Title of Invention

PYRAZOLINE DERIVATIVES, THEIR PREPARATION AND APPLICATION AS MEDICAMENTS.

Abstract The present invention relates to new pyrazoline derivatives having the general formula (I), as well as to their physiologically acceptable salts, to process in human/veterinary therapy and to pharmaceutical compositions containing them. The new compounds of the invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments. In particular, they can be used for the preparation of medicaments used for the treatment of inflammation and other troubles associated to inflammation and other process mediated by cyclooxygenase-2, for example arthritis, pain treatment or fever treatment.
Full Text PYRAZOLINE DERIVATIVES, THEIR PREPARATION AND THEIR
APPLICATION AS MEDICAMENTS
Field of the invention
The present invention relates to new pyrazoline derivatives, of general
10 formula (I), and to physiologically acceptable salts thereof, to the procedures for
their preparation, to ther application as medicaments in human and/or veterinary
therapy and to the pharmaceutical compositions that contain them.
The new compounds object of the present invention can be used in the
pharmaceutical industry as intermediates and for the preparation of medicaments.
Background of the invention
Non-steroid anti-inflammatory drugs (NSAIDS) are traditionally classified as
anti-inflammatory, antipyretic and analgesic agents"for the symptomatic alleviation
of inflammation, fever and light to moderate pain. The main indications for these
drugs are osteoarthritis, rheumatoid arthritis and other inflammatory diseases of
articulations, as well as for the treatment of inflammations associated with small
lesions and as analgesics of broad use. The NSAIDS are essentially inhibitors of
acute inflammatory response, but in rheumatic disorders they have little effect on
the underlying degenerative changes occurring in tissue.
The discovery of the main mechanism of action of the NSAIDS by inhibition
of cyclooxygenase (COX) [J.R. Vane, Nature, 1971, 231, 232] provided a
2
Satisfactory explanation of their therapeutic action and established the importance
that certain prostaglandins have as mediators in inflammatory disease [R.J.
Flower, J.R. Vane, Biochem. Pharm., 1974, 23, 1439; J.R. Vane, R.M. Botting,
Postgrad Med. J., 199c, S6 (Suppl 4), S2]. The gastric toxicity of the classic
5 NSAIDS, as well as their beneficial effects, is due to the suppression of
prostaglandin synthesis by inhibition of the COX enzyme. Although several
strategies have been followed (enteral coating to prevent adsorption in the
stomach, parenteral administration, pro-drug formulation, etc) to reduce the
gastrointestinal lesions provoked by the NSAIDS, none of these modifications
10 have provided a significant impact on the incidence of serious adverse reactions
such as perforation and haemorrhaging.
The discovery of an induced prostaglandin-synthetase, denominated
cyclooxygenase-2 (COX-2), different from the constitutive enzyme, currently
denominated cyclooxygenase-1 (COX-1)[J. Sirois, J.R. Richards, J. Biol. Chem.,
15 1992, 267, 6382], has renewed the interest in the development of new anti-
inflammatory drugs. The identification of the isoform COX-2 has led to the
hypothesis that it could be responsible for the production of prostaglandins in
places where inflammation occurs. As a result, selective inhibition of this
isoenzyme would reduce the inflammation without producing the side effects of
20 gastric and renal toxicity. The COX-1 isoenzyme is essentially expressed in most
of tissues with the function of synthesising prostaglandins which regulate the
normal cell activity. On the other hand, the isoenzyme COX-2 is not normally
present in cells but in chronic inflammation the levels of the protein COX-2
increase in parallel with the over-production of prostaglandins [J.R. Vane, R.M.
25 Botting, Inflamm. Res., 1995, 44, 1]. Therefore, a selective COX-2 inhibitor has
the same anti-inflammatory, antipyretic and analgesic properties as a
conventional non-steroid anti-inflammatory agent and also inhibits the uterine
contractions induced by hormones and presents potential anti-carcinogenic
effects and beneficial effects in the prevention of the development of Alzheimer
30 disease. On the other hand, a selective COX-2 inhibitor reduces the potential
3
gastrointestinal toxicity, reduces the potential renal side effects and reduces the
effects of bleeding time.
The tri-dimensional structure of COX-1 has been determined by x-ray
diffraction [D. Picot, P.J. Loll, R.M. Garavito, Nature, 1994, 367, 243]. Three of the
5 helixes of the structure form the entrance to the cyclooxygenase channel and its
insertion in the membrane allows the arachidonic acid to access the active site
from inside the bilayer. The active site of cyclooxygenase is a large hydrophobic
channel and the authors argue that the NSAIDS inhibit COX-1 by excluding
arachidonic acid from the upper part of the channel. Recently [R.S. Service,
10 Science, 1996, 273, 1660], the three-dimensional structure of COX-2 has been
described, which allows comparison of the similarities and differences between
the two isoforms and therefore study of new drugs that selectively inhibit COX-2.
The structures of COX-1 and COX-2 show that the sites where the anti-
inflammatory agents bind to the enzymes are very similar but there is a difference
15 of at least one important amino acid. A voluminous isoleucine present in the
active site of COX-1 is replaced by a valine in COX-2. The isoleucine blocks the
lateral cavity that is separated from the principle bond of both isoenzymes. The
blocked cavity of COX-1 does not impede the binding of classic NSAIDS, but an
inhibitor that needs the extra support point supplied by the lateral cavity will bind
20 more easily to COX-2 than to COX-1. As a result, a model for a new generation of
anti-inflammatory agents is one where the inhibitors of cyclooxygenase have a
large preference for the lateral cavity of COX-2.
In the chemical literature derivatives of nitrogenated heterocyclic aromatics
of five members have been described with COX-2 inhibitory activity. Within these
25 azole derivatives are the pyrrols [W.W. Wilkerson, et al, J. Med. Chem., 1994, 37,
988; W.W. Wilkerson, et al, J. Med. Chem., 1995, 38, 3895; I.K. Khanna, et al, J.
Med. Chem., 1997, 40, 1619], pyrazoles [T.D. Penning, et al, J. Med. Chem.,
1997, 40, 1347; K. Tsuji, et al, Chem. Pharm. Bull., 1997, 45, 987; K. Tsuji, et al,
Chem. Pharm. Bull., 1997, 45, 1475], or imidazoles [Khanna, et al, J. Med. Chem.,
30 1997, 40, 1634].
4
We have now discovered that the novel compounds derived from
pyrazolines of general formula (I) show interesting biological properties and these
make them particularly useful for their employment in human and/or veterinary
therapy. The compounds object of this invention are useful as agents with anti-
5 inflammatory activity and for other diseases wherein cyclooxygenase-2 plays a
part, without having the gastric and renal toxicity of the classic NSAIDS.
Detailed description of the invention
10 The present invention provides new pyrazolines that inhibit the enzyme
cyclooxygenase-2, with application in human and/or veterinary medicine as anti-
inflammatories and for other diseases wherein cyclooxygenase-2 plays a part,
and that have low or gastric and real toxicity.These anti-inflammatories
therefore have a better safety profile. The new compounds object of the present
15 invention are derivatives of A2-pyrazolines, also known as 4,5-dihydro-1H-
pyrazoles, They are therefore non-aromatic nitrogenated heterocyclic compounds.
As a result the pyrazoline rings are not planar as opposed to the azoles described
previously. The compounds object of the present invention have the general
formula (I)
20
25
30
wherein
Ri represents an hydrogen atom, a methyl, fluoromethyl,
35 difluoromethyl, trifluoromethyl, carboxylic acid, lower carboxylate of 1 to 4 carbon
atoms, carboxamide or cyano group,
5
R2 represents a hydrogen atom or methyl group,
R3, R4, R7 and R8, identical or different, represent an atom of hydrogen,
chlorine or fluorine, a methyl, trifluoromethyl or methoxy group,
one of R5 and R6 represents an atom of hydrogen, chlorine or fluorine,
5 a methyl, trifluoromethyl, methoxy or trifluoromethoxy group, and the other of R5
and R6 is a methylsulphonyl, aminosulphonyl or acetylaminosulphonyl group;
with the proviso that when R1 represents a methyl group, then:
R2 represents a hydrogen atom or a methyl group,
R3 and R8, identical or different, represent an atom of hydrogen,
10 chlorine or fluorine, a methyl or trifluoromethyl group,
R4 represents a hydrogen or fluorine atom, a methyl, trifluoromethyl or
methoxy group,
R5 represents a fluorine atom, trifluoromethyl, trifluoromethoxy,
methylsulfonyl or aminosulphonyl group,
15 R6 represents a hydrogen, chlorine, fluorine atom, a methyl,
trifluoromethyl, methoxy, trifluoromethoxy, metylsulfonyl or aminosulphonyl
group,
with the proviso that one of both R5 and R6 represents a
metylsulfonyl or aminosulphonyl group; and
20 R7 represents a hydrogen, chlorine or fluorine atom, a methyl,
trifluoromethyl or methoxy group.
The new compounds of general formula (I) have an asymmetric carbon atom
and so can be prepared enantiomerically pure or as racemates. The racemates of
compounds (I) can be resolved into their optical isomers by conventional
25 methods, such as separation by chiral stationary phase chromatography for
example, or by fractionated crystallisation of their diastereoisomeric salts, which
can be prepared by reacting the compounds (I) with enantiomerically pure acids.
Similarly, they can also be obtained by enantioselective synthesis using
enantiomerically pure chiral precursors.
30 The present invention also relates to the physiologically acceptable salts of
the compounds of general formula (I), in particular, to the addition salts formed
6
with mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric
acid, etc, and with organic acids such as citric, maleic, fumaric acid, tartaric acids
or its derivatives, p-toluenesulphonic, methanosulphonic, camphosulphonic acid
etc.
The novel derivatives of general formula (I) can be used in mammals,
including man, as anti-inflammatory agents for the treatment of inflammation and
for the treatment of other disorders associated with inflammation, such as
analgesics for the treatment of pain and migraine, and as anti-pyretics in the
treatment of fever. For example, the new derivatives of general formula (I) can be
used in the treatment of arthritis, including but limited to the treatment of
rheumatoid arthritis, spondyloarthropathies, gouty arthritis, systemic lupus
erythematosus, osteoarthritis and juvenile arthritis. The novel derivatives of
general formula (I) can be used in the treatment of asthma, bronchitis, menstrual
disorders, tendinitis, bursitis and different states that affect the skin such as
psoriasis, eczema, burns and dermatitis. The novel derivatives of general formula
(I) can also be used in the treatment of gastrointestinal afflictions such as
syndrome of inflamed intestine, Crohn"s disease, gastritis, irritated colon
syndrome and ulcerous colitis.
The novel derivatives of general formula (I) can be prepared, in accordance
with the invention, following the methods that are indicated below:
Method A
The preparation of the compounds of general formula (I) is carried out by
reacting a compound of general formula (II)
(II)
wherein Ri represents an hydrogen atom, a methyl, fluoromethyl, difluoromethyl,
trifluoromethyl or carboxylic acid group, and R2l R3, R4 and R5 have- the same
meaning as that indicated for general formula (I), with a phenylhydrazine of
general formula (III) in base or salt form
wherein R6, R7 and R8 have the same meaning as that described previously for
general formula I.
The reaction is carried out in the presence of a suitable solvent such
as, for example, alcohols such as methanol, ethanol, ethers such as dioxane,
tetrahydrofuran, or mixtures thereof or other solvents. The reaction takes place in
acid medium, that can be organic, such as acetic acid, for example, or inorganic
such as hydrochloric acid for example, or a mixture of both, or in a base medium
such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium
methoxide or sodium ethoxide for example, or a mixture thereof. The acidic or
base medium itself can act as a solvent. The most suitable temperatures vary
between room temperature and the reflux temperature of the solvent and the
reaction times can lie between several hours and several days.
METHOD B
The preparation of the compounds of general formula (I), wherein Ri
represents a carboxylate of a lower alkyl with 1 to 4 carbon atoms and R2, R3, R4,
R5, R6, R7 and R8 have the same meaning as that given above, is effected by
8
reacting a compound of general formula (I) wherein R1 represents a carboxylic
acid group (COOH) and R2, R3, R4, R5, R6, R7 and R8 have the same meaning as
that given above, with a suitable reagent to form the acid chloride such as thionyl
chloride or oxa!y! chloride for example, and then carrying out an esterification
reaction with an aliphatic alcohol of 1 to 4 carbon atoms in the presence of an
organic base, such as triethylamine or pyridine, or by direct reaction of carboxylic
acid with the corresponding anhydrous alcohol saturated with gaseous hydrogen
chloride. The reaction is carried out in the reagent as its own solvent or in other
appropriate solvents such as halogenated hydrocarbons such as
dichloromethane, chloroform or carbon tetrachloride, ethers such as dioxane,
tetrahydrofuran, ethyl ether or dimethoxyethane. The most appropriate
temperatures vary between 0° C and the reflux temperature of the solvent and the
reaction times lie between ten minutes and 24 hours.
METHOD C
The preparation of the compounds of general formula (I), wherein R1
represents a carboxamide group and R2l R3, R4, R5, R6, R7 and R8 have the same
meaning as that indicated above, is carried out be reacting a compound of
general formula (I) wherein R1 represents a carboxylic acid group (COOH) and R2,
R3, R4, R5, R6, R7 and R8 have the same meaning as that indicated above, with a
suitable reagent for forming the corresponding acid chloride, for example, thionyl
chloride or oxalyl chloride and then reacting with ammonia, that can be in the form
of concentrated aqueous solution or dissolved in a suitable solvent. The reaction
is carried out in a suitable solvent such as, for example, ethers such as dioxane,
tetrahydrofuran, ethyl ether or dimethoxyethane. The most suitable temperatures
vary between 0° C and the reflux temperature of the solvent and the reaction
times lie between 1 and 24 hours.
METHOD D
The preparation of the compounds of general formula (I), wherein R1
represents a cyano group and R2, R3, R4, R5, R6, R7 and R8 have the same
9
meaning as that indicated above, is carried out by reacting a compound of
general formula (I) wherein R1 represents a carboxamide group and R2, R3, R4, R5,
R6, R7 and R8 have the same meaning as that indicated above, with a suitable
reagent such as, for example, the complex dirrsethylformamide-thiony chloride or
methanosulphonyl chloride. The reaction is carried out in a suitable solvent such
as, for example, dimethylformamide or pyridine. The most suitable temperatures
vary between 0° C and the reflux temperature of the solvent and the reaction
times lies between fifteen minutes and 24 hours.
METHOD E
The compounds of general formula (II), intermediates in the preparation of
the compounds of general formula (I), are commercially available or can be
obtained using different known methods among which the following are found:
METHOD E-1
The preparation of the compound of general formula (II), wherein R1,
represents a mono- di- or trifluoromethyl group, R2 represents an hydrogen atom
and R3, R4 and R5 have the same meaning indicated above for the compounds of
general formula (I), is carried out by reaction of a benzaldehyde of general
formula (IV)
wherein R3, R4 and R5 have the same meaning as that given above for the general
formula (I), with N-phenyl(mono, di or trifluoro)acetimidoyl chloride in the
presence of a dialkyl phosphonate, such as phosphonate of diethylmethyl, and a
strong organic base, such as LDA (lithium diisopropylamide), or by the Wittig
reaction with mono-, di- or trifluoroacetylmethylenetriphenylphosphorane and a
base such as sodium carbonate or potassium carbonate. The reaction is carried
out in a suitable solvent such as, for example, dichloromethane, chloroform or
benzene, or an ether such as tetrahydrofuran, ethyl ether, dimethoxyethane or
dioxane. The most suitable temperatures vary between -70° C and the reflux
temperature of the solvent, and the reaction times lie between fifteen minutes and
twenty hours.
METHOD E-2 The preparation of the compounds of general formula (II), wherein
R1 represents a methyl or trifluoromethyl group, R2 represents a methyl group and
R3, R4 and R5 have the same meaning indicated above for the compounds of
general formula (I), is carried out be reacting a compound of general formula (V)
whirein R2 represents a methyl group and R3 R4 and R5 have the same meaning
as that indicated above for the compounds of general formula (I), with mono-, di-
or trifluoroacetic anhydride in the presence of the complex dimethyl sulphide-
boron trifluoride. The reaction is carried out in a suitable solvent such as, for
example, halogenated hydrocarbons such as dichloromethane, chloroform or
carbon tetrachloride or ethers such as dioxane, tetrahydrofuran, ethyl ether or
dimethoxyethane. The most suitable temperatures vary between -70° C and the
reflux temperature of the solvent, and the reaction times lie between twenty
minutes and twenty hours.
METHODE-3
The preparation of compounds of general formula (II), wherein R1 represents
a methyl or trifluorometyl group, R2 represents an hydrogen atom and R3, R4 and
R5 have the same meaning as that indicated previously for the compounds of
general formula (!), are carried out by different procedures among which can be
found, for example, the Claisen-Schmidt reaction between a benzaldehyde of
general formula (IV) and acetone or 1,1,1-trifluoroacetone in presence of an
aqueous solution of alkaline metal hydroxide such as sodium hydroxide or
potassium hydroxide or acetic acid and piperidine; the Wittig-Horner reaction
between a benzaldehyde of general formula (IV) and a 2-oxo-alkyl phosphonate in
the presence of an aqueous solution of a base such as, for example, potassium
carbonate or potassium bicarbonate; the reaction of a benzaldehyde of general
formula (IV) with acid such as zinc dibromide for example or by reaction of a compound of general
formula (VI)
wherein R3, R4 and R5 have the same meaning as that indicated above for the
general formula (I), with trimethylaluminium in the presence of aluminium
trichloride.
The reaction is carried out in a suitable solvent such as, for example, an alcohol
such as methanol or ethanol, a halogenated hydrocarbon such as carbon
tetrachloride, chloroform or dichloromethane, an ether such as tetrahydrofuran,
ethyl ether, dioxane or dimethoxyethane, water or a mixture thereof. The reaction
temperature can vary between -60° C and the reflux temperature of the solvent
and the reaction times can vary between two hours and several days.
12
The preparation of compounds of general formula (II), wherein R1 and R2
represent an hydrogen atom and R3, R4 and R5 have the same meaning as that
indicated above for the compounds of general formula (I), are carried out following
different methods among which can be found, for example, the Wittig-Homer
reaction with a benzaldehyde of general formula IV and then reducing the
unsaturated a,p-ester with a metal hydride such as diisobutylaluminum hydride
(Dibal); by reaction of a benzaldehyde of general formula IV with a,a-
bis(trimethylsilyl)-t-butylacetaldimine in the presence of a Lewis acid such as zinc
dibromide or by condensation of a benzaldehyde of general formula IV with
acetaldehyde in the presence of a alkaline metal hydroxide such as sodium
hydroxide or potassium hydroxide.
METHOD F
The preparation of the compounds of general formula (I), wherein R1, R2, R3, R4,
R7 and R8 have the same meaning as that indicated above and one of R5 and R6
represents an atom of hydrogen, chlorine or fluorine, a methyl, trifluoromethyl,
methoxy or trifluoromethoxy group, and the other of .R5 and R6 is an
acetylaminosulphonyl group, is carried out by reacting a compound of general
formula (I) wherein R1, R2, R3l R4) R7 and R8 have the same meaning as that
indicated above and one of R5 and R6 represents an atom of hydrogen, chlprine or
fluorine, a methyl, trifluoromethyl, methoxy or trifluoromethoxy group, and the
other of R5 and R6 is an acetylaminosulphonyl group, with a suitable reactant such
as, for example, acetyl chloride or acetic anhydride. The reaction is carried out in
the absence of solvent, or in a suitable solvent such as, for example,
dimethylformamide or pyridine. The most suitable temperatures vary between 0° C
and the reflux temperature and the reaction times lie between 15 minutes and 14
hours.
The invention provides pharmaceutical compositions that comprise, as well as
a pharmaceutically acceptable excipient, at least one compound of general
formula (I) or a physiologically acceptable salt thereof. The invention also relates
to use of a compound of general formula (I) and its physiologically acceptable
salts in the preparation of a medicament for the treatment of inflammation and/or
for the treatment of other disorders associated with inflammation. In the following
examples the preparation of novel compounds according to the invention is
indicated. Some typical forms of use are also disclosed for different fields of
application, as well as pharmaceutical formulae applicable to the compounds
object of the invention. The examples that are indicated below, given by way of*
illustration, should not in any way limit the scope of the invention.
Example 1 (entry 1 of the Tables).- 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-
metylphenyl)-3-trifluoromethyl-1H-pyrazole

Preparation of (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (Method E-1)
Into a flask with dry inert atmosphere, 15 ml of anhydrous THF is introduced
and the flask cooled to -70° C. A solution of 2 M LDA in THF-hexane (5 ml, 10
mmoles) and diethylmethyl phosphonate (0.75 ml, 5 mmoles) dissolved in 5 ml of
THF are added and the flask shaken for 30 minutes. Then, N-
phenyltrifluoroacetimidoyl chloride (1.04 g , 5 mmoles) is added dropwise,
(prepared according to Tamura, K.; Mizukami, H. et al.; J. Org. Chem., 1993, 58,
32-35) while continuing the shaking in the same conditions for 1 hour. P-
toluenaldehyde (0.6 g, 5 mmoles) is added, the cold bath removed and the flask
left with shaking at room temperature for 16 hours. 10 ml of 2N HCI are added
with shaking for a further 4 hours. The THF is eliminated with a rotavapor, the ,
mixture extracted with ethyl ether (3x20 ml) and the combined organic extracts
washed with 5% sodium bicarbonate solution and with saturated sodium chloride
solution until reaching a pH ˜ 6. The mixture is dried over anhydrous sodium
sulphate and evaporated. The crude oil obtained is purified using column
chromatography through silica gel under pressure (eluting with AcOEt-petrol ether
1:9) to obtain (E)- 1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.8 g, yield:
75%) in the form of a clear oil.
IR (film, cm"1): 1715, 1601, 1201, 1183, 1145, 1056,811,703
1H-NMR (CDCI3): 6 2.4 (s. 3H); 6.97 (d, J=18Hz, 1H); 7.25 (d, J=9Hz, 2H); 7.54 (d,
J=9Hz, 2H); 7.95 (d, J=18Hz, 1H).
Thin layer chromatography (TLC) (Petrol ether): Rf=0.16
Preparation of 1 -(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-
trifluoromethyl-1H-pyrazole (METHOD A)
A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.82 g, 3.69
mmoles) and (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.79 g, 3.69
mmoles) in 15 ml of acetic acid is refluxed for 3 hours under a nitrogen
atmosphere. It is cooled, poured over water and extracted with AcOEt. The
organic solution is washed with water, dried over anhydrous sodium sulphate and
evaporated to dryness under vacuum. The crude product thus obtained is
crystallised from EtOH-petrol ether to give 1-(4-aminosulphonylphenyl)-4,5-
dihydro-5-(4-methylphenyl)-3-trifluoromethyl-1/7-pyrazole (0.65 g, yield: 45%).
m.p. = 140-3°C.
IR (KBr, cm"1): 3356, 3268, 1594, 1326, 1170, 1139, 1120, 1097
1H-NMR (CDCI3): 5 2.34 (s, 3H); 2.99-3.06 (dd, J=6.9 and 14 Hz; 1H); 3.66-3.73
(dd, J=12.6 and 14 Hz, 1H); 4.69 (broad s, 2H); 5.38-5.45 (dd, J=6.9 and 12.6 Hz,
IH); 7.04-7.11 (2d, J=8.1 and 9.3 Hz, 4H); 7.17 (d, J=8.1 Hz, 2H); 7.70 (d, J=9.3
Hz, 2H).
13C-NMR (CDCI3): 20.9; 41.2; 64.5; 113.4; 120.5 (q, J=268 Hz); 125.3; 127.6;
130.1; 133.2; 136.7; 138.3; 138.8 (q, J=38 Hz); 146.0.
TLC (AcOEt): Rf=0.89
Example 2. (entry 2 in the Tables) 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-
phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole
Preparation of (E)-1,1,1 -trifluoro-4-methyl-4-phenyl-3-butene-2-one (METHOD E-
2). To a solution of dimethyl sulphide-boron trifluoride (3.9 g, 30 mmoles) in 75 ml
of dichloromethane cooled to -60° C trifluoroacetic anhydride (6.3 g, 30 mmoles)
is added slowly. The mixture is shaken for 10 minutes and a solution of methylstyrene (3.54 g, 30 mmoles) in 15 ml de dichloromethane added slowly,
maintaining the temperature at -60° C. Then the temperature is allowed to rise to -
50° C, and kept at this value for 15 minutes, then allowed to rise to 0° C and the
mixture shaken under these conditions for 30 minutes. 50 ml of ethyl ether and 50
ml of an aqueous solution of 10% sodium bicarbonate solution are added. The
phases are separated and the aqueous phase washed with more ether. The
combination of the ether phases is washed with water, dried over anhydrous
sodium sulphate and evaporated to dryness with a rotavapor. The crude product
thus obtained is purified using column chromatography through silica gel under
pressure eluting with petrol ether. 2.0 g (51%) of unreacted starting a-
methylstyrene and 2.35 g of (E)-1,1,1 -trifluoro-4-phenyl-3-butene-2-one (yield:
75%) were recovered in the form of colourless oil.
IR (film, cm-1): 1709, 1596, 1204,1142, 1072.
1H-NMR (CDCI3): 6 2.71 (s, 3H); 6.8 (s, 1H); 7.45 (m, 3H); 7.6 (m, 2H).
Preparation of 1 -(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-
trifluoromethy-1H-pyrazole (METHOD A)
In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-methyl-4-(4-
methylphenyl)-3-butene-2-one (1.75 g, 8.2 mmoles), 4-(aminosulphonyl)-
phenylhydrazine chlorohydrate (2 g, 9 mmoles) and piperidine (0.85 g, 10
mmoles) are added, dissolved in 100 ml of ethanol, and heated under reflux for
5.5 hours. The mixture is cooled, the solvent eliminated with a rotavapor, water
added to the residue and the solution extracted with AcOEt. The organic phase is
washed with water, dried over anhydrous sodium sulphate and evaporated to
dryness. The crude product is purified using column chromatography through
silica gel under pressure, eluting with AcOEt-petrol ether (4:6) obtaining 1-(4-
aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-
pyrazole in the form of a white solid (1.46 g, yield: 47%) with a m.p.=60-6°C
IR (KBr, cm*1): 3384, 3266, 1593, 1498, 1327, 1151, 1099, 703.
1H-NMR (CDCI3): 5 1.6 (s, 3H); 2.8 (m,1H); 3.1 (m, 1H); 4.5 (broad s, 2H); 7.2 (m,
3H); 7.4-7.55 (m, 4H); 7.7 (d, 2H).
13C-NMR (CDCI3): 27.6; 54.2; 63.1; 114.6; 124.0 (q, J=268 Hz); 125.6; 127.4;
127.8; 129.1; 131.0; 142.0 (q, J=38 Hz); 142.6; 147.5.
Example 3 (entry 3 in the Tables).- 1 -(4-aminosulphonylphenyl)-5-(2,4-
difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole
Preparation (E)-1,1,1 -trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (Method
E-3)
In a flask 2,4-difluorobenzaldehyde (20 g, 0.14 moles), glacial acetic acid
(12.2 g, 0.2 moles) and piperidine (12.2 g, 0.14 moles) are dissolved in THF (300
ml). The solution is cooled to 5-10°C and CF3COCH3 (8 g, 0.07 moles) bubbled
through it. It is removed from the cold bath, the temperature increased to room
temperature and the mixture kept at this temperature for 1.5 hours with continuous
shaking. CF3COCH3 (5 g, 0.045 moles) is added once again and the mixture left
for 1.5 hours with shaking. Once again 5 g is added and the mixture shaken for a
further 1.5 hours. This step is repeated until a total of 35 g (0.31 moles) of
CF3COCH3 have been added. A solution of 20% (50 ml) is added and the solvent
eliminated under reduced pressure. 50 ml of water is added and the solution
extracted with AcOEt. The organic phase is washed with water, 5% H2SO4, water
and the mixture dried over anhydrous sodium sulphate. The solution is filtered
and evaporated. The resulting crude product is distilled, obtaining 18.1 g of (E)-
1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one with a m.p. of 50-1 °C.
IR(KBr, cm"1): 1717, 1602, 1583, 1277, 1146, 1059, 706
1H-NMR (CDCI3): 5 6.9 (m, 2H); 7.05 (d, J=16 Hz, 1H); 7.6 (m, 1H); 8.0 (d, J=16
Hz, 1H).
Preparation of 1 -(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyMH-pyrazole (METHOD A)
A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (47.8 g, 0.21
moles) and (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (53.1 g of
95%, 0.21 moles) in 315 ml of acetic acid is refluxed for 24 hours under a nitrogen
atmosphere. The mixture is cooled, poured over water and filtered. It is washed
with toluene and the crude product thus obtained crystallised from isopropanol.
46.2 g is obtained. The mother waters of crystallisation from crystallisation, once
concentrated, give another 12.6 g of product. In total 58.8 g (68%) of 1-(4-
aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-
pyrazole with a melting point of 160-2°C.
The following procedure can also be followed:
In a flask with an inert atmosphere sodium ethoxide (0.53 g, 7.72 mmoles) is
dissolved in 45 ml of ethanol. 1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one
(prepared according to method E-1) (0.913 g, 3.86 mmoles) and 4-
(aminosulphonyl)phenylhydrazine chlorohydrate (0.87 g, 3.87 mmoles) are added
and the mixture was refluxed for 16 hours. The mixture was cooled, evaporated to
dryness, cold water added, and the mixture acidified by adding acetic acid and the
precipitated solid filtered. This solid was redissolved in ether, treated with active
C, filtered and the solvent eliminated with a rotavapor. The resulting residue was
crystallised from ethyl ether-petrol ether (50:50) to give 1-(4-
aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-
pyrazole (1.02 g, yield: 65%) in the form of a solid m.p.= 160-2°C.
IR (KBr, cm-1): 3315, 3232, 1617, 1593, 1506, 1326, 1179, 1099, 1067.
1H-NMR (CDCI3): 5 3.0 (dd, J=6.3 and 11.4 Hz, 1H); 3.80 (dd, J=11.4 and 12.6 Hz,
1H); 4.79 (broad s, 2H); 5.70 (dd, J=6.3 and 12.6 Hz, 1H); 6.8-6.95 (m, 2H); 7.01-
7.09 (m, 3H); 7.74 (d, J=8.7 Hz, 2H).
Example 4 (entry 4 of the TablesV- 4,5-dihydro-1 -(4-methylphenyl)-5-(4-
methylsulphonylphenyl)-3-trifluorometyl-1H-pyrazole (METHOD A)
In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-(4-
methylsulphonylphenyl)-3-butene-2-one (prepared according to the method E-1)
(1.83 g, 6.58 mmoles) and 4-methylphenylhydrazine chlorohydrate (1.04 g, 6.58
mmoles) are dissolved in 50 ml de ethanol. A few drops of hydrochloric acid are
added, and the mixture refluxed under an inert atmosphere for 4 days. The
mixture is cooled and the product crystallised. The solution is filtered and the
product recrystallised from ethanol. 4,5-dihydro-1-(4-methylphenyl)-5-(4-
methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole (0.8 g, yield: 32%) is
obtained in the form of a solid with a melting point of 140-3°C.
IR(KBr, cm"1): 1516, 1310, 1148, 1131, 1060, 774
1H-NMR (CDCI3): 5 2.2 (s, 3H); 2.9(dd, J=7.8, 17.1 Hz, 1H); 3.05(s, 3H); 3.7(dd,
J=12.9, 17.1 Hz, 1H); 5.45(dd, J=7.8, 12.9 Hz, 1H); 6.8(d, J=8.4 Hz, 2H); 7(d,
J=8.4 Hz, 2H); 7.45(d, J=8.4 Hz, 2H); 7.9(d, J=8.4 Hz, 2H)
Example 5 (entry 39 in the Tables).- methyl 4,5-dihydro-5-(4-methylphenyl)-1-(4-
methylsulphonylphenyl)-1H-pyrazole-3-carboxylate (METHOD B)
4,5-dihydro-5-(4-methylphenyl)-1 -(4-methylsulphonylphenyl)-1 H- pyrazole-3-
carboxylic acid (6.9 g, 19.3 mmoles) and thionyl chloride (3.5 ml, 48 mmoles) are
dissolved in 50 ml of tetrahydrofuran and the mixture shaken at room temperature
for 16 hours. The mixture is evaporated to dryness with a rotavapor and the crude
acid chloride so obtained is dissolved in 150 ml of methanol in a flask with inert
atmosphere, and 8 ml (58 mmoles) of triethylamine added and the mixture shaken
at room temperature for 2 hours. Water is added, the solid filtered and washed
with abundant water and methanol. The desired methyl ester is thus obtained (5.8
g, yield: 82%) in the form of a cream coloured solid with a m.p. =155-160°C.
IR( KBr, cm"1): 1741, 1561, 1260, 1226, 1135, 1089
1H-NMR (CDCI3): 2.3(s, 3H); 3(s, 3H); 3.1(dd, J=6, 18.3Hz, 1H); 3.75(dd, J=12.6,
18.3HZ, 1H); 5.4(dd, J=6, 12.6Hz, 1H); 7-7.25(m, 6H); 7.7(d, J=8.7Hz, 2H)
Example 6 (entry 41 in the Tables).- Preparation of 1-(4-aminosulphonylphenyl)-
4,5-dihydro-5-(4-methylphenyl)-1 H-pyrazole-3-carboxamide (METHOD C)
1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-
carboxylic acid (3.7 g, 10.3 mmoles) and thionyl chloride (3 g, 25.8 mmoles) are
dissolved in 70 ml of tetrahydrofuran and shaken at room temperature for 16
hours. The mixture is evaporated to dryness with a rotavapor and the crude acid
chloride so obtained dissolved in 30 ml of methanol in a globe of inert atmosphere
and cooled to 0° C. 9 ml of concentrated ammonium hydroxide solution dissolved
in 20 ml of THF is added. The mixture is shaken at room temperature for 16 hours
and the solvent eliminated with the rotavapor. Water is added to the residue and
the mixture extracted with ethyl acetate, which is washed with water, dried over
anhydrous sodium sulphate and evaporated to dryness. The crude residue so
obtained is crystallised from ethyl acetate-petrol ether to give 2.6 g (yield: 72%) of
the desired compound with a m.p.=210-5°C.
IR (KBr, cm-1): 3450, 3337, 1656, 1596, 1345, 1141
1H-NMR (d4-CH3OH): 8 2.4(s, 3H); 3.05(dd, J=6, 17.7Hz, 1H); 3.8(dd, J=12.9,
17.7Hz, 1H); 5.6(dd, J=6, 12.9Hz, 1H); 7.2-7.3(m, 6H); 7.75(d, J=8.7Hz, 2H)
Example 7 (entry 43 in the Tables).- Preparation of 3-cyano-4,.5-dihydro-5-(4-
methylphenyl)-1 -(4-methylsulphonylphenyl)-1 H-pyrazole (METHOD D)
In a flask with inert atmosphere 6.3 ml of anhydrous DMF is placed, the flask
cooled to 0° C and 2.1 ml of thionyl chloride slowly added. The flask is shaken for
2 hours in these conditions. A solution of 4,5-dihydro-5-(4-methylphenyl)-1-(4-
methylsulphonylphenyl)-1H-pyrazole-3-carboxamide (3.8 g, 10.6 mmoles) in 30 ml
of DMF is added and the mixture shaken for 5 hours at 0° C and, then, for 16
hours at room temperature. The contents of the flask are poured onto ice and the
solid precipitate filtered. 3.35 g (yield: 93%) of crude product are obtained which
is crystallised from ethyl acetate giving a yellow solid with a m.p. =162-4°C.
IR (KBr, cm"1): 2220, 1593, 1500, 1389, 1296, 1143
1H-NMR (CDCI3): 5 2.3(s, 3H); 3-3.1(s+dd, 4H); 3.75(dd, J=12.6, 18Hz, 1H);
5.5(dd, J=6.3, 12.6Hz, 1H); 7-7.2(m, 6H); 7.7(d, J=8.7Hz, 2H)
Example 8 (entry 64 of the Tables).- 1 -(4-acetylaminosulphonylphenyl)-5-(2,4-
difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1 H-pyrazole (METHOD F)
0.58 g (1.43 mmoles) of 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-
dihydro-3-trifluoromethyl-1H-pyrazole and 2 ml of acetyl chloride are heated
under reflux for 2 hours. The mixture is cooled, evaporated to dryness under
reduced pressure and the resulting residue dissolved in AcOEt, washed with
water, dried over Na2SO4 and evaporated to dryness. 0.49 g (76%) of 1-(4-
acetylaminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro3 trifluoromethyl-
1 H-pyrazole were obtained in the form of a white solid with a m.p. =172-4°C.
IR(KBr, cm"1): 3302, 1723, 1593, 1506, 1337, 1165
1H-NMR (CDCI3): 5 2.0 (s, 3H); 3.0 (dd, J=6.6, 18.0Hz, 1H); 3.8(dd, J=12.9,
18.0Hz, 1H); 5.7(dd, J=6.6, 12.9Hz, 1H); 6.9 (m, 2H); 7.05 (m+d, 3H); 7.85 (d,
J=8.7Hz, 2H); 8.1 (s, 1H)
Examples 9 and 10 (entries 75 and 76 in the Tables).- (+)-1-(4-
aminosulphonvlphenvl)-5-(2.4-difluorophenvl)-4.5-dihvdro-3-trifluoromethvl-1H-
pyrazole and (-)-1-(4-amino sulphonylphenvl)-5-(2.4-difluorophenvl)-4.5-dihvdro-
3-trifluoromethvl-1 H-pyrazole
The racemic mixture (±)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-
4,5-dihydro-3-trifluoromethyl-1H-pyrazole is resolved into its enantiomers by high
performance liquid chromatography using a CHIRALPAK AS column with 10m
particles and dimensions of 25 x 2 cm (Daicel), mobile phase 0.1% diethylamine
in methanol and a flow rate of 8 ml/min. At a retention time of 7.4 minutes (+)-1-(4-
aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-
pyrazole is obtained as a white solid with a melting point of: 173-4°C;
enantiomeric purity 99.9 %; [a]D=+183.9 (c=1 CH3OH). At a retention time of 9.2
minutes (-)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1H-pyrazole is obtained as a white solid with a m.p.: 173-4°C;
enantiomeric purity >99,9%; [a]D=-189.4 (c=1 CH3OH).
Following the same procedure the examples corresponding to entries 17 and 78
in the tables are obtained.
Table 1 shows some examples that are encompassed by the general formula
(I) and in Table 2 the data are indicated for identification of these compounds.
The examples 1 -36, 44-63 and 65-74 have been prepared according to method A,
examples 37-39 according to method B, examples 40-42 according to method C,
example 64 according to method F and the enantiomerically pure compounds 75-78
by resolution of the racemic mixture.
The products object of the invention are potent, orally active, anti-
inflammatory agents, and selective inhibitors of COX-2, with a notable analgesic
activity, lack ulceregenic effects and are very active in the experimental arthritis
test. With a view to demonstrating these activities, by way of example, some
pharmacological assays are now indicated.
Inhibition of the synthesis of prostaglandins in inflammatory exudate and mucus
membrane in rat.
In this assay, as well as demonstrating the selective inhibition of COX-2, the
anti-inflammatory activity is also demonstrated, along with the absence of effects
on gastric prostaglandins, after oral administration. The assay was carried out by
modification of a method described by O. Tofanetti et al. (Med. Sci. Res. 1989, 17,
745-746). The products under study are administered orally at an initial screening
dose of 40 mg/kg. One hour after treatment the rats were anaesthetised and a
sponge soaked in carrageenan was implanted subcutaneously in the
interscapular zone. Six hours after implantation the rats were sacrificed and the
interscapular sponges extracted as well as gastric mucous. Next the PGE2 content
was determined by immunoassay for each one of the samples, in the sponge
exudate on the one hand and in the gastric mucus on the other. The inhibition of
PGE2 in the inflammatory exudate demonstrates anti-inflammatory activity, both of
COX-2 and COX-1 inhibitors, whereas inhibition of PGE2 in the gastric mucus is
considered a COX-1 inhibitory effect.
Table 3 summaries the results obtained with the compound of examples 3
and in table 4 the ED-50 (effective dose-50) is shown, as well as its selectivity. It
is a more potent anti-inflammatory that the reference product.
TABLE 3.- C0X-2/C0X-1 activity in vivo
Inhibition of PGE2
Product (Dose 40 mg/kg, po) Inflammatory exudate Gastric mucus
Example 3 92% 0
Meloxicam 97% 65%
Nabumetone 93% 0
TABLE 4. - ED-5C of the COX-2/COX-1 activity in vivo
Product Inhibition of PGE2
ED-50 (mg/kg, po)
Inflammatory exudate Gastric mucus
Example 3 3.6 >40
Nabumetone 11.0 >40
Analgesic activity against "hvperalaesia" bv thermal stimulus of pre-inflamed rat
paw.
In this assay the analgesic activity in rat was monitored following the method
described by K. Hargreaves et al. (Pain, 1988, 32, 77-78). Firstly, a suspension of
carrageenan was injected into the back right paw of each rat. After two hours the
products under study were administered orally at a screening dose of 40 mg/kg.
Two hours after treatment a heat source was applied to the sole of each back paw
of the rats and the time measured that they took to remove the paw measured.
Hyperalgesia was determined by comparing the percentage of algesia of the paw
injected with carrageenan to the other back paw. The analgesic activity was
calculated comparing these hyperalgesia values of the groups treated with
product with those of the group treated with the vehicle only.
In table 5 the results obtained with the compound of example 3 and
summarised and in table 6 the ED-50 is presented, showing that this product is
more active that other selective inhibitors of COX-2 in the assay of activity against
thermal hyperalgesia.
TABLE 5. - Analgesic activity against hyperalgesia by thermal stimulus.
Product % Activity
(Dose = 40 mg/kg, po)
Example 3 100%
Nimesulide 97%
Nabumetone 95%
TABLE 6. -ED-50 of analgesic activity against hyperalgesia by thermal stimulus.
Product ED-50 (mg/kg, po)
Example 3 0.2
Nimesulide 1.0
Nabumetone 2.1
Gastrointestinal effects (GO : induction of ulcers in rats submitted to cold stress.
In this assay possible ulcerogenic effects at a gastrointestinal level were
determined after oral administration. To do this a modification of the method
described by K. D. Rainsford (Agents and actions, 1975, 5, 553-558) was
followed. Firstly the rats received the products under study orally at different
doses. After two hours had elapsed the rats were placed in a chest freezer at -15°
C for 1 hour. Afterwards they were left for 1 hour at room temperature. The
animals were then sacrificed and the stomach extracted. The stomach was kept in
saline solution for 15 minutes. After this time the percentage of surface area with
gastric ulcers was determined using a Project C.S.V. vs 1.2 image analyser for
each stomach. For each product the maximum dose that did not lead to
ulcerogenesis was determined by linear regression analysis of the dose-
response.
The results obtained with the compound of example 3 are summarised in
table 7. It has been shown not to have ulcerogenic effects, even at very high
doses, as was to be expected from a COX-2 selective product. On the other hand,
dichlophenac and piroxicam, both selective COX-1 inhibitors, exhibited
ulcerogenic effects at very low doses.
TABLE 7. -Induction of ulcers in rats submitted to cold stress.
Product Maximum non-
Ulcerogenic dose
(mg/kg, po)
Example 3 >80
Dichlophenac 1.2
Piroxicam 1.7
Anti-arthritic activity in rat
In this study the anti-arthritic activity in rat of the compound of example 3 has
been studied. To do so the method described by B. J. Jaffee et al. (Agents and
Actions, 1989, 27, 344-346) was followed. Firstly, the Freund adjuvant was
injected (Mycobacterium butiricum suspended in soy-bean oil) through the sub-
sole of the back left paw of the rats. After 14 days, when the secondary
inflammation had developed in the uninjected paw, which is considered the
experimental arthritis, treatment with the product under study or with the vehicle
for the control group was started. The compound of example 3 was administered
orally at a dose of 10 mg/kg/day for 11 days. The volume of the paw with
secondary inflammation in the last days of treatment was measured. The anti-
arthritic activity was calculated by comparing the average volume of the paw with
secondary inflammation of the group treated with the compound of example 3 and
the control group for 5 days.
The results obtained show that the compound of example 3 has a high anti-
arthritic activity, as treatment with 10 mg/kg/day, po, led to an inhibition of
secondary inflammation, i.e. of an anti-arthritic activity, of 71%.
On the basis of their good pharmacodynamic properties, the derivatives of
pyrazolines in accordance with the invention, can be used in satisfactory manner
in human and animal therapy, in particular as anti-inflammatory agents for the
treatment of inflammation and for the treatment of other disorders associated with
inflammation, such as anti-arthritics, analgesics for the treatment of pain and
migraine, or as antipyretics in the treatment of fever.
In human therapy, the administration dose of the compounds of the present
invention varies as a function of the seriousness of the affliction to treat. Normally
the dose will lie between 100 and 400 mg/day. The compounds of the invention
will be administered, for example, in the form of capsules, tablets, or injectable
solutions or suspensions.
Below, by way of example, two pharmaceutical compositions containing the
compounds object of the present invention are shown.
Pharmaceutical formulations
Example of formula per tablet:
Example 3 50 mg
Corn flour 16 mg
Colloidal silicon dioxide 1 mg
Magnesium stearate 1 mg
Povidone K-90 3 mg
Pre-gelatinised starch 4 mg
Micro-crystalline cellulose 25 mg
Lactose 200 mg
Example of formula for capsule:
Example 3 100 mg
Corn flour 20 mg
Colloidal silicon dioxide 2 mg
Magnesium stearate 4 mg
Lactose 200 mg
1. A derivative of pyrazoline of general formula (I)
wherein
R1 represents an hydrogen atom, a methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, carboxylic acid, lower carboxylate of 1 to 4 carbon
atoms, carboxamide or cyano group,
R2 represents an hydrogen atom or a methyl group,
R3, R4, R7 and R8, identical or different, represent an atom of hydrogen, chlorine or
fluorine, a methyl, trifluoromethyl or methoxy group,
one of R5 and R6 represents an atom of hydrogen, chlorine or fluorine, a
methyl, trifluoromethyl, methoxy or trifluoromethoxy group, and the other of R5 and
R6 is a methylsulphonyl, aminosulphonyl or acetylaminosulphonyl group;
with the proviso that when R1 represents a methyl group, then:
R2 represents a hydrogen atom or a methyl group,
R3 and R8, identical or different, represent an atom of hydrogen, chlorine
or fluorine, a methyl or trifluoromethyl group,
R4 represents a hydrogen or fluorine atom, a methyl, trifluoromethyl or
methoxy group,
R5 represents a fluorine atom, trifluoromethyl, trifluoromethoxy,
methylsulfonyl or aminosulphonyl group,
R6 represents a hydrogen, chlorine, fluorine atom, a methyl,
trifluoromethyl, methoxy, trifluoromethoxy, metylsulfonyl or aminosulphonyl
group,
with the proviso that one of both R5 and R6 represents a
metylsulfonyl or aminosulphonyl group; and
R7 represents a hydrogen, chlorine or fluorine atom, a methyl,
trifluoromethyl or methoxy group;
and its physiologically acceptable salts.
2. A compound, as claimed in claim 1, selected from the following group:
[I] 1-(4-Aminosulfonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl-
1H-pyrazole
[2] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-methyl-5-(4-methylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[3] 1-(4-Aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[4] 4,5-Dihydro-1-(4-methylphenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[5] 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-phenyl-3-trifluoromethyl-1 H-
pyrazole
[6] 4,5-Dihydro-5-phenyl-1 -(4-methylsulphonylphenyl)-3-trifluoromethyl-1 H-
pyrazole
[7] 4,5-Dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[8] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-fluorophenyl)-3-trifluoromethyl-
1 /-/-pyrazole
[9] 4,5-Dihydro-5-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-
1 H-pyrazole
[10] 4,5-Dihydro-1-(4-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-
1 H-pyrazole
[II] 1-(4-Aminosulphonylphenyl)-5-(3,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[12] 5-(2,4-Dichlorophenyl)-4,5-dihydro-1 -(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[13] 1-(4-Aminosulphonylphenyl)-5-(2,4-dichlorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[14] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-methylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[15] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(3-methylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[16] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-fluorophenyl)-3-trifluoromethyl-
1 H-pyrazole
[17] 4,5-Dihydro-5-(2-fluorophenyl)-1 -(4-methylsulphonylphenyl)-3-trifluoromethyl-
1H-pyrazole
[18] 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-(3-fluorophenyl)-3-trifluoromethyl-
1 H-pyrazole
[19] 4,5-Dihydro-5-(3-fluorophenyl)-1 -(4-methylsulphonylphenyl)-3-trifluoromethyl-
1 H-pyrazole
[20] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-methoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[21] 1-(4-Aminosulphonylphenyl)-5-(3-chloro-4-fluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[22] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-3-trifluoromethyl-5-(4-
trifluoromethoxyphenyl) -1 H-pyrazole
[23] 1-(4-Aminosulphonylphenyl)-5-(2,3-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[24] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2,4-dimethylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[25] 5-(3,4-Difluorophenyl)-4,5-dihydro-1-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[26] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-fluorophenyl)-3-methyl-1H-
pyrazole
[27] 4,5-Dihydro-5-(4-fluorophenyl)-3-methyl-1 -(4-methylsulphonylphenyl)-1 H-
pyrazole
[28] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-
pyrazole
[29] 4,5-Dihydro-3-methyl-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl) -1H-
pyrazole
[30] 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-3-methyl-5-(4-
trifluoromethylphenyl)-1 H- pyrazole
[31] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1 H-pyrazole
[32] 4,5-Dihydro-5-phenyl-1 -(4-methylsulphonylphenyl) -1 H-pyrazole
[33] 4,5-Dihydro-3-methyl-1-(4-methylsulphonylphenyl)-5-(4-
trifluoromethylphenyl)-1 H- pyrazole
[34] 1 -(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1 H-pyrazole-3-
carboxylic acid
[35] 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1H-pyrazole-3-carboxylic
acid
[36] 4,5-dihydro-5-(4-methylphenyl)-1 -(4-methylsulphonylphenyl)-1 H-pyrazole-3-
carboxylic acid
[37] Methyl 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-
pyrazole-3-carboxylate
[38] Methyl 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1 H-pyrazole-3-
carboxylate
[39] Methyl 4,5-Dihydro-5-(4-methylphenyl)-1 -(4-methylsulphonylphenyl)-1 H-
pyrazole-3-carboxylate
[40] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1H-pyrazole-3-
carboxamide
[41 ] 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1 H-pyrazole-3-
carboxamide
[42] 4,5-Dihydro-5-(4-methylphenyl)-1 -(4-methylsulphonylphenyl)-1 H-pyrazole-3-
carboxamide
[43] 3-Cyano-4,5-dihydro-5-(4-methylphenyl)-1 -(4-methylsulphonylphenyl)-1 H-
pyrazole;
[44] 1-(4-Aminosulphonylphenyl)-4)5-dihydro-5-(3,4-dimethylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[45] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(3-methyl-4-methoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[46] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(3-fluoro-4-methoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[47] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-fluoro-4-methoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[48] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2,4-dimethoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[49] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-fluoro-2-methoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[50] 1-(4-Aminosulphonylphenyl)-3-difluoromethyl-4,5-dihydro-5-(2,4-
dimethylphenyl)-1 H-pyrazole
[51] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2,3,4-trifluorophenyl)-3-
trifluoromethyl-1 H-pyrazole
[52] 1-(4-Aminosulphonylphenyl)-5-(2-chloro-4-fluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[53] 1 -(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-fluoro-4-
trifluoromethylphenyl)-3-trifluoromethyl-1 H-pyrazole
[54] 1-(4-Aminosulphonylphenyl)-5-[2,4-(bistrifluoromethyl)phenyl]-4,5-dihydro-
3-trifluoromethyl-1 H-pyrazole
[55] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-methyl-3-fluorophenyl)-3-
trifluoromethyl-1 H-pyrazole
[56] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-methyl-4-methoxyphenyl)-3-
trifluoromethyl-1 H-pyrazole
[57] 1-(4-Aminosulphonylphenyl)-5-(2,4-difluorophenyl)-3-difluoromethyl-4,5-
dihydro-1 H-pyrazole
[58] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-fluoro-2-
trifluoromethylphenyl]-3-trifluoromethyl-1 H-pyrazole
[59] 1-(2,4-Difluorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[60] 1 -(4-Aminosulphonylphenyl)-5-(2-chlorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[61] 1-(4-Aminosulphonylphenyl)-5-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[62] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-fluoro-2-methylphenyl]-3-
trifluoromethyl-1 H-pyrazole
[63] 1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(2-fluoro-4-methylphenyl]-3-
trifluoromethyl-1 H-pyrazole
[64] 1-(4-Acetylaminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[65] 1-(4-Chlorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[66] 4,5-Dihydro-1 -phenyl-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1 H-
pyrazole
[67] 4,5-Dihydro-1-(2-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[68] 1-(4-Chloro-2-methylphenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[69] 4,5-Dihydro-1-(3-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[70] 4,5-Dihydro-1-(3-methylphenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[71] 4,5-Dihydro-1-(2,4-dimethylphenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[72] 1 -(2-Chlorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1H- pyrazole
[73] 4,5-Dihydro-1-(2-methylphenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1/-/- pyrazole
[74] 1-(2,4-Dichlorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1/-/- pyrazole
[75] (+)-1-(4-Aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[76] (-)-1-(4-Aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-
trifluoromethyl-1 H-pyrazole
[77] (+)-4,5-Dihydro-1-(4-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole
[78] (-)-4,5-Dihydro-1-(4-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-
trifluoromethyl-1 H-pyrazole;
[79] 4,5-Dihydro-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1-(2-
trifluoromethylphenyl)-1 H-pyrazole;
and physiologically acceptable salts thereof.
3. A procedure for preparing a derivative of pyrazoline of general formula (I),
as claimed in claim 1, characterised by reacting a compound of general formula
wherein Ri represents an hydrogen atom, a methyl, fluoromethyl, difluoromethyl,
trifluoromethyl or carboxylic acid group, and R2, R3, R4 and R5 have the same
meaning as that indicated in claim 1, with a phenylhydrazine of general formula
(III) in base or salt form
wherein R6, R7 and R8 have the same meaning as that described for claim 1.
4. A procedure for the preparation of a derivative of pyrazoline of general
formula (I), as claimed in claim 1, wherein Ri represents a carboxylate of a lower
alkyl with 1_to 4 carbon atoms and R2R3R4R5 R6R7and R8have the same
meaning as that given in claim 1, characterised by reacting a compound of
general formula (I) wherein R1 represents a carboxylic acid group (COOH) and R2,
R3, R4, R5, R6, R7 and R8 have the same meaning as that given in claim 1, with a
suitable reagent to form the acid chloride such as thionyl chloride or oxalyl
chloride for example, and then carrying out an esterification reaction with an
aliphatic alcohol of 1 to 4 carbon atoms in the presence of an organic base, such
as triethylamine or pyridine, or by direct reaction of carboxylic acid with the
corresponding anhydrous alcohol such as herein described saturated with
gaseous hydrogen chloride.
5. Procedure for the preparation of a derivative of pyrazoline of general
formula (I), as claimed in claim 1, wherein R1 represents a carboxamide group and
R2, R3, R4, R5, R6, R7 and R8 have the same meaning as that indicated in claim 1,
characterised by reacting a compound of general formula (I) wherein R1
represents a carboxylic acid group (COOH) and R2, R3, R4, R5, R6, R7 and R8 have
the same meaning as that indicated in claim 1, with a suitable reagent for forming
the corresponding acid chloride, for example, thionyl chloride or oxalyl chloride
and then reacting with ammonia, in the manner such as herein described.
6. A procedure for the preparation of a derivative of pyrazoline of general
formula (I), as claimed in claim 1, wherein R1 represents a cyano group and R2,
R3, R4, R5, R6, R7 and R8 have the same meaning as that indicated in claim 1,
characterised by reacting a compound of general formula (I) wherein R1
represents a carboxamide group and R2, R3, R4, R5, R6, R7 and R8 have the same
meaning as that indicated in claim 1, with a suitable reagent such as, for example,
the complex dimethylformamide-thionyl chloride or methanosulphonyl chloride.
7. A procedure for the preparation of a derivative of pyrazoline of general
formula (I), as claimed in claim 1, wherein R1, R2, R3, R4, R5, R7 and R8 have the
same meaning as that indicated in claim 1 and R6 represents an
acetylaminosulphonyl group, or R1, R2, R3, R4, R6, R7 and R8 have the same
meaning as that indicated in claim 1 and R5 represents an acetylaminosulphonyl
group/characterised by reacting a compound of general formula (I) wherein Ri, R2,
R3, R4, R5, R7 and R8 have the meaning indicated in claim 1 and R6 represents an
aminosulphonyl group, or R1, R2, R3, R4, R6, R7 and R8 have the meaning indicated
in claim 1 and R5 represents an aminosulphonyl group, with a suitable reagent
such as, for example, acetyl chloride or acetic anhydride.
8. Procedure for the preparation of a derivative of pyrazoline of general
formula (I), as claimed in claim 1, enantiomerically pure, characterised by effecting
the resolution of a racemic mixture of the compound of general formula (I) by
chromatography with chiral stationary phase or formation of a salt with an
enantiomerically pure acid.
9. Procedure for the preparation of a physiologically acceptable salt of a
derivative of pyrazoline of general formula (I), as claimed in claim 1, comprising
reacting a compound of general formula (I) with an inorganic acid such as herein
described or with an organic acid such as herein described in the presence of a
suitable solvent.
10. A pharmaceutical composition, comprising one or more compounds of
general formula (I), or a physiologically acceptable salt thereof, as claimed in
claims 1 and 2, and pharmaceutically acceptable excipients.
11. A pharmaceutical composition as claimed in claim 10, in the manufacture
of a medicament for the treatment of inflammation and for the treatment of other
- s
disorders associated with inflammation and other processes mediated by
cyclooxygenase-2 or of those processes wherein benefit is derived by inhibition or
cyclooxygenase-2 in mammals including man.
12. A pharmaceutical composition as claimed in claim 10, in the manufacture
of a medicament for the treatment of inflammation in mammals, including man.
13. A pharmaceutical composition as claimed in claim 10, in the manufacture
of a medicament for the treatment of disorders associated with inflammation in
mammals, including man.
14. A pharmaceutical composition as claimed in claim 12, in the manufacture
of a medicament for the treatment of arthritis in mammals, including man.
15. A pharmaceutical composition as claimed in claim 12, in the manufacture
of a medicament for the treatment of pain in mammals, including man.
16. A pharmaceutical composition as claimed in claim 12, in the manufacture
of a medicament for the treatment of fever in mammals, including man.
The present invention relates to new pyrazoline derivatives having the general formula (I), as well as to their physiologically acceptable
salts, to process in human/veterinary therapy and to pharmaceutical compositions containing them. The new compounds of the invention
can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments. In particular, they can be used for
the preparation of medicaments used for the treatment of inflammation and other troubles associated to inflammation and other process
mediated by cyclooxygenase-2, for example arthritis, pain treatment or fever treatment.

Documents:

in-pct-2000-00668-kol-abstract.pdf

in-pct-2000-00668-kol-assignment.pdf

in-pct-2000-00668-kol-claims.pdf

in-pct-2000-00668-kol-correspondence.pdf

in-pct-2000-00668-kol-description (complete).pdf

in-pct-2000-00668-kol-form 1.pdf

in-pct-2000-00668-kol-form 13.pdf

in-pct-2000-00668-kol-form 18.pdf

in-pct-2000-00668-kol-form 3.pdf

in-pct-2000-00668-kol-form 5.pdf

in-pct-2000-00668-kol-gpa.pdf

in-pct-2000-00668-kol-letter patent.pdf

in-pct-2000-00668-kol-priority document others.pdf

in-pct-2000-00668-kol-priority document.pdf

in-pct-2000-00668-kol-reply f.e.r.pdf


Patent Number 216904
Indian Patent Application Number IN/PCT/2000/668/KOL
PG Journal Number 12/2008
Publication Date 21-Mar-2008
Grant Date 19-Mar-2008
Date of Filing 17-Dec-2000
Name of Patentee LABORATORIOS DEL DR. ESTEVE S.A.
Applicant Address AVENIDA MARE DE DEU DE MONTSERRAT, 221, E-08041, BARCELONA
Inventors:
# Inventor's Name Inventor's Address
1 CUBERES-ALTISENT MARIA ROSA AVENIDA MARE DE DEU DE MONTSERRAT, 221. E-08041. BARCELONA
2 BERROCAL-ROMERO JUANA MARIA -DO-
3 CONTI-JOCH-LLOBET MARIA MONTSERRAT -DO-
4 FRIGOLA- CONSTANSA JORDI -DO-
PCT International Classification Number A 61 K 31/41
PCT International Application Number PCT/ES99/00156
PCT International Filing date 1999-05-27
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 P 9801129 1998-05-29 Spain