FR2472564A1 - 1-Aryl-4-aryl:sulphonyl-3-amino-propoxy-1H-pyrazole derivs. - hypolipaemics and hypocholesterolaemics of low toxicity and non-ulcerogenic - Google Patents

1-Aryl-4-aryl:sulphonyl-3-amino-propoxy-1H-pyrazole derivs. - hypolipaemics and hypocholesterolaemics of low toxicity and non-ulcerogenic Download PDF

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FR2472564A1
FR2472564A1 FR7932107A FR7932107A FR2472564A1 FR 2472564 A1 FR2472564 A1 FR 2472564A1 FR 7932107 A FR7932107 A FR 7932107A FR 7932107 A FR7932107 A FR 7932107A FR 2472564 A1 FR2472564 A1 FR 2472564A1
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Henri Techer
Gilles Monnier
Marcel Pesson
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BELLON LABORATOIRES
Bellon Labor SA Roger
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28Two oxygen or sulfur atoms

Abstract

<P> ARYL-1 ARYLSULFONYL-4 1H-PYRAZOLOLS-3 OF FORMULA: <BR/> (CF DRAWING IN BOPI) <BR/> AND THEIR ALKALI SALTS OF FORMULA: <BR/> (CF DRAWING IN BOPI) <BR These compounds are useful as synthesis intermediates, especially for the preparation of the ARYL-1 ARYLSULFONYL-4G-AMINO PROPOXY-3H-PYRAZOLE FORMULA: <BR/> (CF DRAWING IN BOPI ) <BR/> A HYPOCHOLESTEROLEMIANTES AND HYPOLIPEMIANTES ACTIVITIES. </ P>

Description

New aryl-1 arylsulfonyl-4H-pyrazolols-3
The patent application No. 79 17507 filed on July 5, 1979 for "new pyrazole derivatives" and their therapeutic application of which the present application is a divisional application relates to novel derivatives of 1H-pyrazole characterized by the presence, on this heterocycle, of an aryl ring, optionally substituted at 1, of a t-aminopropoxy (N-mono- or disubstituted) residue at 3 and an aryl-sulphonyl residue (optionally substituted) at 4.

The compounds according to the invention described in said basic application have the general formula (I):

Figure img00010001

 In this formula, the various substituents have the following definitions.

 R1 represents a hydrogen or halogen atom or a lower alkyl radical, a lower alkoxy radical, or a trifluoromethyl radical. The substituents thus defined may occupy on the aromatic ring, to which they are attached, a meta (3 ') or para (4') position.

 R2> R3 and R4 each represent a hydrogen or halogen atom or a lower alkyl, lower alkoxy, or a trifluoronyl radical.

 R5 and R6> taken separately may each be a hydrogen atom or a lower alkyl radical. Taken together, R5 and R6 can form, with the nitrogen atom to which they are attached, a nitrogenous heterocycle with 5 or 6 knuckles, this heterocycle possibly containing another heteroatom such as oxygen.

 The term "lower alkyl or lower alkoxy" refers to a radical of 1 to 3 carbon atoms.

 More particularly, R1, R2, R3> R4 each represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy or trifluoromethyl radical.

 R5> R6, taken separately, may each designate a hydrogen atom or a methyl or ethyl radical, or, taken together, R5, R6 may form, with the nitrogen atom to which they are attached, a pyrrolidino, piperidino or morpholino.

 It is known that 1,4-diaryl-N-monoalkyl- and N-dialkylaminoalkoxy-3-pyrazoles are endowed with analgesic and anti-inflammatory properties (French Patent Application No. 2,301,250). The Applicant has found, surprisingly and unpredictably, that the base compounds, mainly characterized by the presence of a 4-arylsulfonyl residue on the pyrazole ring, as well as their non-toxic acid salts are endowed with hypocholesterolemic and hypolipidemic agents susceptible to therapeutic applications.

When R 5 and R 6 each represent a lower alkyl radical or are included in a heterocycle as defined above, the products of the basic application can be obtained by condensation of a 3-halo-1-dialkylamino propane (III), preferably 1-chloro-3-dialkylamino propane, with the salt of an aryl-arylsulphonyl-4H-pyrazolol-3 and an alkali metal M (II):

Figure img00020001

 As alkali metals, sodium or potassium is preferably used.

 The reaction is conducted at a temperature between 60 and 1200C, in a solvent or a mixture of suitable solvents.

the use of a lower fatty tertiary alcohol, such as tertiary butyl alcohol, is particularly desirable. To facilitate the dissolution of salt (II), it is also favorable to add the medium of a dipolar aprotic solvent, such as DMF or DMSO. DMF is then preferably used at a rate of 1/2 volume to 1 volume per volume of alcohol employed.

 In principle, the reaction requires the implementation of equimolar proportions of the metal derivative (II) and the halo derivative (III). However, it is best to use a slight excess of the latter.

 The metal derivative (II) is conveniently prepared in situ by adding a molecule of a 4-aryl-4-arylsulphonyl-pyrazolol to a solution of alkali metal alkoxide (eg potassium), obtained by dissolving a gram atom of metal in an excess of tertiary alcohol.

 The solution (or suspension) of the metal derivative (II) is optionally added with a suitable volume of DMF, then a slight excess (1.1 to 1.2 moles) of a 1-chloro-3-dialkylamino propane is added thereto. and the mixture is stirred and heated, protected from moisture, at a temperature between 60 and 1000C until the end of the reaction, which takes 5 to 8 hours.

 The solvent (s) are removed by vacuum distillation and the residue is taken up in water. The product of the reaction is extracted with a suitable solvent. The organic solution is washed with a dilute solution of an alkaline hydroxide (to remove the unreacted pyrazolol) and then with water. It is dried (K2CO3) and filtered. The solvent is distilled off in vacuo. The crystalline residue is purified by recrystallization from a suitable solvent.

 The bases (I) are converted into salts of inorganic or organic acids that are non-toxic according to the known general methods.

According to one variant, the products of the basic claim can be obtained by reaction of primary or secondary amines with aryl-arylsulphonyl-4-pyrazoles, substituted in 3 with a propoxy chain which itself has a substituent at the 7-position. X 'allowing the displacement reaction by the basic reagent (V)

Figure img00030001

 For this purpose, the compounds (IV) in which X 'represents a halogen atom, such as chlorine, bromine or iodine, an arylsulphonyloxy residue or, preferably, an alkylsulphonyloxy residue, especially methylsulphonyloxy (mesyloxy), may be used.

 The reaction of the compounds (IV) and amines (V) is carried out at temperatures between 50 and 1500 C.

 It is recommended to use an excess of amine at a rate of at least 2.5 moles of the latter per mole of compound (IV) used, the excess serving as an acceptor for the acidic molecules formed in the reaction. It is also possible to use the amine (V) only in slight excess, provided to add the medium of an acid acceptor which may be a fatty tertiary amine, such as triethylamine, a heterocyclic substance basic, such as pyridine or one of its methyl higher homologues, or a basic inorganic agent, such as an alkali metal carbonate.

 With amines with a boiling point of at least 800 ° C., it is possible to operate in the presence of an excess of amine acting as a solvent, or by heating the refluxing reagents, in a point solvent. suitable boiling point, preferably chosen from lower alcohols or aromatic hydrocarbons.

 With amines whose boiling points are below 800 ° C., an autoclave is carried out in one of the solvents mentioned above.

 Within the above-defined temperature and concentration limits, the reaction is generally complete after 2 to 6 hours of heating. The solvent and excess amine are distilled off in vacuo. The residue is taken up in a dilute solution of a strong mineral acid, or better methanesulfonic acid. The solution is filtered and made alkaline by the addition of a concentrated solution of an alkaline hydroxide. The product of the reaction is extracted with a suitable solvent.

 It is isolated and purified, as previously indicated.

The intermediate compounds (IV) are obtained according to the known processes from the corresponding alcohols (vi)

Figure img00040001

 In particular, methanesulfonyloxy compounds (X '= -OSO 2 -CH 3) are obtained by the action of methanesulfochloride on alcohols (VI) in aprotic solvents, such as chloroform, dichloromethane or aromatic carbides, such as benzene. The operation is carried out in the presence of hydrophilic acceptors, such as fatty tertiary amines or pyridine bases.

Alcohols (vT) are obtained by reaction of 3-chloropropanol with a salt of an aryl-arylsulphonyl-4H-pyrazolol (II):

Figure img00050001

 The reaction is preferably carried out in an apolar aprotic solvent such as toluene, optionally supplemented with 20 to 50% of a polar aprotic solvent, such as DMF, which allows a better solubilization of the metal derivative (II).

 The latter is obtained by the action of an anhydrous alkoxide (1 mole) on the corresponding aryl-1 arylsulfonyl-4H-pyrazolol-3, in the solvent or solvent mixture defined above.

 The reaction between the metal derivative (II) (1 mole) and the 3-chloropropanol is preferably carried out in the presence of a slight excess of the latter (1.1 to 1.2 moles) at a temperature of between 80 and l200C. Under these conditions, the reaction is complete after 15 to 20 hours of heating. The product of the reaction is isolated as indicated in French Patent Application No. 2,301,250 for analogous compounds derived from 1,4-diaryl-pyrazoles.

 The aryl-arylsulfonyl-4H-pyrazolOb-3 (XII), as well as their metal salts (II), are intermediate synthetic compounds useful in particular for the preparation of the compounds of the basic application; they are substances not yet described.

The subject of the present invention is therefore the novel aryl-1 arylsulphonyl-4H-pyrazolols-3 of formula

Figure img00060001

in which
R1 represents a hydrogen or halogen atom, or a lower alkyl, lower alkoxy, or a trifluoromethyl restrain, meta or para position of the phenyl ring; R2> R3, R4 each represent a hydrogen or halogen atom, or a lower alkyl or lower alkoxy radical, or a trifluoromethyl radical; the term "lower alkyl or lower alkoxy" denoting a hydrocarbon of 1 to 3 carbon atoms and their alkaline salts of formula
Figure img00060002

wherein M is an alkali metal atom.

 More particularly, in these formulas, R 1, R 2, R 3 and R 4 may be identical or different and each represents a hydrogen, fluorine, chlorine or bromine atom, or a methyl, methoxy or trifluoromethyl radical.

 The compounds (XII) can be obtained by two methods.

1) According to the first method (method A), aryl-1 arylsulphonyl-4H-pyrazol-3-3 are obtained, according to known methods, by oxidation of aryl-1 arylmercapto-4-pyrazol-3 (XI). These are themselves unknown; their preparation can be carried out by a process similar to that described by the applicant, in the French patent application 2 301 250, for obtaining 1,4-diarylH-pyrazolols-3

Figure img00070001

 a) From a lower alkyl arylthioacetate, preferably ethyl, is prepared, according to a method known per se, an arylthio malonaléhydate of ethyl (VIII). For this purpose, the arylthioacétate (1 mole) is condensed and an excess of ethyl formate (2 to 3 moles), in the presence of a slight excess (1.1 to 1.3 moles) of a lower alkoxide of an alkaline metal, in a neutral solvent polar, preferably an aromatic carbide, such as benzene or toluene.

 The reaction is conducted first at low temperature (0-50C), then the mixture is left for 12 to 18 hours at room temperature.

The soda derivative of malonaléhydate (VIII) is thus obtained, which is extracted from the mixture by exhaustion with water. The aqueous solution is acidified with a strong mineral acid; the ethyl arylmercaptomalonaléhydate thus released is extracted with a suitable solvent. The combined extracts are washed with water and dried (Na 2 SO 4). Evaporation of the solvent leaves the crude malonaléhydate, which is sufficiently pure for the next operation. The yields are between 80 and 100%.

 b) According to the methods described in the aforementioned French application, an ethyl arylthiomalonaléhydate (VIII) is first condensed with an ethyl arylcarbazate (IX) to give a p- (2-ethoxycarbonyl-2-arylmercapto) -vinylcarbazate (X) which, without being isolated, is directly cyclized to aryl-1 arylmercapto-4-pyrazolol-3.

 The condensation of malonaléhydate (VIII) and arylcarbazate (IX) is conducted, as is known, by heating the two products, in equimolecular proportions, at the reflux of a solvent with a boiling point between 80 and 1500C and giving an azeotrope with the water of the reaction. Benzene or toluene is preferably used. The water is collected in a suitable separator, which makes it possible to follow the evolution of the reaction which is stopped when the quantity of water formed no longer increases.

 The cyclization of the intermediate (X) thus obtained can be carried out directly in the reaction mixture, by adding one mole (or a slight excess: 1.1-1.2 mole) of an alcoholate of a alkali metal, in solution in the corresponding alcohol.

 The reaction is conducted at reflux. The pyrazolol salt (XI) precipitates in the medium. After cooling, this salt is drained and then it is dissolved or suspended in water. Acidification of the medium, at pH 5, with an inorganic or organic acid, liberates the pyrazolol (XI) which is drained, washed with water and recrystallized in a suitable solvent.

 Industrially, it may be more convenient to cyclize the intermediate (X) with an alkali metal hydroxide, preferably potassium hydroxide. In this case, when the reaction between malonaléhydate (VIII) and arylcarbazate (IX) is complete, the solvent is distilled off under vacuum. The residue is dissolved in a lower alcohol, preferably ethanol, or methanol, and the solution is treated with potassium hydroxide in concentrated aqueous solution. A sufficient amount of reagent is used to neutralize the carbonic acid formed in the reaction. Operating at 50-60 C, the reaction is complete in 30 min.

The pyrazolol is isolated and purified as before.

 c) The oxidation of aryl-arylmercapto-4H-pyrazolols (XI) to aryl-arylsulfonyl-4H-pyrazolols (XII) can be carried out by any of the general methods used for this type of reaction.

The use of hydrogen peroxide as an oxidizing agent in an acetic medium is particularly convenient to use and is preferably used.

 In this case, the arylmercapto derivative (XI) (1 mole) is dissolved or suspended in 10 to 20 volumes of acetic acid. The mixture is stirred and added with an excess of perhydrol (3 to 5 moles), then it is brought to 80 C.

 The reaction is usually complete in 3 to 5 hours. It happens that, during this period, the raw material, initially insoluble, goes into solution, then the product of the reaction precipitates.

 After cooling, the mixture is diluted with an equal volume of water, the sulfone (XII) which is insoluble is drained, washed with water, dried and then recrystallized in a suitable solvent. Often, the crude product is sufficiently pure to be used directly in the preparation of the compounds according to the invention.

 2) The second method (method B) has two steps.

 Firstly, a lower alkyl arylsulfonylacetate (XIII), condensed with an arylhydrazine (XIV), provides a ss-arylsulfonylacetylhydrazine (XV).

In a second step, this arylsulfonylhydrazine is cyclized to the corresponding pyrazolol-3 by the action of a derivative of formic acid, corresponding to the general formula HC-X1X2X3

Figure img00090001

 The reaction of a lower alkyl arylsulfonylacetate (XIII) with an arylhydrazine (XIV) can not be obtained directly by simple heating of the two reagents.

 According to a claim of the invention, it is possible to carry out this condensation in the presence of a strong organic base, especially a fatty tertiary amine, such as triethylamine, tributylamine or triethanolamine which promotes the reaction.

 The mixture of alkyl arylsulfonylacetate (1 mole), arylhydrazine (1 mole) and tertiary base (1 mole) is heated at a temperature between 40 and 100 C. To ensure a complete reaction of the ester (XIII), it may be necessary to use an excess of hydrazine (XIV) (1.1 to 1.5 moles); the corresponding excess of tertiary amine is then used.

 In order to avoid the oxidation of hydrazine during the reaction, it is preferable to operate in a nitrogen atmosphere.

 The reaction can also be carried out in a solvent whose boiling point is at least equal to the reaction temperature.

An amount of solvent is then used such that all the reagents therein are at a concentration of between 10 and 50%.

 The solvents that can be used are preferably chosen from those known to promote the aminolysis of the esters, such as butanol, glycol, 2-methoxy ethanol and 2-ethoxyethanol; among them, those which are fully miscible with water are especially used, which facilitates the isolation of the product of the reaction.

 As the lower alkyl arylsulfonylacetates, the unbranched alkyl esters of C 1 to C 5 can be used, but it is recommended to employ preferably the methyl esters which are more reactive.

When these are used either by the dry route or in the presence of a solvent (for example glycol), operating under the conditions defined above, at 500C, the reaction is generally complete after 12 hours of heating. When the mixture is cooled, it is diluted with water, which causes the precipitation of the hydrazide (XV) which is drained, washed with water and recrystallized from a suitable solvent.

As has been mentioned, the heterocyclization of arylhydrazides (XV) can be carried out by treatment of the latter by means of formic acid-derived reagents which correspond to the general formula HC-X1X2X3. Among the compounds of this type most commonly used in similar reactions, mention may be made of: a) lower alkyl orthoformates (X1 = X2 = X3 = -OR), more especially
methyl or ethyl orthoformates, b) diacetals of dimethylformamide (X1 = X2 = OR, X3 = -N (CH3) 2), especially
dimethylaminoacetal (-OR = -O-CH3), c) bisdimethylaminoalkoxymethanes (Xl = X3 = -NtCH3) 2 X2 = OR), more specifically
bisdimethylaminomethoxymethane and bisdimethylamino-tert butoxymethane.

 The study of the use of these different reagents in the cyclization reaction of the compounds (XV) has shown that the use of orthoformates is not appropriate for this case. Indeed, under the conditions usually used for reactions of the same type (heating of a compound (XV) (1 mole) with an excess of ethyl or methyl orthoformate (3-4 moles), in the presence acetic acid), pyrazolols-3 (XII) are only obtained with poor yields.

Heating at 90-1000 ° C. for 5 to 12 hours, a hydrazide (XV) (1 mole), dissolved in DMF, with a dialkylketal of dimethylformamide (for example dimethylketal) or a bisdimethylaminoalkoxymethane (by example, bisdimethylamino-tert-butyloxymethane), in excess (1.1 to 1.5 moles), provides an enamine compound (XV)

Figure img00110001

 The latter, which is not isolated, is treated in aqueous solution with a strong mineral acid, which leads to the cyclized product (XII) with good yields (80-90%).

However, dialkylketals of dimethylformamide and bisdimethylaminoalkoxymethanes are comatose reagents and a relatively delicate and long preparation. Their use, as described
above, would be difficult to apply on an industrial scale.

According to a method according to the invention, it can be
overcome these disadvantages by preparing a solution in dimethylformamide of a bisdimethylaminoalkoxymethane which is not isolated. This
solution is used directly for the reaction with the hydrazide.

The principle of the preparation of bisdimethylaminoalkoxymethanes has been described by H. Bredereck et al. (Chem Ber 1968, 101, pages 41-50). The method (Equation A) consists in reacting, in a polar anhydrous medium, an alkali metal alkoxide on a dimethylformamidinium salt.
Equation A

Figure img00120001

Formamidinium salts are sometimes of a delicate preparation. However, arylsulfonates, especially benzenesulphonate (XVII) are readily obtained, according to H. ULERY (J. Org Chem 1965, 30, 2464-2465 (Equation B)
Equation B

Figure img00120002

 For example, heating is carried out at gentle reflux for 4 hours, 1 mole of benzene-sulfochloride in 2.5 to 3 times its volume of DMF. In these conditions, benzenesulfonate (XVII) is quantitatively formed and crystallizes. by cooling at a temperature below 300 C.

The isolation of this salt is difficult because of its hygroscopicity.

The Applicant has found that (a) under the conditions of reaction B, the hydrochloric acid formed remains
quantitatively in solution in DMF; b) if said solution is treated by the sufficient amount of an alcoholate
anhydrous alkali, to neutralize this acid and ensure the reaction of the
formamidinium salt according to equation A (ie 2 moles of alcoholate for
1 mole of benzene sulphochloride), we obtain a solution of one
dimethylaminoalkoxymethane which can be directly used for
heterocyclization of hydrazides - (XV).

 To conduct this reaction, a hydrazide (XV) Cl mole) is heated under a stream of nitrogen, at a temperature of between 80 and 1000 ° C, in the presence of an excess of the reagent prepared as indicated above, during 5 to 6 h. After cooling, the solution is diluted by 2 to 4 times its volume of water. It is brought to pH 3-4 by the addition of a strong mineral acid. The pyrazolol (II) which precipitates is filtered off and recrystallized in a suitable solvent.

 In this operation, to ensure a complete reaction of the hydrazide, an excess of reagent obtained is preferably used by treating 1.1 to 1.5 moles of benzene sulfochloride per 1 mole of hydrazide.

 The following nonlimiting examples are given to illustrate the preparation of the compounds according to the invention.

EXAMPLE I p-Chlorophenylsulfonyl-4-phenyl-1H-pyrazolol-3
This example illustrates the preparation, according to method A, of the pyrazolols-3 according to the invention.

 a) Ethyl p-chlorophenylthiomalonaldehyde 38 g of sodium (1.65 65 gram atom) are dissolved in 450 cm of absolute ethanol. The excess alcohol is removed by distillation under vacuum (12 mmHg) at 1000C in a nitrogen atmosphere. The sodium ethoxide 3 sec, thus obtained, is covered with 750 cm 3 of toluene and the mixture is vigorously stirred away from air and moisture; it is cooled externally. A mixture of ethyl p-chlorophenylthioacetate (346 g, 1.5 mol) and ethyl formate (222 g, 3 mol) is added dropwise over 1 hour at 0 ° to 50 ° C. ). The mixture is stirred for a further 2 hours at 5 ° C and then left overnight at room temperature.

 The suspension of the sodium enolate is taken up in 900 cm3 of ice water, with stirring. The aqueous phase is separated and the organic phase is washed with 100 cm 3 of NaOH. The alkaline extracts are combined with the aqueous phase, which is brought to pH 1 by the addition of concentrated HCl.

The product of the reaction is extracted with ether (3 × 500 cm 3). The organic solution is dried (Na 2 SO 4) and then filtered. The solvent is evaporated under vacuum (12 mmHg) at 400C. 377 g (yield 97%) of ethyl p-chlorophenylthiomalonalhydate sufficiently pure for the following operation are thus obtained.

b) p-Chlorophenylthio-4-phenyl-1H-pyrazolol-3
In a 1-liter flask (equipped with a stirrer, a dropping funnel and a separator, Dean-Stark connected to an ascending condenser), the mixture is heated under reflux with stirring: toluene ( 320 cm 3-phenyl-ethyl carbazate (144 g, 0.8 mole), p-chlorophenylthiomalone-ethyl hydrate (207 g, 0.8 mole) The reflux is maintained until the amount of water formed in the reaction no longer increases, which takes about 3 hours.

 The solvent is removed by distillation under vacuum (12 mmHg) at 1000C. The oily residue is dissolved in 220 cm3 of methanol. Solution 3 is brought to 500 ° C. and a solution of potassium hydroxide (158 g) in 100 cm 3 of water is added. This addition is conducted at such a rate that the heating caused by the reaction maintains a controllable reflux of the solvent, which takes about 1 hour. The mixture is stirred for another 30 minutes. After cooling, 1100 cm3 of water are added to dissolve the precipitated salts. The solution is cautiously acidified (significant release of carbon dioxide) using concentrated HCl (220 cm).

After stirring for 1 h at room temperature, the precipitate is filtered off, washed with water and dried under phosphoric vacuum. 181 g (75%) of p-chlorophenylthio-4-phenyl-1H-pyrazolo-3 are obtained,
F. 2140C. For analysis, a sample is recrystallized from 2-methoxy ethanol.

Analysis for C15H11ClN2OS (MW 302.78)
Calculated% C 59.50 H 3.66 N 9.25 C1 11.71
Found% C 59.52 H 3.86 N 9.05 C1 11.93 3
c) In a 3,000 cm three-necked flask equipped with a stirrer, a dropping funnel, a thermometer and an ascending condenser, a suspension of 181 g (0.6 mole) of the pyrazolol described in b), in 1800 cm of glacial acetic acid, is stirred, 180 cm (1.8 mole) of 30% perhydrol; the mixture is stirred and heated at 80 ° C. for 4 hours. During this time, the raw material goes into solution, and then the product of the reaction precipitates partially.

After returning to room temperature, the reaction mixture
3 nel is added with 1800 cm of water. The precipitate is drained, washed with water and dried at 80 ° C. 145 g (73%) of p-chlorophenylsulfonyl-4-phenyl-1H-pyrazolo-3, F.sub.22C are obtained.

Analysis for C15H11ClN2O3S (MW 334, 78)
Calculated% C 53.81 H 3.31 N 8.37 C1 10.59
Found% C 53.71 H 3.49 N 8.30 Cl 10.75
EXAMPLE II
By operating. as described in Example I b), and using suitably substituted ethyl arylthioacetates and ethyl aryl-3 carbazates, aryl-1 aryl-4-mercapto-3-pyrazolol whose constants are shown in Table II below have been prepared.

 By oxidation with perhydrol, as indicated in Example I (c), they lead to the corresponding sulfones whose constants are given in Table IV below.

EXAMPLE III p-Chlorphenylsulfonyl-4-phenyl-1H-pyrazolo-3
This example illustrates the preparation, according to method B, of the pyrazolols-3 according to the invention.

1) ss- (p-chlorophenylsulfonyl-2-acetyl) -phenylhydrazine
In a three-necked flask comprising a mechanical stirrer, a gas inlet, a thermometer and an ascending condenser equipped with a CaCl 2 guard, a mixture is heated at 500 ° C. for 12 hours, with stirring and a stream of anhydrous nitrogen. p-chlorophenylsulfonyl-2-methyl acetate (224 g, 0.9 moles), ethylene glycol (540 cm), phenylhydrazine (146 g, 1.35 moles) and triethylamine (180 cm3, 1.3 moles).

 From the beginning of heating, raw materials go into solution. The product of the reaction begins to precipitate after 4 hours.


3
The mixture is cooled and diluted with 1100 cm of water.

The precipitate is drained, washed with water and dried at 50 ° C.

 217 g (74% yield) of ss- (p-chlorophenylsulfonyl-2-acetyl) -phenylhydrazine, mp 1710C.

 For analysis, a sample is recrystallized from ethanol, F. 171 C.

Analysis for C14H13ClN2O3S CPM 324.79)
Calculated% C 51.77 H 4.03 N 8.63 C1 10.92 S 9.87
Found% C 51.65 H 4.14 N 8.46 C1 10.92 S 9.40
heterocyclisation
a) A solution of N, N, N ', N'-tetramethylformamidinium benzenesulphonate is prepared by adding 74.2 g (0.42 mol) of benzenesulfochloride to 210 cm of anhydrous DMF. The mixture is stirred, protected from moisture, for 2 hours at room temperature and then heated for 4 hours under reflux. The solution is cooled to 30 C. in order to avoid crystallization of the reagent which takes place at lower temperatures.

 (b) In a 3 1 to 4-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel, ascending condenser (equipped with a soda lime guard) and an inlet 32.8 g (0.84 atom-gram) of potassium in 670 cm3 of tert-butanol are dissolved with dry nitrogen.

 The refrigerant is placed in a downward position and connected to a receiving flask, itself connected to the vacuum of a water pump, via a desiccant tube (CaCl2) intended to prevent the introduction of moisture into the water. the device. The excess tert-butanol is removed under vacuum (20 mm) at 100 C.

 The dry potassium tert-butoxide, thus prepared, is supplemented with 210 cm 3 of anhydrous DMF. The suspension is stirred and maintained under a stream of dry nitrogen. The solution of tetramethylformaidinium benzenesulphonate prepared according to a) and maintained at 300 ° C. is added thereto. The mixture is stirred for 3 hours at room temperature, in a nitrogen atmosphere, protected from humidity.

 91 g (0.28 moles) of p- (p-chlorophenylsulfonyl-2-acetyl) -phenylhydrazine are rapidly added. By maintaining the nitrogen stream and stirring, the temperature is brought to and maintained at 900 ° C. for 5 hours during which the dimethylamine formed in the reaction is evolved.

 After cooling to room temperature, the mixture is taken up in 800 cm 3 of water. The solution is stirred and brought to pH 3-4 by addition of concentrated HCl (35 cm). The solid is drained, washed with water and dried at 80 ° C. 88 g (90%) of p-chlorophenyl-4-sulfonyl phenyl-1H-pyrazolol-3 are obtained, F. 216 C identical to the product described in FIG. example I c).

 By replacing potassium tertiobutylate in b) with the equivalent amount of sodium methoxide, the same product is obtained with identical yield.

EXAMPLE IV
By operating, as described in Example HI-1) from suitably substituted methyl p-arylsulfonylacetates and optionally substituted phenylhydrazines, the 2-s-arylsulfonyl-2-acetyl arylhydrazines, the constants of which are described, are obtained. in Table III below.

 The constants of 4-aryl-4-arylsulfonyl-3-pyrazolols are described in Table IV below.

These 4-aryl-4-arylsulphonyl-3-pyrazolols are used in Examples 1 to 23 which follow as synthesis intermediates for
the preparation of aryl-1 arylsulphonyl-4-yl-aminopropoxy-1H-pyrazoles of formula I with hypocholesterolemic and hypolipidemic activities.

EXAMPLE 1 p-Chlorophenylsulfonyl-4 &gamma; -dimethylaminopropoxy-3-phenyl-1H-pyrazole
(I, R1 = R2 = R3 = H, R4 = C1; R5 = R6 =
In a three-liter three-necked flask equipped with a stirrer, a dropping funnel, a thermometer and an ascending condenser, a solution of potassium tertiobutylate is prepared.
3 by dissolving 21.5 g (0.55 gram atom) of potassium in 440 cm of tert-butanol. 180 g (0.595 moles) of p-chlorophenylsulfonyl-phenyl-1H-pyrazolol-3 and 450 cm 3 of dimethylformamide are added thereto.

 The mixture is heated for 30 minutes under reflux. After cooling to 30 ° C., 78.5 g (0.646 mol) of N- (3-chloro-propyl) -dimethylamine are added. The reaction is completed by refluxing with stirring for 5 h.

Most of the solvents are removed by distil lation in a vacuum bath of the water pump (12 mmHg). The residue is
3 taken up by 400 cm of water. The aqueous suspension is extracted with
3 3 methylene chloride (400 cm, then 2 x 200 cm). The combined extracts are washed with 2N sodium hydroxide (3 × 75 cm) and then with a saturated solution of sodium chloride (200 cm). The organic solution is dried over K2CO3 and decolorized by stirring with animal black; it is filtered and concentrated to dryness under vacuum from the water pump. The residue is recrystallized from ethanol (400 cm). 183 g (yield 81%) of p-chlorophenyl-4-sulfonyl-3-dimethylaminopropoxy-phenyl-1H-pyrazole, mp 109 ° C. are obtained.

Analysis for C20H22ClN3O3S CPM 419.92)
Calculated% C 57.20 H 5.28 N 10.01 C1 8.44
Found% C 57.49 H 5.48 N 9.81 C1 8.51
methanesulfonate
3
183 g of the previous base, dissolved in 900 cm 3 of ethyl acetate, are added 41.9 g of methanesulfonic acid.

The precipitate is filtered off and recrystallized from an acetone-isopropyl ether mixture. 196 g (87% yield) of p-chlorophenylsulphonyl-4-dimethylaminopropoxy-1-phenyl-1H-pyrazole methanesulphonate are obtained.
F. 1510C.

Analysis for C20H22ClN3O3S, HO3SCH3 (MW 516.03)
Calculated% C 48.88 H 5.08 N 8.14
Found% C 48.82 H 5.13 N 8.37
The process described in Example 1 is repeated to prepare the compounds of Examples 2 to 17 from suitably substituted arylsulfonyl-4-aryl-1H-pyrazol-3-yl. The constants of the bases obtained as well as those of their methanesulphonates are described in Table I below.

EXAMPLE 18
a) A solution of potassium tertiobutylate is prepared by dissolving 4.8 g of metal (0.123 gram atom) in 100 cm 3 of tert-butanol. The excess solvent is removed by evaporation in vacuo, protected from moisture, in a nitrogen atmosphere. To the dry alcoholate thus obtained, a solution of 40 g of p-chlorophenylsulfonyl-4-phenyl-1H-pyrazolol-3 in a mixture of 90 cm 3 of DMF and 360 cm 3 of toluene is added. The mixture is stirred and heated for 30 minutes at reflux. 12.4 g (0.13 mol) of 3-chloropropanol are added to it. The reaction is terminated by refluxing and stirring for 20 h.

The solvents are removed by concentration in vacuo (12 mmHg) at 100 ° C. The residue is taken up in 90 cm 2N KOH to dissolve the unreacted pyrazolol. The aqueous suspension is extracted
3 and then 2 x 100 cm per 200 cm, then 2 x 100 of ethyl acetate. The combined organic solutions are washed with water, dried over K 2 CO 3 and decolorized by stirring with animal black. After filtration, they are evaporated to dryness at 100 ° C. under vacuum.

 The solid residue is recrystallized from ethanol (100 cm3). 16.5 g of p-chlorophenylsulphonyl-4-hydroxypropoxy-3-phenyl-1H-pyrazole, mp 1090 ° C., are obtained.

Analysis for C18H17ClN2O4S CPM 392.86)
Calculated% C 55.03 H 4.36 N 7.13 C1 9.03 S 8.16
Found% C 54.81 H 4.43 N 7.28 C1 9.22 S 8.10
b) A solution of 13 g of the above alcohol (0.035 mol) in 70 cm3 of methylene chloride is supplemented with 5.4 g (0.053 mol) of triethylamine. The mixture is stirred and cooled to -10 ° C. 4.5 g (0.039 mol) of methanesulfochloride are added dropwise thereto. After stirring for 30 min at 0-5 C, the solution is poured over 25 cm of ice water. The organic phase is separated by decantation; it is washed successively with water, a solution of sodium bicarbonate and then again with water. It is dried (Na 2 SO 4), filtered and then evaporated to dryness under vacuum. The solid residue is recrystallized from 250 cm 3 of ethanol. 15.1 g of 4-p-chlorophenylsulfonyl-7-methanesulfonyloxypropoxy-3-phenyl-1H-pyrazole, m.p.

Analysis for ClgHl9ClN2O6S2 CPM 470.95)
Calculated% C 48.45 H 4.07 N 5.95 C1 7.53 S 13.62
Find% C 48.88 H 4.16 N 6.16 C1 7.75 S 13.22
c) 4.3 g of the above ester (0.009 mol) and 4.1 g of dimethylamine (0.09 mol) in 40 cm3 of ethanol are heated for 7 hours at 3 900 ° C. in a 100 cm steel autoclave .

 After cooling, the solvent and the excess amine are removed by concentration in vacuo.

 The residue is dissolved in 40 cm 3 of an N-methanesulphonic acid solution. The solution is filtered to separate a slight insoluble material, extracted with ether (3 × 20 cm 3) and then made alkaline by addition of sodium hydroxide solution. The precipitate is extracted with methylene chloride (3 × 50 cm 3). The combined organic solutions are washed with water and then dried (K 2 CO 3). After filtration, they are concentrated to dryness under vacuum.

3.1 g (81% yield) of p-chlorophenylsulfonyl-4-dimethylaminopropoxy-3-phenyl-1H-pyrazole, m.p. 1090C, identical to the product described in Example 1, are obtained.

EXAMPLE 19 p-Chlorophenylsulfonyl-4 &gamma; -morpholinopropoxy-3-phenyl-1H-pyrazole
7 g (0.015 mole) of the ester prepared according to Example 18 b)
and 7.8 g (0.09 mol) of morpholine are heated for 8 hours at 950C. excess
of amine is distilled off under vacuum (12 mmHg) at 100.degree.
is dissolved in 100 cm of 0.5N methanesulfonic acid. After filtration,
the solution is made alkaline by adding sodium hydroxide solution. The product
of the reaction is isolated as described in Example 18c). The base
3
crude is recrystallized from 80 cm 3 of ethanol. We obtain 6.3 g (yield
92%) of p-chlorophenylsulphonyl-4-t-morpholinopropoxy-3-phenyl-1H
pyrazole, F. 1440C.

Analysis for C22H24ClN3O4S CPM 461.96)
Calculated% C 57.20 H 5.24 N 9.10 C1 7.68 S 6.94
Found% C 57.23 H 5.28 N 9.24 C1 7.83 S 6.70
methanesulfonate
3
5.8 g of base, dissolved in 200 cm 3 of acetone, are added 1.2 g of methanesulfonic acid. The precipitate is drained and recrystallized in 120 cm3 of ethanol. 6.3 g (89% yield) of salt are obtained, mp 2250 ° C.

Anslyse for C22H24ClN3O4S, HO3SCH3 (MW 558.87)
Calculated% C 49.50 H 5.06 N 7.53 Cl 6.35 S 11.49
Found% C 49.88 H 5.18 N 7.50 Cl 6.34 S 11.25
EXAMPLE 20 p-Chlorophenylsulfonyl-4 &gamma; 3-methylaminopropoxy-1-phenyl-1H-pyrazole
15 g (0.032 mol) of the ester described in Example 18 b) and 32 g of 33% aqueous methylamine are dissolved in 150 cm3 of ethanol.

The mixture is heated for 7 hours at 900 ° C. in an autoclave. After cooling, the reaction product is isolated as described in Example 18c). It is purified by recrystallization from hexane. 19 g (83% yield) of p-chlorophenylsulfonyl-4-ylmethylaminopropoxy-3-phenyl-1H-pyrazole are obtained,
F. 740C.

Analysis for ClgH20ClN3O3S (MW 405.90)
Calculated% C 56.22 H 4.97 N 10.35 Cl 8.74 S 7.90
Found% C 56.00 H 5.03 N 10.37 Cl 8.68 S 8.10
methanesulfonate
8 g of base, dissolved in 160 cm 3 of ethyl acetate, are added 1.9 g of methanesulfonic acid. The precipitate is drained and recrystallized from acetone. 8.4 g of salt are obtained, mp 1480 ° C.

Analysis for C14H20ClN3O3S, HO3SCH3 (MW 502, 00)
Calculated% C 47.85 H 4.82 N 8.37 Cl 7.06 S 12.77
Found% C 47.89 H4.97 N8.63 Cl 7.22 S 12.89
EXAMPLE 21 p-Chlorophenylsulfonyl-4 &gamma; -ethylaminopropoxy-3-phenyl-1H-pyrazole
7.9 g (0.017 mole) of ester described in Example 18 b) and 7.6 g (0.17 mole) of ethylamine, dissolved in 100 cm 3 of ethanol, are heated for 7 hours at 90.degree. C in an autoclave. The product of the reaction is isolated as indicated in Example 18c). It is purified by recrystallization from isopropyl ether. 6 g (85% yield) of p-chlorophenylsulfonyl-4 &gamma; 3-ethylaminopropoxy-1-phenyl-1H-pyrazole, m.p.
Analysis for C20H22ClN3O3S (PM 419, 92)
Calculated% C 57.20 H 5.28 N 10.00 Cl 8.44- S 7.64
Found% C 56.90 H 5.21 N 10.05 Cl 8.36 S 8.00
methanesulfonate
5.8 g of base, dissolved in 200 cm 3 of ethyl acetate, are added 1.3 g of methanesulfonic acid. The precipitate is recrystallized from acetone. 6.3 g (88% yield) of the salt are obtained,
F. 1490C.

Analysis for C20H22ClN3O3S, HO3SCH3 (MW 516.03)
Calculated% C 48.87 H 5.08 N 8.14 C1 6.87 S 12.43
Found% C 48.65 H5.08 N 8.20 Cl 7.15 S 12.44
EXAMPLE 22 p-Chlorophenylsulfonyl-4-phenyl-1 &gamma; 3-Piperidinopropoxy-1H-pyrazole
6.85 g of the mesyl ester described in Example 18 (b) and 7 g of piperidine are heated for 4 hours at 1000 ° C. in a water bath. The excess of piperidine is distilled off under vacuum. The product of the reaction is isolated as indicated in Example 18c). It is purified by recrystallization from isopropyl ether (150 cm3). 3.7 g of base are obtained, melting in two stages: F.sub.155.degree. C., solidification, then F.sub.160 C.

Analysis for C23H26ClN3O3S CPM 459.98)
Calculated% C 60.05 H 5.70 C1 7.71 S 6.97
Find% C 60.40 H 5.81 C1 7.79 s 6.95
3.3 g of the base, dissolved in 100 cm3 of ethyl acetate, are added 2 cm of a 4N solution of HCl in ethanol.

The precipitate is drained and dried in the phosphoric vacuum. 3.5 g of hydrochloride, F. 206 C.

EXAMPLE 23 p-Chlorophenylsulfonyl-4-phenyl-17-pyrrolidinopropoxy-3H-pyrazole
4.07 g of the methyl ester described in Example 18 b)
3 and 1.36 g of pyrrolidine dissolved in 20 cm 3 of toluene are heated for 3 hours at 900 ° C. The solvent is evaporated under vacuum, the residue is taken up in 20 cm3 of a 2N methanesulfonic acid solution. The product of the reaction is isolated as indicated in Example 18c). After recrystallization from isopropyl ether, 2.6 g of base are obtained, mp 125 ° C.

Analysis for C22H24ClN3O3S CPM 445.96)
Calculated% C 59.25 H 5.42 N 9.42
Found% C 59.40 H 5.53 N 9.63
3
2.45 g of this base, dissolved in 75 cm 3 of ethyl acetate, are added with 2 cm 4N HCl in ethanol. The precipitate is drained and dried in the phosphoric vacuum. 2.6 g of hydrochloride are obtained, mp 2100 ° C.

TABLE I

Figure img00220001

Figure img00220002

<SEP> Formulas <SEP> (PM) <SEP> Bases <SEP> Methaesulfonates
<tb> Ex <SEP> N <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> FC <SEP> (Yield <SEP>%) <SEP> Analyzes <SEP> FC
<tb><SEP> 2 <SEP> H <SEP> H <SEP> Cl <SEP> H <SEP> C20H22ClN3O3S <SEP> C <SEP> H <SEP> N <SEP> S
<tb><SEP> (419.92) <SEP> Calc. <SEP>% <SEP> 57.20 <SEP>;<SEP> 5.28 <SEP>;<SEP> 10.01 <SEP>;<SEP> 7.64 <SEP> 164 <SEP><SEP> C
<tb><SEP> 112 <SEP> C <SEP> (80) <SEP> (a) <SEP> Tr. <SEP>% <SEP> 56.91 <SEP>;<SEP> 5.40 <SEP>;<SEP> 10.06 <SEP>;<SEP> 8.00 <SEP> (isopropanol)
<tb><SEP> C <SEP> H <SEP> N <SEP> S <SEP> 165 <SEP> C
<tb><SEP> 3 <SEP> H <SEP> Cl <SEP> H <SEP> H <SEP> C20H22ClN3O3S <SEP> Calc. <SEP>% <SEP> 57.20 <SEP>;<SEP> 57.28 <SEP>;<SEP> 10.01 <SEP>;<SEP> 7.64 <SEP> acetone <SEP> (1 <SEP> v.)
<tb><SEP> (419.92) <SEP> Tr. <SEP>% <SEP> 56.90 <SEP>;<SEP> 5.32 <SEP>;<SEP> 10.10 <SEP>;<SEP> 7.76 <SEP> acetate <SEP> of ethyl <SEP> (2 <SEP> v.)
<tb><SEP> C <SEP> H <SEP> N <SEP> S <SEP> 144 <SEP> C
<tb><SEP> 134 <SEP> C <SEP> (80) <SEP> (b) <SEP> Calc. <SEP>% <SEP> 59.53 <SEP>;<SEP> 5.50 <SEP>;<SEP> 10.42 <SEP>;<SEP> 4,71 <SEP> (ethanol)
<tb><SEP> 4 <SEP> H <SEP> H <SEP> H <SEP> F <SEP> C20H22FN2O3S <SEP> Tr. <SEP>% <SEP> 59.75 <SEP>;<SEP> 5.67 <SEP>;<SEP> 10.52 <SEP>;<SEP> 4.79
<tb><SEP> (403.27
<tb><SEP> 75 <SEP> C <SEP> (72) <SEP> (c)
<tb><SEP> C <SEP> H <SEP> N <SEP> S <SEP> 166 <SEP> C
<tb><SEP> 5 <SEP> H <SEP> H <SEP> H <SEP> Br <SEP> C20H22BrN3O3S <SEP> Calculation <SEP>% <SEP> 51.72 <SEP>;<SEP> 4.77 <SEP>;<SEP> 9.05 <SEP>;<SEP> 6.90 <SEP> (ethanol)
<tb><SEP> (464,38) <SEP> Tr. <SEP>% <SEP> 52,12 <SEP>;<SEP> 4.64 <SEP>;<SEP> 9.25 <SEP>;<SEP> 6.70
<tb><SEP> 114 <SEP> C <SEP> (77) <SEP> (d)
<tb> Table I (continued 1)

Figure img00230001

<SEP> Formulas <SEP> (PM) <SEP> Bases <SEP> Methanesulfonates
<tb> Ex <SEP> N <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> FC <SEP> (Yield <SEP>%) <SEP> Analyzes <SEP> FC
<tb><SEP> C21H24HN3O4S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> (Solvents <SEP> from <SEP> Recrystallization)
<tb><SEP> 6 <SEP> H <SEP> H <SEP> H <SEP> -OCH3 <SEP> (415,50) <SEP> Calc.% <SEP> 60.70 <SEP>;<SEP> 6.06 <SEP>;<SEP> 10.11 <SEP>;<SEP> 7.72 <SEP> 160 C
<tb><SEP> 100C <SEP> (68) <SEP> (c) <SEP> Tr. <SEP>% <SEP> 60.95 <SEP>;<SEP> 6.25 <SEP>;<SEP> 10.17 <SEP>;<SEP> 7.40 <SEP> (ethanol)
<tb><SEP> C21H25N3O3S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 166 C
<tb><SEP> 7 <SEP> H <SEP> H <SEP> H <SEP> -CH3 <SEP> (399,50) <SEP> Calc.% <SEP> 63,13 <SEP>;<SEP> 6.31 <SEP>;<SEP> 10.52 <SEP>;<SEP> 8.03 <SEP> (ethanol)
<tb><SEP> 111 C <SEP> (74) <SEP> (c) <SEP> Tr. <SEP>% <SEP> 63.20 <SEP>;<SEP> 6.46 <SEP>;<SEP> 10.59 <SEP>;<SEP> 7.96
<tb><SEP> C21H22F3N3O3S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 140C
<tb><SEP> 8 <SEP> H <SEP> H <SEP> CF3 <SEP> H <SEP> (453.28) <SEP> Calculation% <SEP> 55.62 <SEP>;<SEP> 4.89 <SEP>;<SEP> 9.27 <SEP>;<SEP> 7.07 <SEP> (acetate <SEP> ethyl)
<tb><SEP> 96 C <SEP> (76) <SEP> (c) <SEP> Tr. <SEP>% <SEP> 55.63 <SEP>;<SEP> 5.03 <SEP>;<SEP> 9.23 <SEP>;<SEP> 7.26
<tb><SEP> C20H23N3O3S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 165 <SEP> C
<tb><SEP> 9 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> (385.37) <SEP> Calc.% <SEP> 62.31 <SEP>;<SEP> 6.01 <SEP>;<SEP> 10.90 <SEP>;<SEP> 8.32 <SEP> (ethanol)
<tb><SEP> 97 C <SEP> (82) <SEP> (e) <SEP> Tr <SEP>. <SEP>% <SEP> 61, <SEP> 91 <SEP>;<SEP> 5.93 <SEP>;<SEP> 11.15 <SEP>;<SEP> 8.31
<tb><SEP> C20H21ClN3O3S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 170 C
<tb><SEP> 10 <SEP> H <SEP> H <SEP> Cl <SEP> Cl <SEP> (454,37) <SEP> Calc. <SEP>% <SEP> 52.86 <SEP>;<SEP> 4.66 <SEP>;<SEP> 9.25 <SEP>;<SEP> 7.06 <SEP> (ethanol)
<tb><SEP> 121 C <SEP> (69) <SEP> (c) <SEP> Tr. <SEP>% <SEP> 52.96 <SEP>;<SEP> 4.73 <SEP>;<SEP> 9.39 <SEP>;<SEP> 7.36
<tb> Table I (continued 2)

Figure img00240001

<SEP> Methanesulfonates
<tb><SEP> Forms <SEP> (PM) <SEP> Bases <SEP> FC
<tb> Ex <SEP> N <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> FC <SEP> (Yield <SEP>%) <SEP> Analyzes <SEP> (Solvents <SEP> of <SEP> recrystallization)
<tb> 11 <SEP> H <SEP> Cl <SEP> H <SEP> Cl <SEP> C20H21CL2N3O3S <SEP> C <SEP> H <SEP> N <SEP> Cl
<tb><SEP> (454,37) <SEP> Calc. <SEP>% <SEP> 52.86 <SEP>;<SEP> 4.66 <SEP>;<SEP> 9.25 <SEP>;<SEP>15.61;<SEP> 152 C
<tb><SEP> 130C <SEP> (70) <SEP> (c) <SEP> Tr <SEP>. <SEP>% <SEP> 53.04 <SEP>;<SEP> 4.70 <SEP>;<SEP> 9.46 <SEP>;<SEP>15.33;<SEP> (isopropanol)
<tb> 12 <SEP> H <SEP> H <SEP> Cl <SEP> -OCH3 <SEP> C21H24ClN3O4S <SEP> C <SEP> H <SEP> N <SEP> S
<tb><SEP> (449.95) <SEP> Calculation <SEP>% <SEP> 56.05 <SEP>;<SEP>5.38;<SEP> 9.34 <SEP>;<SEP> 7.13 <SEP> 163 C
<tb><SEP> 96 C <SEP> (80) <SEP> (c) <SEP> Tr. <SEP>% <SEP> 56,21, <SEP>;<SEP> 5.45 <SEP>;<SEP> 9.39 <SEP>;<SEP> 6.99 <SEP> (ethanol)
<tb> 13 <SEP> (4 ') Cl <SEP> H <SEP> H <SEP> Cl <SEP> C20H21Cl2N3O3OS <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 126 C
<tb><SEP> (454,37) <SEP> Calc. <SEP>% <SEP> 52.86 <SEP>;<SEP> 4.66 <SEP>;<SEP> 9.25 <SEP>;<SEP> 7.06 <SEP> Acetones <SEP> (3 <SEP> vol.)
<tb><SEP> 138 C <SEP> (77) <SEP> (d) <SEP> Tr <SEP>. <SEP>% <SEP> 52.96 <SEP>;<SEP> 4.70 <SEP>;<SEP> 9.28 <SEP>;<SEP> 7,17 <SEP> Acetate <SEP> of ethyl <SEP> (7 <SEP> vol.)
<tb> 14 <SEP> (4 ') F <SEP> H <SEP> H <SEP> Cl <SEP> C20H21ClFN3O3S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 134 C
<tb><SEP> (437.91) <SEP> Calculation <SEP>% <SEP> 54.85 <SEP>;<SEP> 4.83, <SEP> 9.60 <SEP>;<SEP> 4.34 <SEP> (acetone)
<tb><SEP> 136 C <SEP> (85) <SEP> (e) <SEP> Tr <SEP>. <SEP>% <SEP> 54.73 <SEP> 4.87 <SEP>;<SEP> 9.62 <SEP>;<SEP> 4.80
<tb> 15 <SEP> (4 ') H3CO <SEP> H <SEP> H <SEP> Cl <SEP> C21H24ClN3O4S <SEP> C <SEP> H <SEP> N <SEP> S <SEP> 117 C
<tb><SEP> (449.95) <SEP> Calc. <SEP>% <SEP> 56.05 <SEP>;<SEP> 5.38 <SEP>;<SEP> 9.34 <SEP>;<SEP> 7,13 <SEP> Acetone <SEP> (1 <SEP> vol. <SEP>)
<tb><SEP> 103 C <SEP> (74) <SEP> (c) <SEP> Tr <SEP>. <SEP>% <SEP> 56,21 <SEP>;<SEP> 5.51 <SEP>;<SEP> 9.40 <SEP>;<SEP> 7.26 <SEP> Acetate <SEP> Ethyl <SEP> (2 <SEP> vol.)
<tb> Table I (continued 3)

Figure img00250001

<SEP> Methanesulfonates
<tb><SEP> Formulas <SEP> (PM) <SEP> Bases <SEP> FC
<tb> Ex <SEP> N <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> FC <SEP> (Yield <SEP>%) <SEP> Analyzes <SEP> (Solvent <SEP> of <SEP> recrystallization)
<tb><SEP> 16 <SEP> (4 ') H3C <SEP> H <SEP> H <SEP> Cl <SEP> C21H24ClN3O3S <SEP> C <SEP> H <SEP> N <SEP> S
<tb><SEP> (433.95) <SEP> Calc. <SEP>% <SEP> 58.12 <SEP>;<SEP> 5.57 <SEP>;<SEP> 9.68 <SEP>;<SEP> 7.39 <SEP> 172 C
<tb><SEP> 95 C <SEP> (55) <SEP> (f) <SEP> Tr. <SEP>% <SEP> 58.06 <SEP>;<SEP> 5.60 <SEP>;<SEP> 9.53 <SEP>;<SEP> 7.44 <SEP> Acetone] (1 <SEP> vol.)
<tb><SEP> Acetates <SEP> of Ethyla <SEP> (3 <SEP> vol.)
<tb><SEP> 17 <SEP> (3 ') F3C <SEP> H <SEP> H <SEP> Cl <SEP> C21H21ClF3N3O3S <SEP> C <SEP> H <SEP> N
<tb><SEP> (487.92) <SEP> Calc. <SEP>% <SEP> 51.59 <SEP>;<SEP> 4.34 <SEP>;<SEP> 8.61 <SEP> 139 C
<tb><SEP> 138 C <SEP> (70) <SEP> (c) <SEP> Tr <SEP>. <SEP>% <SEP> 51.71 <SEP>;<SEP> 4.37 <SEP>;<SEP> 8.65 <SEP> (acetate <SEP> ethyl)
<tb> Recrystallization solvents: a) ethanol (1 vol.) - isopropyl ether (1 vol.);
b) ethanol (1 vol.) - isopropyl ether (2 vol.);
c) isopropyl oxide;
d) ethanol;
e) 2-propanol;
f) heptane.

TABLE II

Figure img00260001

Figure img00260002

<tb> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> F C. <SEP> Yield <SEP> Solvent <SEP> of <SEP> recrystallization
<tb> H <SEP> C1 <SEP> H <SEP> H <SEP> 197 <SEP> 31 <SEP> Ethanol
<tb> H <SEP> H <SEP> H <SEP> F <SEP> 174 <SEP> 44 <SEP> Ethanol
<tb> H <SEP> H <SEP> H <SEP> H3C <SEP> 179 <SEP> 54 <SEP> Acetone
<tb> H <SEP> H <SEP> H <SEP> H <SEP> 198 <SEP> 56 <SEP> Ethanol
<tb> H <SEP> H <SEP> C1 <SEP> Cl <SEP> 220 <SEP> 66 <SEP> Methoxy-2 <SEP> Ethanol
<tb> Cl <SEP> H <SEP> u <SEP> Cl <SEP> 212 <SEP> 48 <SEP> butanone-2
<tb> F <SEP> H <SEP> H <SEP> Cl <SEP> 196 <SEP> 49 <SEP> Ethanol
<tb> H3CO- <SEP> H <SEP> H <SEP> Cl <SEP> 234 <SEP> 74 <SEP> butanone-2
<tb> H3C- <SEP> H <SEP> R <SEP> Cl <SEP> 250 <SEP> 49 <SEP> butanone-2
<Tb>
TABLE III

Figure img00270001

Figure img00270002

<tb> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> F C. <SEP> Yield <SEP>% <SEP> Solvent <SEP> of <SEP> recrystallization
<tb> (3) <SEP> F3C- <SEP> H <SEP> H <SEP> Cl <SEP> 168 <SEP> 41 <SEP> methanol
<tb> H <SEP> H <SEP> Cl <SEP> H <SEP> 169 <SEP> 36 <SEP> Ethanol
<tb> H <SEP> H <SEP> H <SEP> Br <SEP> 175 <SEP> 52 <SEP> Acetone
<tb> H <SEP> H <SEP> H <SEP> CH3O- <SEP> 168 <SEP> 40 <SEP> methanol
<tb> H <SEP> H <SEP> F3C- <SEP> H <SEP> 183 <SEP> 54 <SEP> Ethanol
<tb> H <SEP> H <SEP> H <SEP> H <SEP> 180 <SEP> 45 <SEP> Methoxy-2 <SEP> Ethanol
<tb> H <SEP> H <SEP> H <SEP> Cl <SEP> 162 <SEP> 20 <SEP> Ethanol
<tb> H <SEP> H <SEP> Cl <SEP> H3CO- <SEP> 190 <SEP> 44 <SEP> Ethanol
<tb> TABLE IV

Figure img00280001

Figure img00280002

<SEP> Method <SEP> FC <SEP> Analyzes
<tb> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> (Yield <SEP>%) <SEP> Formula <SEP> gross <SEP> (PM) <SEP> Calculated <SEP>% <SEP > Found <SEP>%
<tb><SEP> C16H10ClF3N2O3S <SEP> C <SEP> 47.71 <SEP> C <SEP> 47.84
<tb> (3) <SEP> CF30 <SEP> H <SEP> H <SEP> Cl <SEP> B <SEP> (77) <SEP> 251 <SEP> H <SEP> 2.50 <SEP> H <SEP> 2.63
<tb><SEP> 402.78 <SEP> N <SEP> 6.96 <SE> N <SEP> 7.08
<tb><SEP> C <SEP> 53.81 <SEP> C <SEP> 54.04
<tb> H <SEP> H <SEP> Cl- <SEP> H <SEP> B <SEP> (81) <SEP> 224 <SEP> C15H11ClN2O3S <SEP> H <SEP> 3.31 <SEP> H <SEP> 33.4
<tb><SEP> 334.78 <SEP> N <SEP> 8.37 <SEP> N <SEP> 8.47
<tb><SEP> C <SEP> 53.81 <SEP> C <SEP> 54.10
<tb> H <SEP> Cl <SEP> H <SEP> H <SEP> A <SEP> (88) <SEP> 215 <SEP> C15H11ClN2O3S <SEP> H <SEP> 3.31 <SE> H <SE > 3.47
<tb><SEP> 334.78 <SEP> N <SEP> 8.37 <SEP> N <SEP> 8.47
<tb> Table IV (continued 1)

Figure img00290001

<SEP> Method <SEP> FC
<tb> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> (Yield <SEP>%) <SEP> Formula <SEP> gross <SEP> (PM) <SEP> calculated <SEP>% <SEP > Found <SEP>%
<tb><SEP> C15H11FN2O3S <SEP> C <SEP> 56.59 <SEP> C <SEP> 56.65
<tb> H <SEP> H <SEP> H <SEP> F <SEP> A (92) <SEP> 213 <SEP> 318.32 <SEP> H <SEP> 3.48 <SE> H <SEP> 3.64
<tb><SEP> N <SEP> 8.80 <SEP> N <SEP> 8.91
<tb><SEP> C15H11bRN2O3S <SEP> C <SEP> 47.50 <SEP> C <SEP> 47.56
<tb> H <SEP> H <SEP> H <SEP> Br <SEP> B <SEP> (84) <SEP> 230 <SEP> 379 <SEP>, <SEP> 24 <SEP> H <SEP> 2 , 92 <SEP> H <SEP> 3.10
<tb><SEP> N <SEP> 7.39 <SEP> N <SEP> 7.44
<tb><SEP> C16H14N2O4S <SEP> C <SEP> 58.17 <SEP> C <SEP> 57.92
<tb> H <SEP> H <SEP> H <SEP> OCH3 <SEP> B <SEP> (70) <SEP> 228 <SEP> 330.35 <SEP> H <SEP> 4.27 <SEP> H <SEP> 4.27
<tb><SEP> N <SEP> 8.48 <SEP> N <SEP> 8.49
<tb><SEP> C16H14N2O3S <SEP> C <SEP> 61.13 <SEP> C <SEP> 60.95
<tb> H <SEP> H <SEP> H <SEP> CH3 <SEP> A <SEP> (92) <SEP> 229 <SEP> 314.35 <SEP> H <SEP> 4.49 <SE> H <SEP> 4.45
<tb><SEP> N <SEP> 8.91 <SEP> N <SEP> 8.98
<tb><SEP> C16H11F3N2O3S <SEP> C <SEP> 52.17 <SEP> C <SEP> 52.50
<tb> H <SEP> H <SEP> CF3 <SEP> H <SEP> B <SEP> (78) <SEP> 212 <SEP> 368.33 <SEP> H <SEP> 3.01 <SEP> H <SEP> 3.17
<tb><SEP> N <SEP> 7.61 <SEP> N <SEP> 7.72
<tb><SEP> A <SEP> (93) <SEP> C15H12N2O3S <SEP> C <SEP> 59.98 <SEP> C <SEP> 60.21
<tb> H <SEP> H <SEP> H <SEP> H <SEP> 248 <SEP> 300.33 <SEP> H <SEP> 4.03 <SE> H <SEP> 4.07
<tb><SEP> B <SEP> (83) <SEP> N <SEP> 9.33 <SEP> N <SEP> 9.25
<tb> Table IV (continued 2)

Figure img00300001

<SEP> Method <SEP> FC <SEP> Analyzes
<tb> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> (Yield <SEP>%) <SEP> Formula <SEP> gross <SEP> (PM) <SEP> Calculated <SEP>% <SEP > Found <SEP>%
<tb> H <SEP> H <SEP> Cl <SEP> Cl <SEP> A <SEP> (92) <SEP> 240 <SEP> C15H10ClN2O3S <SEP> C <SEP> 48.79 <SEP> C <SEP > 48.67
<tb><SEP> 369.23 <SEP> H <SEP> 2.73 <SE> H <SEP> 2.71
<tb><SEP> N <SEP> 7.39 <SEP> N <SEP> 7.82
<tb> H <SEP> Cl <SEP> H <SEP> Cl <SEP> B <SEP> (57) <SEP> 211 <SEP> C15H10Cl2N2O3S <SEQ> C48.79 <SEP> C <SEP> 48.98
<tb><SEP> 369.23 <SEP> H <SEP> 2.73 <SEP> H <SEP> 2.86
<tb><SEP> N <SEP> 7.59 <SE> N <SEP> 7.57
<tb> H <SEP> H <SEP> Cl <SEP> OCH3 <SEP> B <SEP> (91) <SEP> 243 <SEP> C16H13ClN2O4S <SEP> C <SEP> 52.67 <SEP> C52.30
<tb><SEP> 364 <SEP> 80 <SEP> H <SEP> 3.59 <SEP> H <SEP> 3.60
<tb><SEP> N <SEP> 7.68 <SE> N <SEP> 7.77
<tb> (4) Cl- <SEP> H <SEP> H <SEP> Cl <SEP> A <SEP> (87) <SEP> 260 <SEP> C15H10Cl2N2O3S <SEP> C <SEP> 48.79 <SEP > C <SEP> 48.84
<tb><SEP> 369.23 <SEP> H <SEP> 2.73 <SEP> H <SEP> 2.76
<tb><SEP> N <SEP> 7.59 <SEP> N <SEP> 7.70
<tb> (4) F <SEP> H <SEP> H <SEP> Cl <SEP> A <SEP> (86) <SEP> 261 <SEP> C15H10ClFN2O3S <SEP> C <SEP> 51.07 <SEP > C <SEP> 51.10
<tb><SEP> 352.77 <SEP> H <SEP> 2.86 <SEP> H <SEP> 2.90
<tb><SEP> N <SEP> 7.94 <SEP> N <SEP> 8.02
<tb> (4) OCH3 <SEP> H <SEP> H <SEP> Cl <SEP> A <SEP> (89) <SEP> 224 <SEP> C16H13ClN2O4S <SEP> C <SEP> 52.67 <SEP> C <SEP> 52.99
<tb><SEP> 364.80 <SEP> H <SEP> 3.59 <SEP> H <SEP> 3.68
<tb><SEP> N <SEP> 7.68 <SEP> N <SEP> 7.60
<tb> (4) CR3- <SEP> H <SEP> H <SEP> Cl <SEP> A <SEP> (86) <SEQ> 232 <SEP> C16H13ClN2O3S <SEP> C <SEP> 55.09 <SEP > C <SEP> 55.09
<tb><SEP> 348.80 <SEP> H <SEP> 3.76 <SE> H <SEP> 3.79
<tb><SEP> N <SEP> 8.03 <SEP> N <SEP> 8.02
<Tb>

Claims (6)

  1.  wherein M is an alkali metal atom.
    Figure img00310002
    R2, R3, R4, each represents a hydrogen or halogen atom, or a lower alkyl or lower alkoxy radical, or a trifluoromethyl radical, the term "lower alkyl or lower alkoxy" denoting a radical of 1 to 3 carbon atoms; as well as their alkaline salts of formula
    R1 represents a hydrogen or halogen atom, or a lower alkyl, lower alkoxy, or a trifluoromethyl residue, in the meta or para position of the phenyl ring;
     in which
    Figure img00310001
     1. New aryl-1 arylsulfonyl-4H-pyrazolols-3 of Formula
  2. 2. New compounds according to claim 1, characterized in that R1, R2, R3 and R4 may be identical or different and each represents a hydrogen, fluorine, chlorine or bromine atom, or a methyl, methoxy radical. or trifluoromethyl.
  3. 3. p-Chlorophenylsulfonyl-4-phenyl-1H-pyrazolol-3 and its alkali salts.
  4. 4. Process for the Preparation of 4-Arylsulphonyl-1H-pyrazolol-3 Compounds of Formula
    Figure img00320001
     in which R1, R2, R3, R4 are as defined in claim 1 or 2, characterized in that it comprises two stages
     in a first step, a lower alkyl arylsulfonylacetate is condensed
    Figure img00320002
     (R = lower alkyl of 1 to 3 carbon atoms) with an arylhydrazine
    Figure img00320003
     to obtain p-arylsulfonylacetylhydrazine
    Figure img00320004
     and, in a second step, the arylsulfonylhydrazine is cyclized to pyrazolol-3 corresponding to formula XII by the action of a diacetal of dimethylformamide or of a bisdimethylaminoalkoxymethane.
  5. 5. Process according to claim 4, characterized in that the condensation is carried out in the presence of a strong organic base, in particular a fatty tertiary amine.
  6. 6. Process for preparing aryl-1 arylsulfonyl-4H-pyrazol-3-compounds of formula
    Figure img00330001
     in which R1, R2, R3, R4 are as defined in claim 1 or 2, characterized in that it comprises the oxidation of a corresponding aryl-1 arylmercapto-4-pyrazolol-3 of formula
    Figure img00330002
     by means of hydrogen peroxide in acetic medium.
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WO1994013643A1 (en) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrazoles and pyrazolopyrimidines having crf antagonist activity
US6005109A (en) * 1997-10-30 1999-12-21 Pflizer Inc. Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
US6103900A (en) * 1992-12-17 2000-08-15 Pfizer Inc Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
WO2006021462A1 (en) * 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
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EP1829875A1 (en) 2006-03-01 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Pyrazole derivatives as sigma receptor inhibitors
EP1829867A1 (en) 2006-03-03 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Imidazole compounds having pharmaceutical activity towards the sigma receptor
JP2009528315A (en) * 2006-03-01 2009-08-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ Pyrazole derivatives as sigma receptor inhibitors
US8293740B2 (en) 2004-08-27 2012-10-23 Laboratories Del Dr. Esteve, S.A. Sigma receptor inhibitors
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
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US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
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WO1994013643A1 (en) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrazoles and pyrazolopyrimidines having crf antagonist activity
US5712303A (en) * 1992-12-17 1998-01-27 Pfizer Inc. Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
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US6103900A (en) * 1992-12-17 2000-08-15 Pfizer Inc Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
US6441018B2 (en) 1992-12-17 2002-08-27 Pfizer Inc. Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
US6448265B1 (en) 1992-12-17 2002-09-10 Pfizer, Inc. Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
US6005109A (en) * 1997-10-30 1999-12-21 Pflizer Inc. Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
WO2006021462A1 (en) * 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
US8470867B2 (en) 2004-08-27 2013-06-25 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
US8314096B2 (en) 2004-08-27 2012-11-20 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
US8293740B2 (en) 2004-08-27 2012-10-23 Laboratories Del Dr. Esteve, S.A. Sigma receptor inhibitors
EP2325174A1 (en) 2004-08-27 2011-05-25 Laboratorios Del. Dr. Esteve, S.A. Sigma receptor inhibitors
JP2008510767A (en) * 2004-08-27 2008-04-10 ラボラトリオス デル ドクトール エステベ エセ.ア. Sigma receptor inhibitor
AU2005276590B2 (en) * 2004-08-27 2011-05-19 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
US7696199B2 (en) 2004-08-27 2010-04-13 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
JP2009528315A (en) * 2006-03-01 2009-08-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ Pyrazole derivatives as sigma receptor inhibitors
US8202872B2 (en) * 2006-03-01 2012-06-19 Laboratorios Del Dr. Esteve, S.A. Pyrazole derivatives as sigma receptor inhibitors
EP1829875A1 (en) 2006-03-01 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Pyrazole derivatives as sigma receptor inhibitors
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US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
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