, mood disorders,
delirium disorders, psychotic disorders in general, for the
treatment of schizophrenia and depression, as well as for the
treatment of disorders associated with the use of psychotropic
substances, in particular in the case of abuse of a substance
and/or dependence on a substance, including alcohol dependency and
nicotine dependency.
[0056] The compound of formula (I) according to the invention can
be used as medicinal product for treating neuropathies, migraine,
stress, diseases of psychosomatic origin, epilepsy, locomotor
disorders, in particular dyskinesias or Parkinson's disease.
[0057] The compound of formula (I) according to the invention can
also be used as a medicinal product in the treatment of memory
disorders, cognitive disorders, in particular in the treatment of
senile dementia and Alzheimer's disease, as well as in the
treatment of attention disorders or vigilance disorders.
Furthermore, the compound of formula (I) may be useful as a
neuroprotective agent, in the treatment of neurodegenerative
diseases.
[0058] The compound of formula (I) according to the invention can
be used as a medicinal product in the treatment of appetite
disorders, cravings (for sugars, carbohydrates, drugs, alcohol or
any appetizing substance) and/or eating disorders, in particular as
an anorexigenic agent or for the treatment of obesity or bulimia,
as well as for the treatment of type II diabetes or
non-insulin-dependent diabetes. Furthermore, the compound of
formula (I) according to the invention can be used as a medicinal
product in the treatment of gastrointestinal disorders, diarrheic
disorders, ulcers, vomiting, urinary and bladder disorders,
cardiovascular disorders, fertility disorders, inflammatory
phenomena, infectious diseases and as a medicinal product for
anticancer chemotherapy.
[0059] According to the present invention, the compound of formula
(I) is most particularly useful for treating psychotic disorders,
in particular schizophrenia; for treating appetite disorders and
obesity, for treating for memory and cognitive disorders; for
treating alcohol dependency or nicotine dependency, i.e. for
withdrawal from alcohol and for withdrawal from tobacco.
[0060] According to one of its aspects, the present invention
relates to the use of a compound of formula (I), its
pharmaceutically acceptable salts and the solvates thereof for the
treatment of the disorders and diseases indicated above.
[0061] According to another of its aspects, the present invention
also relates to the use of the compounds of formula (I), in their
native form or in radiolabelled form, as a pharmacological tool in
man or animals, for detecting and labelling the CB.sub.1
receptors.
[0062] The compound according to the invention is generally
administered as a dosage unit.
[0063] The said dosage units are preferably formulated in
pharmaceutical compositions in which the active principle is mixed
with a pharmaceutical excipient.
[0064] Thus, according to another of its aspects, the present
invention relates to pharmaceutical compositions containing, as
active principle, a compound of formula (I), one of its
pharmaceutically acceptable salts or a solvate thereof.
[0065] The compound of formula (I) above and its pharmaceutically
acceptable salts or solvates can he used at daily doses of from
0.01 to 100 mg per kg of body weight of the mammal to be treated,
preferably at daily doses of from 0.02 to 50 mg/kg. In human
beings, the dose can preferably range from 0.05 to 4000 mg per day,
more particularly from 0.1 to 1000 mg per day depending on the age
of the individual to be treated or the type of treatment, i.e.
prophylactic or curative treatment. Although these doses are
examples of average situations, it is possible to have special
cases in which-higher doses or lower doses are suitable, and such
doses also belong to the invention. According to the usual
practice, the dose which is suitable for each patient is determined
by the doctor according to the method of administration and the
age, weight and response of the said patient.
[0066] In the pharmaceutical compositions of the present invention
for oral, sublingual, inhaled, subcutaneous, intramuscular,
intravenous, transdermal, local or rectal administration, the
active principle can be administered in unit administration form,
as a mixture with conventional pharmaceutical supports, to animals
and to human beings. The appropriate unit forms of administration
comprise oral-route forms such as tablets, gel capsules, powders,
granules and oral solutions or suspensions, sublingual and buccal
administration forms, aerosols, topical administration forms,
implants, subcutaneous, intramuscular, intravenous, intranasal or
intraocular administration forms and rectal administration
forms.
[0067] In the pharmaceutical compositions of the present invention,
the active principle is generally formulated in dosage units
containing from 0.05 to 1000 mg, advantageously from 0.1 to 500 mg
and preferably from 1 to 200 mg, of the said active principle per
dosage unit for daily administrations.
[0068] When a solid composition is prepared in tablet form, a
wetting agent such as sodium lauryl sulphate can be added to the
micronized or non-micronized active principle, and the whole is
mixed with a pharmaceutical vehicle such as silica, gelatin,
starch, lactose, magnesium stearate, talc, gum arabic or the like.
The tablets can be coated with sucrose, various polymers or other
suitable materials or alternatively they can be treated such that
they have sustained or delayed activity and such that they release
a predetermined amount of active principle continuously.
[0069] A preparation in gel capsule form is obtained by mixing the
active principle with a diluent such as a glycol or a glycerol
ester and by incorporating the mixture obtained into soft or hard
gel capsules.
[0070] A preparation in the form of a syrup or elixir can contain
the active principle together with a sweetener, preferably a
calorie-free sweetener, methyl paraben and propyl paraben as
antiseptic agents, as well as a flavour enhancer and a suitable
colorant.
[0071] The water-dispersible powders or granules can contain the
active principle as a mixture with dispersants, wetting agents or
suspending agents, such as polyvinylpyrrolidine, as well as with
sweeteners or flavour enhancers.
[0072] For rectal administration, use is made of suppositories
which are prepared with binders that melt at the rectal
temperature, for example cocoa butter or polyethylene glycols.
[0073] For parenteral, intranasal or intraocular administration,
aqueous suspensions, isotonic saline solutions or sterile,
injectable solutions which contain pharmacologically compatible
dispersants and/or solubilizing agents, for example propylene
glycol or polyethylene glycol, are used.
[0074] Thus, to prepare an aqueous solution which can be injected
intravenously, a co-solvent such as, for example, an alcohol, for
instance ethanol or a glycol such as polyethylene glycol or
propylene glycol, and a hydrophilic surfactant such as Tween.RTM.
80, can be used. To prepare an oily solution which can be injected
intramuscularly, the active principle can be dissolved with a
triglyceride or a glycerol ester.
[0075] Creams, ointments or gels can be used for local
administration.
[0076] For transdermal administration, patches in multilayer form
or containing a reservoir in which the active principle may be in
alcoholic solution can be used.
[0077] For administration by inhalation, an aerosol is used
containing, for example, sorbitan trioleate or oleic acid as well
as trichlorofluoromethane, dichlorofluoromethane,
dichlorotetrafluoroethane or any other biologically compatible
propellent gas; it is also possible to use a system containing the
active principle alone or combined with an excipient, in powder
form.
[0078] The active principle can also be formulated in the form of
microcapsules-or microspheres, optionally with one or more supports
or additives.
[0079] The active principle can also be in the form of a complex
with a cyclodextrin, for example .alpha.-, .beta.- or
.gamma.-cyclodextrin, 2-hydroxypropyl-.beta.-cyclodextrin or
methyl-.beta.-cyclodextrin.
[0080] Among the forms for sustained release which are useful in
the case of chronic treatments, it is possible to use implants.
These can be prepared in the form of an oily suspension or in the
form of a suspension of microspheres in an isotonic medium.
[0081] The pharmaceutical compositions of the present invention can
contain, along with the compound of formula (I) or one of its
pharmaceutically acceptable salts or solvates, other active
principles which can be useful in the treatment of the disorders or
diseases indicated above.
[0082] In the present description, the following abbreviations are
used:
3 DCM: dichloromethane LiHMDS: lithium hexamethyldisilazide TMSCl:
chlorotrimethylsilane PTSA: para-toluenesulphonic acid NBS:
N-bromosuccinimide MTBE: methyl tert-butyl ether RT: room
temperature m.p.: melting point TLC: thin layer chromatography NMR:
nuclear magnetic resonance. The NMR spectra are recorded at 200 MHz
in DMSO-d.sub.6 s: singlet; d: doublet; t: triplet; q: quadruplet;
m: broad peak or multiplet; dd: doubled doublet.
[0083] Preparation 1
[0084] Ethyl
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-ca-
rboxylate
[0085] A) Lithium ethyl
4-(4-bromophenyl)-3-methyl-4-oxido-2-oxobutenoate
[0086] 21.6 g of LiHMDS are placed in 340 ml of anhydrous ether
under nitrogen and the solution is cooled to -60.degree. C.,
followed by addition of 4 g of bromopropiophenone dissolved in 150
ml of anhydrous ether. This mixture is allowed to warm to
-30.degree. C. and 17.53 ml of ethyl oxalate are then added. After
stirring overnight at RT, the precipitate formed is filtered off
and then rinsed with ether and dried under vacuum. 21.8 g of the
expected compound are obtained.
[0087] B) Ethyl
4-(4-bromophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-met-
hyl-4-oxobutyrate
[0088] 16.8 g of the compound prepared in the above step and 12.5 g
of 2,4-dichlorophenylhydrazine hydrochloride in 150 ml of ethanol
are mixed together and left stirring for 2 and a half hours. The
precipitate formed is filtered off, rinsed with ethanol and then
dried under vacuum. 16.24 g of the expected compound are
obtained.
[0089] C) Ethyl
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole--
3-carboxylate
[0090] 16.24 g of the compound obtained in the above step are
heated for 24 hours in 200 ml of acetic acid and the reaction
medium is then poured into 1 litre of ice-cold water; the
precipitate formed is filtered off, rinsed with water and dried
under vacuum. 12.8 g of the expected compound are obtained, and
this product is recrystallized from methylcyclohexane,
m.p.=133.degree. C.
[0091] D) Ethyl
4-bromomethyl-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)pyra-
zole-3-carboxylate
[0092] 12.8 g of the ester obtained in the above step are placed in
130 ml of carbon tetrachloride and 5.27 g of N-bromosuccinimide are
added, followed by 24 mg of benzoyl peroxide. The mixture is
refluxed for 4 hours and is then filtered and concentrated under
vacuum. The residue is chromatographed on silica, eluting with a
toluene/ethyl acetate mixture (97/3; v/v). 7.24 g of the expected
compound are obtained, m.p.=116.degree. C.
[0093] E) Ethyl
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-
-carboxylate
[0094] 2.26 g of CuBr are introduced as a suspension in 100 ml of
ether, under argon, followed by dropwise addition at -20.degree. C.
of a solution containing 20 ml of 1.6 M methyllithium in ether
diluted in 20 ml of ether. After stirring for 10 minutes at
-20.degree. C., the suspension decolorizes and then becomes clear.
The resulting mixture is cooled to -78.degree. C. and 7 g of the
compound prepared in the above step are added as a solution in 100
ml of ether, over 30 minutes, after which the mixture is allowed to
warm to RT. After stirring for 2 hours, the mixture is hydrolysed
by addition of saturated ammonium chloride solution. The resulting
mixture is extracted with ether and washed with water, and then
with saturated NaCl solution. This solution is dried over
MgSO.sub.4 and then evaporated to dryness. The residue is
chromatographed on silica, eluting with a toluene/ethyl acetate
mixture (96/4; v/v). 3.7 g of the expected compound are obtained,
m.p.=108.degree. C.
[0095] NMR: 1.05 ppm: t: 3H; 1.30 ppm: t: 3H; 2.60 ppm: q: 2H; 4.30
ppm: q: 2H; 7.15 ppm: d: 2H; 7.50-7.75 ppm: m: 5H.
[0096] Prepapation 2
[0097]
5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxyl-
ic acid (II).
[0098] 3.6 g of the ester obtained in Preparation 1 are placed in
54 ml of MeOH and a solution containing 1.08 g of KOH in 6.85 ml of
water is added. The reaction medium is refluxed for 3 hours and
then concentrated under vacuum. The residue is taken up in ice-cold
water, acidified to pH=1 with 1 N HCl and then extracted with DCM.
3.3 g of the expected compound are obtained, m.p.=218.degree.
C.
[0099] NMR: 1.10 ppm: t: 3H; 2.70 ppm: q: 2H; 7.25 ppm: d: 2H;
7.60-7.85 ppm: m: 5H.
[0100] Preparation 3
[0101] Ethyl 3-(4-bromobenzoyl)-2-oxopentanoate
[0102] A solution of 247 g of 4-bromobutyrophenone in 1500 ml of
MTBE is added to a solution of 210 g of LiHMDS in 2500 ml of MTBE,
while keeping the temperature at -20.degree. C. After stirring for
3 hours at this temperature, 210 g of ethyl
2-(1-imidazolyl)-2-oxoacetate in 1000 ml of MTBE are added over 1
hour, at 10.degree. C., and the mixture is left stirring for 18
hours at room temperature. The lithium salt formed is filtered off
and then suspended in 800 ml of MTBE. 800 ml of 6 N hydrochloric
acid are added to the suspension. After separation of the phases by
settling, the ether phase is washed 4 times with 1000 ml of water
and then concentrated under reduced pressure. The expected compound
is isolated (263 g). From the NMR analysis, it is a mixture
containing 8% of the 4-bromobutyrophenone starting material.
[0103] NMR: 0.86 ppm: t: 3H; 1.10 ppm: t: 3H; 1.83 ppm: mt: 2H;
4.15 ppm: q: 2H; 5.19 ppm: t: 1H; 7.70 ppm: d: 2H; 7.98 ppm: d:
2H.
[0104] Preparation 4
[0105] Ethyl
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-ca-
rboxylate
[0106] A) Ethyl
3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)-hydrazono)pen-
tanoate
[0107] A suspension of 155 g of 2,4-dichlorophenylhydrazine
hydrochloride in 1200 ml of ethanol is prepared and 263 g of the
compound of Preparation 3 in 1000 ml of ethanol are added at room
temperature.
[0108] A small portion of the intermediate formed can be isolated
by filtration and characterized.
[0109] NMR: 0.92 ppm: t: 3H; 1.04 ppm: t: 3H; 1.89 ppm: mt: 2H;
4.16 ppm: q: 2H; 4.76 ppm: t: 1H; 7.42 ppm: mt: 2H; 7.60 ppm: s:
1H; 7.75 ppm: d: 2H; 7.93 ppm: d: 2H; 12.31 ppm: s: 1H.
[0110] B) Ethyl
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-
-carboxylate
[0111] The suspension obtained is refluxed for 4 hours and then
left stirring for 18 hours at room temperature. The product formed
is filtered off and then dried under vacuum at 50.degree. C. to
give the expected compound (247 g), m.p.=108.degree. C.
[0112] NMR: 1.07 ppm: t: 3H; 1.28 ppm: t: 3H; 2.58 ppm: q: 2H; 4.32
ppm: q: 2H; 7.16 ppm: d: 2H; 7.53 ppm: dd: 1H; 7.59 ppm: d: 2H;
7.73 ppm: d+small d: 2H.
EXAMPLE
1N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-c-
arboxamide
[0113] A)
5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carbo-
xylic Acid Chloride
[0114] 3.2 g of the acid obtained in the above step are placed in
suspension in 32 ml of toluene, 1.6 ml of thionyl chloride are
added and the mixture is then refluxed for 3 hours. The reaction
medium is concentrated under vacuum and then taken up in toluene.
The operation is repeated several times. 3.3 g of the expected
compound are obtained.
[0115] B)
N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethylpy-
razole-3-carboxamide
[0116] A solution of 0.23 ml of N-aminopiperidine and 0.29 ml of
triethylamine in 20 ml of DCM is prepared, under nitrogen, and is
cooled to a temperature of between 0.degree. C. and 5.degree. C.
0.8 g of the acid chloride obtained in the above step in 20 ml of
DCM is added. After leaving overnight at RT, the resulting mixture
is poured onto ice-cold water and the phases are separated by
settling. The organic phase is extracted with DCM and then washed
with water, with 5% Na.sub.2CO.sub.3 solution and with saturated
NaCl solution. The resulting solution is evaporated to dryness and
the residue is then chromatographed on silica, eluting with a
toluene/EtOAc mixture (80/20; v/v). 0.52 g of the expected compound
is obtained, m.p.=113.degree. C.
[0117] NMR: 1.05 ppm: t: 3H; 1.25-1.65 ppm: m: 6H; 2.65 ppm: q: 2H;
2.80 ppm: m: 4H; 7.15 ppm: d: 2H; 7.50-7.80 ppm: m: 5H; 9.10 ppm:
s: 1H.
EXAMPLE 2
[0118]
N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazo-
le-3-carboxamide
[0119] A)
5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carbo-
xylic acid chloride
[0120] A mixture containing 97 g of thionyl chloride and 118 g of
the compound of Preparation 4 in 1200 ml of toluene is prepared and
is heated gradually to reflux and is then maintained at reflux for
3 hours. The reaction medium is concentrated.
[0121] B)
N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethylpy-
razole-3-carboxamide
[0122] The acid chloride formed is taken up in 380 ml of
methylcyclohexane and 2.8 g of triethylamine in 218 ml of THF are
introduced. The mixture is kept at 50.degree. C.
[0123] A solution of 30 g of N-aminopiperidine and 28 g of
triethylamine in 34 ml of methylcyclohexane is prepared and cooled
to 10.degree. C., and the mixture containing the acid chloride is
added slowly. After stirring for 2 hours at 10.degree. C., the
product formed is filtered off, taken up in 2000 ml of DCM and
washed twice with 2000 ml of water. The product is recrystallized
from 4500 ml of methylcyclohexane and then filtered off and dried.
125 g of the expected compound are obtained.
* * * * *