U.S. patent application number 09/809485 was filed with the patent office on 2001-11-29 for new heterocyclic compounds for therapeutic use.
This patent application is currently assigned to J.B. Chemicals & Pharmaceuticals Limited. Invention is credited to Doshi, Madhukant Mansukhlal, Mody, Shirish Bhagwanlal, Shrikhande, Atul Anant.
Application Number | 20010047023 09/809485 |
Document ID | / |
Family ID | 25201453 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010047023 |
Kind Code |
A1 |
Shrikhande, Atul Anant ; et
al. |
November 29, 2001 |
New Heterocyclic compounds for therapeutic use
Abstract
A class of compounds particularly diaryl pyrazole of general
formulas 1 and 2 where R and R' represents alkyl, hydrogen,
halogens, haloalkyl, cyano, nitro, formyl, carboxyl,
alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl,
alkylthio, alkylsulfinyl, alkylsulphonyl, N- alkylsulfamyl,
N-arylsulfamyl, cyanoamido, amino, amidino, N-monoalkylamido,
N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, N,
N-dialkylsulfamyl with the alkyl, or alkyl part of each such group
containing 1-3 carbon atoms or mixtures thereof optionally their
salts when they exist, and preparation thereof. The compounds of
the present invention are antiinflammatory, antipyretic,
antirheumatic, antiosteoarthritic agents with antibacterial
activity. The particular class of compounds is given below (Formula
1 and Formula 2). 1
Inventors: |
Shrikhande, Atul Anant;
(Maharashtra, IN) ; Doshi, Madhukant Mansukhlal;
(Maharashtra, IN) ; Mody, Shirish Bhagwanlal;
(Maharashtra, IN) |
Correspondence
Address: |
REED SMITH LLP
375 PARK AVENUE
NEW YORK
NY
10152
US
|
Assignee: |
J.B. Chemicals &
Pharmaceuticals Limited
|
Family ID: |
25201453 |
Appl. No.: |
09/809485 |
Filed: |
March 15, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60201343 |
May 2, 2000 |
|
|
|
60216273 |
Jul 6, 2000 |
|
|
|
Current U.S.
Class: |
514/406 ;
548/379.7 |
Current CPC
Class: |
A61K 31/415 20130101;
A61K 45/06 20130101; C07D 231/12 20130101; A61K 31/415 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/406 ;
548/379.7 |
International
Class: |
A61K 031/415 |
Claims
We claim:
1. A compound of general formula 1, and pharmaceutically acceptable
salts there of where R and R' represents alkyl, hydrogen, halogens,
haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkylthio,
alkylsulfinyl, alkylsulphonyl, N-alkylsulfamyl, N-arylsulfamyl,
cyanoamido, amino, amidino, N-monoalkylamido, N-monoarylamido, N,N-
dialkylamido, N-alkyl-N-arylamido, N,N- dialkylsulfamyl with the
alkyl, or alkyl part of each such group containing 1-3 carbon atoms
for the treatment of inflammation and other related disorders and
also the preparation of the same. 9
2. A compound as claimed in claim 1, is preferably selected from:
i)
N-[4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]metha-
ne sulphonamide. ii)
N-[4-[5-(4-Ethylphenyl)-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]phenyl]methane sulphonamide. iii)
N-[4-[5-(4-Methoxyphenyl)-3-(trif-
luoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide. iv)
N-[4-[5-(4-Ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]metha-
nesulphonamide. v)
N-[4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]phenyl]methanesulphonamide. vi)
N-[4-[5-(2,4-Dichlorophenyl)-3-(-
trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide. vii)
N-[4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol
-1-yl]phenyl]methanesulphonamide. viii)
N-[4-[5-(2,4-Dimethylphenyl)-3-(t-
rifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide. ix)
N-[4-[5-(3,4-Dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]m-
ethanesulphonamide. x)
4-[1-[4-(Methanesulphonylamido)phenyl]-3-(trifluoro-
methyl)-1H-pyrazol-5-yl]benzoic acid. xi)
2-[1-[4-(Methanesulphonylamido)p-
henyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoic acid.
3. A compound of general formula 2, and pharmaceutically acceptable
salts thereof where R and R' represents alkyl, hydrogen, halogens,
haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkylthio,
alkylsulfinyl, alkylsulphonyl, N-alkylsulfamyl, N-arylsulfamyl,
cyanoamido, amino, amidino, N-monoalkylamido, N-monoarylamido, N,N-
dialkylamido, N- alkyl-N-arylamido, N,N-dialkylsulfamyl with the
alkyl , or alkyl part of each such group containing 1-3 carbon
atoms for the treatment of inflammation and other related disorders
and also the process for the preparation of the same. 10
4. A compound as claimed in claim 3, is preferably selected from:
i)
1-(3-Chloro-4-fluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-
e. ii)
1-(3-Chlorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole
iii)
1-(4-Chlorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole.
iv)
1-(2,4-Difluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole-
. v)
1-(3-Fluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole.
vi)
1-(4-Fluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole.
vii)
1-(3,4-Dichlorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-
e. viii)
1-(2-Fluoro-4-methylphenyl)-5-(4-methylphenyl)-3-(trifluoromethyl-
)pyrazole. ix)
1-(2-Fluoro-5-methylphenyl)-5-(4-methylphenyl)-3-(trifluoro-
methyl)pyrazole. x)
1-(3-Fluoro4-methylphenyl)-5-(4-methylphenyl)-3-(trifl-
uoromethyl)pyrazole.
5. A pharmaceutical composition or a formulation or any other drug
delivery system comprising a pharmaceutically acceptable carrier or
diluent containing a therapeutically effective amount of the
compound as claimed in claim 1 and claim 3, or a pharmaceutically
acceptable salt thereof.
6. A pharmaceutical composition for treating the inflammatory
conditions susceptible to treatment with NSAID agent comprising, a
nontoxic therapeutically effective amount of a compound as claimed
in claim 1 and 3 and a pharmaceutically acceptable carrier or a
diluent or a prodrug thereof in association with a further
analgesic medicament.
7. A pharmaceutical composition as claimed in claim 6, in a form of
parenteral, oral, sublingual, rectal, vaginal, topical,
transdermal, ocular, intranasal routes or as aerosol.
8. A process for preparation of the compounds as claimed in claim 1
and claim 3, and its its intermediates as described herein in the
specification.
9. The method for treatment or prevention of inflammation and
associated disorder or any other illness in a patient, which
comprises administering a therapeutically effective amount of the
compound of claim 1 and claim 3 or a pharmaceutical salt
thereof.
10. A method of purification of the key intermediates of the
compounds of claim I and 3.
11. A compound of claim 1, is selected from i)
N-[4-[5-(2,4-Dimethylphenyl-
)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide.
12. A compound of claim 3, is selected from: i)
1-(3-Chloro4-fluorophenyl)-
-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole ii)
1-(2-fluoro-4-methylphenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-
e.
Description
RELATED APPLICATION
[0001] This application claims priority to provisional application
Ser. Nos. 60/201,343 filed on 2-5-2000 and 60/21.6,273 filed on
6-7-2000.
FIELD OF INVENTION
[0002] The present invention relates to new heterocyclic compounds
of the general formula 1 and 2 for therapeutic use.
[0003] The invention further relates to pharmaceutical compositions
containing the compounds of the general formula 1 and 2, process
for preparing the same and pharmaceutically acceptable salts
thereof having a selective action on inflammation and its related
disorders.
BACKGROUND OF THE INVENTION
[0004] Nonsteroidal anti-inflammatory drugs (NSAIDS) are compounds
used mainly in the relief of pain, inflammation, and sometimes
fever.
[0005] The combined analgesic and antiinflammatory effects of
NSAIDS make them particularly useful for the symptomatic relief of
painful and/or inflammatory conditions including musculoskeletal
and joint disorders, such as rheumatoid arthritis, osteoarthritis,
spondylo arthopathic, peri-articular and soft tissue disorder.
[0006] NSAIDS have shown to be useful in alleviating symptoms of
inflammation and pain disorders. Prostaglandins (PGs) are
ubiquitous fatty acid derivatives that serve as autocrine/paracrine
mediators involved in many different physiological processes in
addition to their well recognized role in inflammation and immune
response modulation. Prostaglandins elicit a variety of important
and beneficial responses. Among the undesirable properties of
Prostaglandins is their ability to induce pain, fever, and symptoms
associated with the inflammatory response.
[0007] NSAIDS exert their actions primarily by inhibiting the
production of PGs. Recent studies of inflammatory processes has led
to the identification of the key enzyme cycloxygenase (Cox) that is
expressed in inflammatory conditions. Various studies on the
identification of Cox-2 enzyme are reported:-Vane , J. R.; Nature
1994, Made, E. A. ., Smith W. L. ., Dewitt, D. L. J. Biol. Chem.
1993, 268: 6610-14
[0008] Cox is the first enzyme in the prostanoid biosynthetic
pathway catalyzing the conversion of arachidonic acid to PGH2 as
the first step in the synthesis of PGs, Prostacyclins, and
Thromboxane, all of which act as important mediators of biological
and inflammatory responses. Pairet, M., Engekelhardt,G; Fundam.
Clin. Pharmacol 1996,10 ,1-15
[0009] The discovery of second inducible isoenzyme has enabled the
identification of two major isoforms of COX: the constitutive COX
isoform , termed Cox-1 and the inducible isoform, termed the Cox-2
There are now various theories supporting the fact that the
inducible Cox-2 enzyme is responsible for the production of
inflammatory mediators. Drugs of Future 1998, 23, 598-601.
[0010] The commonest side effects occurring during therapy with
NSAIDS are generally gastrointestinal disturbances, these are
usually mild and reversible but in some patients, peptic ulcer and
severe gastrointestinal bleeding have been reported. These adverse
effects on the gastrointestinal tract may be associated with the
inhibition of the form of cyclooxygenase-1 (Cox-1). NSAIDS that are
highly selective inhibitors of the form cycloxygenase -2 ( Cox-2)
may have less gastrointestinal toxicity, hence, interest has
developed in NSAIDS that are highly selective inhibitors of Cox-2,
such as Meloxicam, Nimesulide, Rofecoxib and the like.
[0011] Most widely used NSAIDS like Diclofenac , Flufenamic acid,
Ibuprofen, Indomethacin and the like, inhibit both the forms of the
enzymes (Cox-1 and Cox-2) with many showing selectivity for Cox-1
enzyme.
[0012] Inhibition of COX -1 enzyme causes the common
gastrointestinal side effects as seen in the known NSAIDS like
Diclofenac, Flufenamic acid, Ibuprofen, Indomethacin and the like.
All these antiinflammatory agents have shown undesirable side
effects.
OBJECT OF THE INVENTION
[0013] It is an object of the present invention to provide new
pyrazole derivatives and their pharmaceutical compositions as well
as their therapeutic uses and the processes for preparing the
same.
[0014] At present there is a pharmacoepial dogma establishing a
mandatory connection between anti-inflammatory, antipyretic, other
therapeutic uses and the side effects mainly, gastrointestinal
disturbances caused by the known NSAIDS. This dogma and the
constant need has instigated the inventors to develop a newly
synthesized anti-inflammatory compounds showing antimicrobial and
antipyretic activity with less side effects. The pyrazole class has
shown a promising drug like Celecoxib. The description of various
pyrazole derivatives has been disclosed in U.S. Pat. No. 5,521207,
J. Med. Chem. 1997, 40, 1347-1365
[0015] Pyrazoles have been described for use in the treatment of
inflammation U.S. Pat. No. 5,134,142 to Matsuo et al describes 1,5-
diaryl pyrzoles and specifically
,1-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3-trifluoromethyl pyrazole, as having anti inflammatory
activity.
[0016] In view of the extensive studies on the above derivatives,
the inventors have discovered new compounds of diarylpyrazole class
having more advantageous properties and the manufacturing process
for the said new pyrazole derivatives fulfilling the desirable
features as described herein under.
DESCRIPTION OF THE INVENTION
[0017] The present invention relates to new NSAIDS compounds having
Diarylpyrazole ring of the general formula 1 and formula 2, their
synthesis and their pharmaceutically acceptable addition salts
having a antiinflammatory, antipyretic, or antibacterial
activity.
[0018] The present invention also relates to synthesis of the
intermediates (substituted diketo compounds) of the compounds of
general formula 1: 2
[0019] where R and R' represents alkyl, hydrogen, halogens,
haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkylthio,
alkylsulfinyl, alkylsulphonyl, N-alkylsulfamyl, N-aryl sulfamyl,
cyanoamido, amino, amidino, N-monoalkylamido, N-monoarylamido, N,
N-dial kylamido, N-alkyl-N-aryl amido, N, N-dialkylsulfamyl with
the alkyl , or alkyl part of each such group containing 1-3 carbon
atoms.
[0020] The following diarylpyrazole compounds of the formula 1 and
their pharmaceutically acceptable salts and the corresponding
appropriately substituted intermediates for condensation is given
below:
[0021] 1) N-[4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1
-yl]phenyl]methanesulphonamide prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(4-Methylphenyl)-4,4,4-trifluorobutane -1,3-dione.
[0022] 1A) N-[4-[5-(4-Ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1
-yl]phenyl]methanesulphonamide prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(4-Ethylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0023] 1B)
N-[4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]p-
henyl]methanesulphonamide prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(4-Methoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
[0024] 1C)
N-[4-[5-(4-Ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ph-
enyl]methanesulphonamide prepared by condensation of 4-
(methanesulphonamido)phenylhydrazine hydrochloride and
1-(4-Ethoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
[0025] 1D) N-[4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1
H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation
of 4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(3,4-Dichlorophenyl)- 4,4,4-trifluorobutane -1,3-dione
[0026] 1E)
N-[4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]phenyl]methanesulphonamide prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(2,4-Dichlorophenyl)- 4,4,4-trifluorobutane-1,3-dione
[0027] 1F)
N-[4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ph-
enyl]methanesulphonamide prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(2-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0028] 1G)
N-[4-[5-(2,4-Dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]phenyl]methanesulphonamide prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(2,4-Dimethylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0029] 1H) N-[4-[5-(3,4-Dimethylphenyl)-3-(trifluoromethyl)-1
H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation
of 4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(3,4-Dimethylphenyl)- 4,4,4-trifluorobutane-1,3-dione
[0030] 1I)
4-[1-[4-(Methanesulphonamido)phenyl]-3-(trifluoromethyl)-1
H-pyrazol-5-yl]benzoic acid prepared by the oxidation of
N-[4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl
methanesulphonamide
[0031] 1J)
2-[1-[4-(Methanesulphonamido)phenyl]-3-(trifluoromethyl)-1H-pyr-
azol-5-yl]benzoic acid prepared by the oxidation of
N-[4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]metha-
nesulphonamide
[0032] The present invention also relates to synthesis of the
intermediates (substituted phenyl hydrazine hydrochloride salts) of
the compounds of general formula 2: 3
[0033] where R and R' represents alkyl, hydrogen, halogens,
haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkylthio,
alkylsulfinyl, alkylsulphonyl, N-alkylsulfamyl, N-aryl sulfamyl,
cyanoamido, amino, amidino, N-monoalkylamido, N-monoarylamido,
N,N-dialkylamido, N-alkyl-N-aryl amido, N,N-dialkylsulfamyl with
the alkyl or alkyl part of each such group containing 1-3 carbon
atoms.
[0034] The following diaryl pyrazole compounds of the formula 2 and
their pharmaceutically acceptable salts and the corresponding
appropriately substituted intermediates for condensation are given
below:
[0035] 2)
1-(3-Chloro4-fluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl-
)pyrazole can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-trif- luorobutane-1,3-dione with
3-Chloro-4-fluorophenylhydrazine hydrochloride
[0036] 2A)
1-(3-Chlorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazo- le
can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-trifluorobu- tane-1,3-dione with
3-Chlorophenylhydrazine hydrochloride
[0037] 2B)
1-(4-Chlorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazo- le
can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-trifluorobu- tane-1,3-dione with
4-Chlorophenylhydrazine hydrochloride
[0038] 2C)
1-(2,4-Difluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)py-
razole can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-trifluo- robutane-1,3-dione with
2,4-Difluorophenylhydrazine hydrochloride
[0039] 2D)
1-(3-Fluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazo- le
can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-trifluorobu- tane-1,3-dione with
3-Fluorophenylhydrazine hydrochloride
[0040] 2E)
1-(4-Fluorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)pyrazo- le
can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-trifluorobu- tane-1,3-dione with
4-Fluorophenylhydrazine hydrochloride
[0041] 2F)
1-(3,4-Dichlorophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)py-
razole can be obtained by condensation of
1-(4-Methylphenyl)4,4,4-trifluor- obutane-1,3-dione with
3,4-Dichlorophenylhydrazine hydrochloride
[0042] 2G)
1-(2-Fluoro-4-methylphenyl)-5-(4-methylphenyl)-3-(trifluorometh-
yl)pyrazole can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-tr- ifluorobutane-1,3-dione with
2-Fluoro-4-methyl-phenylhydrazine hydrochloride
[0043] 2H)
1-(2-Fluoro-5-methylphenyl)-5-(4-methylphenyl)-3-(trifluorometh-
yl)pyrazole can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-tr- ifluorobutane-1,3-dione with
2-Fluoro-5-methylphenylhydrazine hydrochloride
[0044] 2I)
1-(3-Fluoro4-methylphenyl)-5-(4-methylphenyl)-3-(trifluoromethy-
l)pyrazole can be obtained by condensation of
1-(4-Methylphenyl)-4,4,4-tri- fluorobutane-1,3-dione with
3-Fluoro4-methyl-phenylhydrazine hydrochloride
[0045] The synthesis of the other compounds of formula 1 and 2
includes the conventional method of condensing the appropriate
hydrochloride salt of substituted phenyl hydrazine with substituted
triflurobutanedione (diketo compounds). This invention also
includes the preparation and purification of the intermediates of
the compounds of formula 1 and 2. Also included in this invention
is the addition products, derivatives, salts formed from
pharmaceutically acceptable acids or bases of the compounds of
particular interest. The salts or derivatives may be prepared by
conventional methods by reacting the appropriate acid or base with
the compounds of the general formula 1 and 2
[0046] The present invention also relates to the pharmaceutical
compositions consisting of a product of the general formula 1 and 2
or its pharmaceutically acceptable salt when they exist, optionally
in combination with any other pharmaceutically compatible substance
which may be inert, or physiologically active.
[0047] The compositions according to the invention may be
administered in the form parenteral, oral, sublingual rectal,
vaginal, topical, transdermal, ocular, or intranasal routes or as
aerosol for the lungs.
[0048] Such compositions can also be administered in the form of
modified release, controlled release, time released formulations
and the like.
[0049] The term `parenteral` as used herein enclose subcutaneous
injection intravenous intramuscular, intrastemal injection or
infusion techniques. The sterile compositions includes aqueous or
non aqueous solutions, suspension or emulsions. The vehicles used
can be selected from water, propylene glycol, vegetable oil,
injectable organic esters or suitable organic solvents. The other
adjuvants includes wetting agents , isotonicity agents, emulsifiers
and dispersants and stabilizers.
[0050] The term `oral` as used includes a composition containing
the non toxic therapeutically effective amount of the compounds of
formula 1 and 2 in a form suitable for oral use. such as tablets,
capsules, troches, lozenges, aqueous or oily suspensions,
dispersible powder or granules, emulsions syrups, elixirs caplets,
chewable waffers and solutions freeze dried for oral or injectable
dosage forms.
[0051] The term `rectal` or `vaginal` includes compositions of the
active component in the form of suppositories which is prepared by
mixing with non irritant ingredients.
[0052] The term `topical` composition includes compositions like
creams ointments, lotions, gels, solutions or suspensions.
[0053] The term `ocular` includes compositions like
installations.
[0054] The term `intranasal` includes compositions like drops,
spray and the like.
[0055] The term `transdermal` includes compositions of the active
component in the form of a patch.
[0056] The amount of the active ingredient that may be combined
with the carrier materials to produce a single dosage form will
vary depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration of humans may contain from 0.5 mg to 5 gms of the
active ingredient compounded with an appropriate and convenient
amount of carrier material which may vary from about 5 to 95% of
the total composition.
GENERAL PROCESS FOR THE PREPARATION OF COMPOUNDS OF FORMULA 1 AND
2
[0057] The compounds of the formula 1 and 2 as described in this
invention can be synthesized in a known procedure as given in the
scheme below:
[0058] PART A: PREPARATION OF SUBSTITUTED PHENYLHYDRAZINE
HYDROCHLORIDE 4
[0059] PART B: PREPARATION OF SUBSTITUTED DIKETO COMPOUNDS 5
[0060] PART C: CONDENSATION 6
[0061] The invention will now be illustrated with the aid of
following non limiting examples. It should be understood , however,
that the invention is not limited to the solely to the particular
examples given below. It will be apparent that those skill in the
art that any modifications, both to the materials and methods, may
be practiced without departing from the purpose and interest of
this invention
[0062] a) all operations carried out at room temperature or ambient
temperature were in the range of 18 to 25 degree C.
[0063] b) evaporation of the solvent was carried out using a rotary
evaporator under reduced pressure (600-4000 pascals;4.5-30mm
Hg)with a bath temperature of upto 60 degree C.
[0064] c) the course of the reaction was monitored by thin layer
chromatography (TLC) and reaction times are given for illustration
only.
[0065] d) melting points are uncorrected, the melting points are
given for the materials prepared as described , polymorphism may
result in isolation of materials with different melting points in
some preparations.
[0066] e) the structure and purity of all final products were
assured by at least one of the following techniques: TLC,
NMR(nuclear magnetic resonance)spectroscopy, IR(lnfrared
spectroscopy), or microanalytical data.
[0067] f) yields are given for illustration only.
[0068] g) when given , NMR data is in the form of delta
(.delta.)values for major diagnostic protons, given in parts per
million ( ppm) relative to tetramethylsilane (TMS) as internal
standard determined at 300 MHz or 400 MHz using the indicated
solvent.
[0069] h) When given, IR data is in the form of absorption / cm for
characteristic absorption of the compound, determined from 400 to
4000 cm using Potassium bromide (KBr) disc
[0070] i) chemical symbols have their usual meanings ; the
following abbreviations have also been used: v( volume ),
w(weight), B.P.( boiling point), M.pt.(melting point) , L(liters),
ml(milliliters),gms(grams), mg(milligrams) , mol (moles), mmol(
millimoles) eq ( equivalents) deg C (degree centigrade), conc. HCI(
concentrated hydrochloric acid)
GENERAL PROCESS FOR THE PREPARATION OF COMPOUNDS OF FORMULA I
[0071] In the step I of the scheme,
4-(methanesulphonamido)phenylhydrazine hydrochloride is prepared by
known conventional methods
[0072] In the step 2,the appropriate acetophenone is treated with
the base and a ester to give the intermediate diketo compound. This
diketo compound is purified by recrystallisation .
[0073] In the step3, the Hydrazine hydrochloride of step 1 and
diketo of step 2 is reacted in solvents for example lower aliphatic
alcohols such as methanol, ethanol, Isopropanol and the like and
lower aliphatic acids such as acetic acid and the like.
[0074] The reaction conditions for diazotisation as in step 1
varies from -10 deg C to +60 deg C
[0075] The general reaction time for step 2 varies from 8-40 hours
and temperature conditions vary from 20 deg C to 60 deg C
[0076] The reaction conditions for the final condensation as in
step 3 varies from 20 deg C to 110 deg C and time period of 6-30
hours.
[0077] The recrystallisation solvents includes from lower aliphatic
alcohols such as methanol, ethanol, Isopropanol and the like, lower
aliphatic hydrocarbons such as hexane, heptane or diethylether or
any other suitable inert solvent.
EXAMPLE--1
[0078] Preparation of
N-[4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]phenyl]methanesulphonamide. 7
PART A
[0079] Preparation of 4-(Methanesulphonamido)Phenylhydrazine
Hydrochloride
[0080] 4-(methanesulphonamido)aniline (M.pt :116-118 deg C) was
prepared from p-nitroaniline and methanesulphonyl chloride in
presence of a base like N,N-dimethylaniline. The resulting
4-(methanesulphonamido)nitrobenze- ne (M.pt: 180-182 deg C) was
then reduced with sodium dithionite under alkaline conditions.
[0081] In a 500 ml round bottom flask provided with efficient
stirring and external cooling arrangement, 119 ml (1.19 mol) of
conc.HCI was cooled to below 5 deg C and 88 gms(0.47 mol)
4-(methanesulphonamido)aniline was added. The hydrochloride thus
precipitated was then diazotised below 0 deg C with 33.4 gms (0.48
mol)sodium nitrite dissolved in 50 ml water and the resulting
diazonium salt was decomposed with 220 gms (1.15mol)sodium
metabisulphite in 500 ml water.
4-(methanesulphonamido)phenylhydrazine hydrochloride thus
precipitated within 30 mins, was filtered and recrystallized from
water. The dried product was 76 gms ( yield 68%). M.pt decomposed
at 240-242 deg C . IR (KBr) cm-1 3257, 1606 ( NH), 1512 (C.dbd.C
),1305 (--SO2NH--), 1127( C.dbd.S)
PART B
[0082] Preparation of
1-(4-Methylphenyl)4,4,4-Trifluorobutane-1,3-Dione
[0083] 125 gms (0.93 mol) of p-Methylacetophenone was dissolved in
250 ml Methanol (anhydrous) and 270 ml of Sodium Methoxide (25% in
methanol) was added slowly maintaining the temperature below 30 deg
C. The reaction mixture was further diluted with 250 ml Methanol
and 128 ml of Ethyltrifluoroacetate(1.0 mol) was added in 4 lots
with a in--between stirring period of 5 hours. The reaction was
stirred at 20 -30 deg C for 16 hours. The reaction mixture was
concentrated under vacuum below 40 deg C to 50% and then poured
over mixture of 150 ml concentrated Hydrochloric acid and 200 gms
ice. The mixture was stirred below 5 deg C for 2 hours and filtered
. the product was washed with water till neutral pH and suck dried
under vacuum 0.25 gms of p-Methylacetophenone was recovered from
the filtrate. The
1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione was dried under
vacuum to give III gms off white crystalline product.( 65%) This
was further recrystallized from Isopropanol to give 90 gms of white
crystals. M.pt 50-52 deg C. IR KBr cm-1 1064 (C-C), 1147 (C.dbd.O),
1199 (CF3), 1458 (C-H), 1608 (aromatic C.dbd.O)
PART C
[0084] Preparation of
N-[4-5-(4-Methylphenyl)-3-Trifluoromethyl)-1H-Pyrazo-
l-1-YL]Phenyl]Methanesulphonamide.
[0085] 15 gms (0.065 mol) of
1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-- dione and 35 gms
(0.15 mol) of 4-(methanesulphonamido)phenylhydrazine hydrochloride
was refluxed in 150 ml anhydrous glacial acetic acid for 36 hours
along with continuous monitoring of the reaction by TLC and then
cooled to below 20 deg C and filtered .The residue was washed with
hot water till neutral pH. The crude product (16 gms)was
recrystallized from Methanol or Methanol and Isopropanol mixture to
give 12 gms (46%) bright orange color product (M.pt 186 deg C) .The
purity was 99.8% by HPLC. Chilling of the mother liquor gave
further 3 gms of 99.0% purity by HPLC.
[0086] 1H NMR CDCl3 ( 300 MHz) :2.1 ( s, 1H , 2.4 (s, 3H), 3.0 ( s,
3H), 7.26 (m, 2H), 7.42 (m, 4H), 7.52 (m, 2H), 9.0 (s, 1H). IR (
KBr) cm-1 3251 (NH), 1691 (--C.dbd.NH), 1525 (C.dbd.C), 1481 (CH3),
1325 (Ar--NH--Ar), 1257 (CF3), 1186 (--SO2NH2--), 1141 (C-N).
[0087] The following compounds (examples 1A-a to 1H-a) was obtained
according to procedures similar to that exemplified in PART B of
Example 1.
[0088] The appropriate acetophenones were used for the preparation
of the diketo intermediates and recrystallized in the similar
manner as above:
[0089] 1A-a) 1-(4-Ethylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0090] This intermediate was prepared from commercially available
4- Ethylacetophenone. The product obtained was a liquid which was
isolated from the reaction mixture by extraction with a suitable
solvent like Ethylacetate. The evaporation of the solvent gave the
diketo compound which was used as such for next step. Yield
obtained was 66%. IR (KBr) cm-1 1228 (C-C), 1149 (aliphatic
C.dbd.O), 1188 (CF3),1512 (CH3), 1328(aromatic C.dbd.O)
[0091] 1B-a)
1-(4-Methoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
[0092] This intermediate was prepared from commercially available
4-Methoxyacetophenone. The recrystallized product was a light
yellow crystalline powder. Yield obtained was 56%. M.pt: 57 deg C
IR ( KBr) cm-1 1255 (OCH3), 1110 (C-C), 1139 (aliphatic
C.dbd.O),1195 (CF3), 1508 (C-H), 1600 (aromatic C.dbd.O)
[0093] 1C-a) 1
-(4-Ethoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
[0094] This intermediate was obtained from commercially available
4- Ethoxyacetophenone .The recrystallized product was obtained in
48% yield as creamish white crystals. M.pt: 54 deg C IR (KBr) cm-1
1271 (C-O-C), 1114 (C-C), 1143 (aliphatic C.dbd.O), 1182 (CF3),
1560 (C-H),1604 (aromatic C.dbd.O)
[0095] 1D-a)
1-(3,4-Dichlorophenyl)-4,4,4-trifluorobutane-1,3-dione
[0096] This intermediate was prepared from commercially available
3,4-Dichloroacetophenone The recrystallized product was obtained in
40% yield as a cream powder. M.pt:40deg C IR (KBr) cm-1 1550 (C-C),
1149 (aliphatic C.dbd.O ), 1072 (CF3), 1469(C-H), 1593 (aromatic
C.dbd.O), 802 (C-Cl)
[0097] 1E-a) 1-(2,4-Dichlorophenyl)-4,4,4-trifluorobutane-1,3
-dione
[0098] This intermediate was prepared from 2,4-
Dichloroacetophenone which is commercially available. The product
obtained was a liquid which was isolated by extraction using a
suitable organic solvent like Ethylacetate. The evaporation of the
solvent gave the diketo product which was used as such for the next
step. The yield was 68%. IR (KBr) cm-1 1551 (C-C), 1150 (aliphatic
C.dbd.O), 1120 (CF3), 1480(C-H), 1608 (aromatic C.dbd.O), 810
(C-Cl)
[0099] 1F-a) 1-(2-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0100] This intermediate was prepared from commercially available
2- methylacetophenone. The product obtained was a liquid which was
isolated from the reaction mixture by extraction with a suitable
solvent like Ethyl acetate. The evaporation of the solvent gave the
diketo product in 64% yield which was used as such for the next
step. IR (KBr) cm-1 at 1147 (aliphatic C.dbd.O), 1199 (CF3 ), 1458
(C-H) 1608 (aromatic C.dbd.O)
[0101] 1G-a)
1-(2,4-Dimethylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0102] This intermediate was prepared from commercially available
2,4-Dimethyl acetophenone . The product obtained was a liquid which
was isolated from the reaction mixture by extraction with a
suitable solvent like Ethyl acetate. The evaporation of the solvent
gave the diketo product in 69% yield which was used as such for the
next step. IR (KBr) cm-1 1170 (aliphatic C.dbd.O), 1182 (CF3 ),1458
(C-H), 1608 (aromatic C.dbd.O)
[0103] 1H-a)
1-(3,4-Dimethylphenyl)-4,4,4-trifluorobutane-1,3-dione
[0104] This intermediate was prepared from commercially available
3,4-dimethylacetophenone . The recrystallized product was obtained
in 48% yield as a pale cream solid. M.pt: 110 deg C IR (KBr)cm-1
1093 (C-C), 1170 (aliphatic C.dbd.O ), 1182 (CF3 ),1 458 (C-H),
1608 (aromatic C.dbd.O)
[0105] The following compounds (examples 1A to 1H) was prepared in
the similar procedure as exemplified in the Part C of example 1
using the appropriate diketo compounds
[0106] 1A) N-[4-[5-(4-Ethylphenyl)-3-trifluoromethyl)-1 H-pyrazol-1
-yl]phenyl]methanesulphonamide.
[0107] Yield: 28% A dark orange powder. M.pt: 189 deg C IR (KBr)
cm-1 3261 (NH), 1697 (--C.dbd.NH), 1512 (C.dbd.C), 1402 (CH3) 1371
(Ar--NH--Ar), 1328 (CF3) 1186 (--SO2NH2), 1147 (C--N) Purity by
HPLC: 99.5%
[0108] 1B)
N-[4-[5-(4-Methoxyphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]ph-
enyl]methanesulphonamide. Yield 56% A dark yellow crystalline
powder. M.pt: 187 deg C IR (KBr) cm-1 3251 (NH), 1701 (--C.dbd.NH),
1510 (C=C), 1336 (Ar--NH--Ar) 1153 (CF3), 1191 (SO2NH2), 1249
(OCH3) Purity by HPLC: 98.96%
[0109] C)
N-[4-[5-(4-Ethoxyphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]phen-
yl]methanesulphonamide.
[0110] Yield: 48% A dark yellow crystalline powder. M.pt: 164 deg C
IR (KBr) cm-1 3340 (NH), 1697 (--C.dbd.NH), 1512 (C.dbd.C), 1253 (
OCH3) , 1325(Ar--NH--Ar), 1151 (CF3),1220 (SO2NH2) Purity by HPLC:
99.46%
[0111] 1D)
N-[4-[5-(3,4-Dichlorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl-
]phenyl]methanesulphonamide.
[0112] Yield: 50% A dark orange yellow powder. M.pt: 186 deg C IR
(KBr) cm-1 3276 (NH), 1701 (C.dbd.NH), 1510 (C.dbd.C), 1371(
Ar--NH--Ar), 1226 (CF3), 1195 (SO2NH2) 1145 (C--N), 815 (C-Cl)
Purity by HPLC : 98.74%
[0113] 1E)
N-[4-[5-(2,4-Dichlorophenyl)--trifluoromethyl)-1H-pyrazol-1-yl]-
phenyl]methanesulphonamide.
[0114] Yield: 28% A dark yellow powder M.pt: 162 deg C IR (KBr)
cm-1 3278 (NH), 1714 (--C.dbd.NH), 1510 (C.dbd.C),
1375(Ar--NH--Ar), 1222 (CF3) 1195 (SO2NH2),1147 ( C--N), 995 (
C-Cl) Purity by HPLC: 99.6%
[0115] 1F)
N-[4-[5-(2-Methylphenyl)-3-trifluoromethyl)-1H-pyrazol-1yl]phen-
yl]methanesuiphonamide
[0116] Yield: 30% A yellow crystalline powder M.pt: 175 deg C
Purity by HPLC: 98.5% IR ( KBr) /cm : 3267( N-H), 1703 (lmine
C=NH), 1510 ( CH3), 1328 (Ar--NH--Ar) 1244 (CF3),1190 (SO2NH2),1157
(C--N)
[0117] 1G)
N-[4-[5-(2,4-Dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]phenyl]methanesulphonamide.
[0118] Yield: 45% A bright yellow color product. M.pt: 152 deg C IR
(KBr) cm-1 3278 (NH), 1705 (--C=NH), 1512 (C.dbd.C), 1384 (CH3)
1332(Ar--NH--Ar), 1224 ( CF3) 1191 (SO2NH2),1153 ( C-N) Purity by
HPLC: 99.0%
[0119] 1H)
N-[4-[5-(3,4-Dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]phenyl]methanesulphonamide.
[0120] Yield: 36% A bright red color powder M.pt:175 deg C IR (KBr)
cm-1 3240 (NH), 1701(--C.dbd.NH ),1514 (C.dbd.C), 1467 (CH3),
1330(Ar--NH--Ar), 1251 (CF3),1186 (SO2NH2),1153 (C--N) Purity by
HPLC: 99.3%
[0121] 1I) Preparation of
4-[4-(Methanesulphonamido)phenyl]-3-(trifluorome- thyl)-1H-
pyrazol-5-yl]benzoic acid.
[0122] A solution of 3 gms of
N-[4-[5-(4-Methylphenyl)-3-trifluoromethyl)--
1H-pyrazol-1-yl]phenyl]methanesulphonamide in 10 ml Acetone was
stirred at room temperature. Jones reagent ( about 8 ml ) was added
dropwise maintaining the room temperature, till the orange color of
Jones reagent persisted. The reaction was stirred at room
temperature for 6 hours and monitored by TLC. The reaction mixture
was concentrated under vacuum and the residue was extracted using a
suitable solvent such as Ethylacetate and this extract was washed
with water and brine . The organic layer was dried over sodium
sulfate and evaporated to give a brown colored product ( 3 gms) The
crude product was recrystallized from Isopropanol to give a pale
brown product. M.pt: 168-70 deg C
[0123] 1J) 2-[1
-[4-(Methanesulphonamido)phenyl]-3-(trifluoromethyl)-1
H-pyrazol-5-yl]benzoic acid.
[0124]
N-[4-[5-(2-Methylphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-
methanesulphonamide was prepared by condensation of
4-(methanesulphonamido)phenylhydrazine hydrochloride and
1-(2-Methylphenyl)-4,4,4-trifluord-butane -1,3- dione by the
process as described in
[0125] Part C of Example 1 This compound was oxidized by Jones
reagent as described in Example 2 to give a bright yellow colored
solid in 26% yield.
[0126] M.pt :164-166 deg C
GENERAL PROCESS FOR THE PREPARATION OF THE COMPOUNDS OF FORMULA
2
[0127] In the step 1, the appropriate phenylhydrazine was obtained
from the corresponding primary aromatic amine by diazotisation with
sodium nitrite and decomposing the diazonium salt with sodium
sulfite and precipitating the hydrazino compound as hydrochloride
salt with HCl.
[0128] In the step 2, the p- Methyl acetophenone was condensed with
Ethyltrifluoroacetate under alkaline conditions to give the
1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione
intermediate.
[0129] In the step3, the Hydrochloride of corresponding hydrazino
compounds of step 1 and diketo compound of step2 is reacted in
solvents for example lower aliphatic alcohols such as methanol,
ethanol, isopropanol and the like and lower aliphatic acids such as
acetic acid and the like.
[0130] The reaction conditions for diazotisation as in step 1
varies from -10 deg C to +60 deg C
[0131] The general reaction time for step 2 varies from 8-40 hours
and temperature conditions vary from 20deg C to 60deg C
[0132] The reactions conditions for the final condensation as in
step 3 varies from 20 deg C to 110 deg C and time period of 6-30
hours.
[0133] The retrystallisation solvents includes from lower aliphatic
alcohols such as methanol, ethanol, isopropanol and the like, lower
aliphatic hydrocarbons such as hexane, heptane or Diethylether., or
any other suitable inert solvent.
EXAMPLE--2
[0134] Preparation of
1-(3-Chloro4-Flurophenyl)-5-(4-Methylphenyl)-3-(Trif-
luoromethyl)Pyrazole. 8
PART A
[0135] Preparation of 3-Chloro-4-Fluorophenylhydrazine
Hydrochloride
[0136] In a 500 ml round bottom flask provided with efficient
stirring and external cooling arrangement, 51 ml (0.5 mole) of
conc. HCl was cooled to below 5 deg C and 25 gms (0.13 mole)
3-chloro-4-fluoroaniline was added. The hydrochloride thus
precipitated was then diazotised below 0 deg C with 12 gms (0.17
mole)sodium nitrite and the resulting diazonium salt was decomposed
with 100 gms ( 0.79 mole)sodium sulphite and 12 ml caustic lye. The
reaction mixture was filtered to remove impurities.225 ml conc. HCI
was added and stirred well and allowed to stand overnight. The
3-chloro-4-fluorophenylhydrazine hydrochloride thus precipitated
was filtered and recrystallized from water. The dried product was
18 gms ( yield 69%) M.pt: decomposed at 193 deg C. IR (KBr) cm-1
2939 and 2690(NH), 1506 (C.dbd.C),1114 (C-F), 744( C-Cl)
PART B
[0137] Preparation of 1- (4- Methylphenyl) -4,4,4-Trifluorobutane
-1,3 -Dione
[0138] The preparation is described in Part B of example 1
PART C
[0139] Preparation of
1-(3-Chloro4-Flurophenyl)-5-(4-Methylphenyl)-3-(Trif-
luoromethyl)Pyrazole.
[0140] 15 gms ( 0.093 mole) of 3-chloro-4-fluorophenylhydrazine
hydrochloride of Part A and 11 gms ( 0.048 mole) of
1-(4-Methylphenyl)-4,4,4-trifluorobutane - 1,3- dione of Part B as
given in example 1 was refluxed in 100 ml glacial acetic acid for
36 hours and then cooled to below 15 deg C and filtered . The
residue was washed with hot water till neutral pH. The crude
product ( 17 gms) was recrystallized from Methanol to give 10 gms (
58% yield) M.pt: 77 deg C . The purity was 99.8% by HPLC IR (KBr)
cm-1 at 1500 (C.dbd.C), 1470 (--C=NH ) 1242 (CF3),1222(C-F), 1157
and 1128 (C-N), 808 (C-Cl)
[0141] The following compounds ( examples 2A -a to 21 -a) was
obtained according to procedures similar to that exemplified in
PART A of Example 3. The appropriate aniline were used for the
preparation of the phenylhydrazine hydrochloride intermediates and
recrystallized in the similar manner as above:
[0142] 2A-a) 3-Chlorophenylhydrazine hydrochloride
[0143] This intermediate was prepared by diazotisation of
commercially available 3-Chloroaniline. The Hydrazine hydrochloride
was recrystallized from water to give a light brown powder in 80%
yield
[0144] M.pt: 215 deg C decomposes
[0145] IR (KBr) cm-1 at 3219 and 3006 (NH), 1602 (N-N), 1500
(C.dbd.C), 779(C-CI)
[0146] 2B-a) 4- Chlorophenylhydrazinehydrochloride
[0147] This intermediate was prepared by diazotisation of
commercially available 4-Chloroaniline. The Hydrazine hydrochloride
was recrystallized from water to give a light pinkish brown powder
in 72% yield
[0148] M.pt: 205 deg C decomposes
[0149] IR (KBr) cm-1 at 3215 and 2989( NH)
[0150] 1585 (N-N), 1496 ( C.dbd.C ), 648( C-Cl)
[0151] 2C-a) 2,4- Difluorophenylhydrazine hydrochloride
[0152] This intermediate was prepared by diazotisation of
commercially available 2,4-Difluroaniline. The Hydrazine
hydrochloride was recrystallized from water to give a light brown
powder in 69% yield
[0153] M.pt: 215 deg C decomposes
[0154] IR (KBr) cm-1 2923 and 2667( NH), 1618 (NH), 1504 (aromatic
C.dbd.C),
[0155] 715 (C-Cl), 1286, 1099 (C-F)
[0156] 2D-a) 3- fluorophenylhydrazine hydrochloride
[0157] This intermediate was prepared by diazotisation of
commercially available 3-Fluoroaniline. The Hydrazine hydrochloride
was recrystallized from water to give a light brown powder in 70%
yield
[0158] M.pt: 237 deg C decomposes
[0159] IR (KBr) cm-1 3448 and 3199( NH), 1581 (NH), 1496 (C.dbd.C),
675(C-CI), 1151,1263 (C-F)
[0160] 2E-a) 4- fluorophenylhydrazine hydrochloride
[0161] This intermediate was prepared by diazotisation of
commercially available 4-Fluroaniline. The Hydrazine hydrochloride
was recrystallized from water to give a light yellow powder in 68%
yield
[0162] M.pt: 180 deg C decomposes
[0163] IR (KBr) cm-1 3448 (NH), 1514 (NH), 1232,1066 (C-F)
[0164] b 2F-a) 3,4- Dichlorophenylhydrazine hydrochloride
[0165] This intermediate was prepared by diazotisation of
commercially available 3, 4-Dichloroaniline. The Hydrazine
hydrochloride was recrystallized from water to give a light cream
powder in 66% yield
[0166] M.pt: 185 deg C decomposes
[0167] IR (KBr) cm-1 3618 and 3209( NH), 1614 (NH), 1475 (C.dbd.C),
671 (C-Cl)
[0168] 2G-a) 2-Fluoro-4-methylphenylhydrazine hydrochloride
[0169] This intermediate was prepared by diazotisation of
commercially available 2- Fluoro- 4-methylaniline. The Hydrazine
hydrochloride was recrystallized from water to give a brown powder
in 70% yield
[0170] M.pt: Above 300 deg C
[0171] IR (KBr) cm-1 3450( NH), 1637 (NH), 1137 (C-F)
[0172] 2H-a) 2-Fluoro-5-Methylphenylhydrazine hydrochloride
[0173] This intermediate was prepared by diazotisation of
commercially available 2-Fluoro- 5-methylaniline. The Hydrazine
hydrochloride was recrystallized from water to give a brown
powder-in 74% yield
[0174] M.pt: Above 300 deg C
[0175] IR (KBr) cm-1 3427( NH), 1617 (NH), 1150 (C-F)
[0176] 21-a) 3-Fluoro-4-Methylphenylhydrazine hydrochloride
[0177] This intermediate was prepared by diazotisation of
commercially available 3-Fluoro-4-Methylaniline. The Hydrazine
hydrochloride was recrystallized from water to give a light pinkish
brown powder in 68% yield
[0178] M.pt: 195 deg C decomposes
[0179] IR (KBr) cm-1 3436 (NH), 1583 (NH), 1508 (C.dbd.C), 640
(C-Cl), 1232,1097 (C-F)
[0180] The following compounds (examples 2A to 2I) was prepared in
the similar procedure as exemplified in the Part C of example 3
using the appropriate hydrochloride salt of hydrazino
compounds:
[0181] 2 A) 1-(3-CHLOROPHENYL)-5-(4-METHYLPHENYL)-3-
(TRIFLUOROMETHYL) PYRAZOLE.
[0182] Yield: 42%
[0183] A white crystalline powder.
[0184] M.pt: 45 deg C
[0185] Purity by HPLC: 98.86%
[0186] IR (KBr) cm-1 at 1595(C.dbd.C), 1471 (--C.dbd.NH), 1232
(CF3), 1157 and 1128 (C--N),806(C-CI)
[0187] 2B) 1-(4-CHLOROPHENYL)-5-(4-METHYLPHENYL)-3-
(TRIFLUOROMETHYL) PYRAZOLE.
[0188] Yield: 57%
[0189] A white crystalline powder
[0190] M.pt: 126 deg C
[0191] Purity by HPLC: 97.9%
[0192] IR (KBr) cm-1 at 1496(C.dbd.C), 1471 (--C.dbd.NH ) 1234
(CF3), 1159 and 1134 (C--N),806(C-Cl)
[0193] 2C) 1-(2,4-DIFLUOROPHENYL)-5-(4-
METHYLPHENYL)-3-(TRIFLUOROMETHYL) PYRAZOLE
[0194] Yield: 36%
[0195] A creamish white crystalline powder.
[0196] M.pt: 83 deg C
[0197] Purity by HPLC: 99.95%
[0198] IR (KBr).cm-1 shows absorption /cm at 1509 (C.dbd.C), 1471
(--C.dbd.NH) 1246 (CF3) 1093(C-F), 1134(C--N)
[0199] 2D) 1 -(3-FLUOROPHENYL)-5-(4-METHYLPHENYL) -3-
(TRIFLUOROMETHYL) PYRAZOLE.
[0200] Yield: 38%
[0201] A white crystalline powder.
[0202] M.pt: 58 deg C
[0203] Purity by HPLC: 97.96%
[0204] IR (KBr) cm-1 at 1602(C.dbd.C), 1471 (--C.dbd.NH ) 1244
(CF3), 1161 and 1128 (C--N)
[0205] 2E)
1-(4-FLUOROPHENYL)-5-(4-METHYLPHENYL)-3-(TRIFLUOROMETHYL)
PYRAZOLE.
[0206] Yield: 6%
[0207] A brown solid.
[0208] M.pt: 68-70deg C
[0209] IR (KBr) cm-1 at 1604 (C.dbd.C), 1477 (--C.dbd.NH ) 1248
(CF3), 1159 and 1130 (C--N),
[0210] 2F)
1-(3,4-DICHLOROPHENYL)-5-(4-METHYLPHENYL)-3-(TRIFLUOROMETHYL)-P-
YRAZOLE.
[0211] Yield: 31%
[0212] A light brown colored powder.
[0213] M.pt: 94 deg C
[0214] Purity by HPLC: 98.86%
[0215] IR (KBr) cm-1 at 1591(C.dbd.C), 1471 (--C.dbd.NH ) 1232
(CF3), 1159 and 1136 (C--N), 817(C-Cl)
[0216] 2G)
1-(2-FLUORO4-METHYLPHENYL)-5-(4-METHYLPHENYL)-3-(TRIFLUOROMETHY-
L)PYRAZOLE.
[0217] Yield: 80%
[0218] A pale brown colored liquid
[0219] B.P.: 145 deg C
[0220] Purity by HPLC: 99.6%
[0221] IR (KBr) cm-1 at 1580(C.dbd.C), 1468 (--C.dbd.NH ) 1228
(CF3), 1145 and 1139 (C--N)
[0222] 2H)
1-(2-FLUORO-5-METHYLPHENYL)-5-(4-METHYLPHENYL)-3-(TRIFLUOROMETH-
YL)PYRAZOLE.
[0223] Yield: 40%
[0224] A light brown colored product
[0225] M.pt: 45 deg C
[0226] IR (KBr) cm-1 at 1600 (C.dbd.C), 1470 (--C.dbd.NH ) 1230
(CF3) , 1150 and 1125 (C--N),
[0227] 2I)
1-(3-FLUORO4-METHYLPHENYL)-5-(4-METHYLPHENYL)-3-(TRIFLUOROMETHY-
L)PYRAZOLE.
[0228] Yield: 80%
[0229] A brown colored viscous oil.
[0230] B.P.: 144 deg C
[0231] IR (KBr) cm-1 at 1595(C.dbd.C), 1471 (--C.dbd.NH ) 1232
(CF3), 1157 and 1128 (C--N),
BIOLOGICAL EVALUATION
[0232] The test compounds of formula 1 and 2 were evaluated for
anti-inflammatory activity and ulcerogenic activity.
[0233] Wistar rats ( 120-180 gms ) were fasted overnight and were
given per oral either vehicle (1% sodium CMC in water) or a test
compound. The paw volume was measured using a Plethysmometer, (UGO-
Basile Italy) based on the principal of water displacement. The
animals were then injected subcutaneously with 0.1 ml of 1% w/v of
Carrageenan suspension in to the plantar tissue of the right hind
paw. The paw volume was measured at 0 hour and subsequently at 1
hour intervals upto 6 hours. The percent increase in the paw volume
was compared with the test compound and control. The difference of
the average values between treated and control groups was
calculated for each time interval and statistically evaluated. The
animals were sacrificed and the stomach of each animal was removed,
a longitudinal incision along the greater curvature was made and
the presence and absence of gastric irritation was determined. All
the treatment groups were coded to eliminate observer's bias. The
results indicate that some of the test compounds exhibits
anti-inflammatory activity comparable with known NSAIDS and these
compounds also revealed mild injury which was significantly less
than the ulcerogenic index of standard NSAID known to cause gastric
lesions.
[0234] It is to be understood that various modifications or changes
that may be made to that described herein above by those of
ordinary skill in the art are also contemplated by the present
invention and are to be included within the spirit and purview of
this application and the following claims:
* * * * *