ES2326725B1 - USE OF SUBSTITUTED PIRAZOLINE COMPOUNDS FOR THE TREATMENT OF FOOD DISORDERS, INCLUDING OBESITY OR METABOLIC SYNDROME IN PATIENTS WITH DEVELOPED DIABETES. - Google Patents

Abstract

Use of substituted pyrazoline compounds for the treatment of eating disorders, which include obesity or metabolic syndrome in patients with diabetes developed.

The present invention relates to the use of substituted pyrazoline compounds for the treatment of eating disorders, which include obesity or syndrome metabolic in patients with developed diabetes.

Description

Use of substituted pyrazoline compounds for the treatment of eating disorders, which include obesity or the metabolic syndrome in patients with developed diabetes.

Field of the Invention

The present invention relates to the use of substituted pyrazoline compounds for the treatment of eating disorders, which include obesity or syndrome metabolic, in human and animal patients with diabetes developed.

Background of the invention

Diabetes, especially type II, has been Converted - simultaneously with obesity and syndrome metabolic - in a very important health problem. Is a widespread disease or a state of health that involves large risks for a significant part of the population doing very Interesting diabetes treatment.

Description of the invention

An object of the present invention is provide compounds for use as active ingredients in medications, which are suitable for the treatment of disorders dietary, which include obesity or metabolic syndrome in patients with developed diabetes.

Said object has been achieved using compounds of substituted pyrazoline of general formula I given below, the stereoisomers, the corresponding salts and the solvates corresponding thereof.

It seems that these compounds have an effect marked in eating disorders that include obesity or Metabolic syndrome in patients with developed diabetes.

Therefore, in one of its aspects this invention relates to the use of a pyrazoline compound substituted of general formula I

one

in the that

quad

R1 represents hydrogen or an alkyl group C 1-4, linear or branched, substituted or not substituted, saturated or unsaturated,

quad

R 2, R 3 and R 4 each of them independently represent hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, SO 2 R 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 for each substituent independently represent alkyl C 1-6 linear or branched,

quad

R 5 and R 6 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, - (C = O) -R 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 R 11, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R11 for each substituent represent independent linear C 1-6 alkyl or branched;

quad

R 7 represents hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 R 11, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R11 for each substituent represent independent linear C 1-6 alkyl or branched;

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof,

quad

for the manufacture of a medicine for treatment of eating disorders, which include obesity or metabolic syndrome in patients with diabetes developed.

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It is very preferred if these compounds according to Formula I applies the following condition (exclusion):

with the condition of

quad

if R 1 and R 7 are H and R 5 and R 6 both represent Cl at position 3 and 4 of the phenyl ring, none of R2, R3 and R4 may represent F in position 4 of the phenyl ring if the other two of R2, R3 and R4 both represent H.

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These compounds have a surprising effect. in eating disorders, which include obesity (which gives place to weight loss) or metabolic syndrome (decreased lipid parameters) and this seems likely to be highly beneficial for patients with diabetes developed.

In addition, the pyrazoline compounds used they are distinguished by a wide spectrum of beneficial effects, while at the same time show relatively few effects no desired, that is, effects that do not contribute positively to or that even interfere with the patient's well-being.

In another of its aspects, the present invention refers to the use of a substituted pyrazoline compound of general formula I

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2

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in the that

quad

R1 represents hydrogen or an alkyl group C 1-4, linear or branched, substituted or not substituted, saturated or unsaturated,

quad

R 2, R 3 and R 4 each of them independently represent hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, SO 2 R 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 for each substituent independently represent alkyl C 1-6 linear or branched,

quad

R 5 and R 6 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, - (C = O) -R 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 R 11, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R11 for each substituent represent independent linear C 1-6 alkyl or branched;

quad

R 7 represents hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 R 11, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R11 for each substituent represent independent linear C 1-6 alkyl or branched;

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof,

quad

for the manufacture of a medicine for treatment of eating disorders, which include obesity or metabolic syndrome in patients with diabetes developed.

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In a preferred embodiment for these compounds according to formula I the following condition applies (exclusion):

none of R2, R3 and R4 can represent SO 2 R 8 at the position for, where R 8 is methyl.

As defined here, the treatment also It includes prophylaxis.

Diabetes, especially type diabetes II, is a very serious health problem. On the one hand diabetes a sometimes it develops based on aspects of the metabolic syndrome as well as for eating disorders such as obesity; on the other the diabetes itself is the biggest risk factor in development of the metabolic syndrome in the first place. A big problem for Any patient / person who has acquired diabetes is the subsequent weight loss because it seems that diabetes influences negatively weight loss, which includes the treatment of eating disorders, especially obesity, which on the other hand It is very desirable to reduce cardiovascular risk. Keep active in these conditions is one of the biggest and surprising Advantages of the compounds according to the general formula I, II and their combination with a compound according to the general formula X.

The metabolic syndrome is described in detail by Eckel et al., The Lancet, Vol. 365 (2005), 1415-1428, included here for reference. Yet agreeing with Eckel et al. there is no definition homogeneous definition of metabolic syndrome that can be clearly derived from the article and the WHO statements that the metabolic syndrome should be considered as a disease that Can and should be treated. The mentioned risk factors include diabetes, especially type II, intolerance to glucose and insulin resistance.

In a preferred embodiment of the present invention, the eating disorder to be treated in patients with a Developed diabetes is obesity.

In a preferred embodiment of the present invention, the eating disorder to be treated in patients with a Developed diabetes is the metabolic syndrome.

Preferred, linear or aliphatic groups branched, saturated or unsaturated, which may be substituted by one or more substituents, they can preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethynyl, Propenyl, propynyl, butenyl and butynyl.

In the context of this invention, it is understood that the alkyl and cycloalkyl radicals mean hydrocarbons saturated and unsaturated (but not aromatic), branched, not branched and cyclic, which may be unsubstituted, monosubstituted or polysubstituted. In these radicals, alkyl C1-2 represents C1- or C2- alkyl, alkyl C1-3 represents C1-, C2- or C3 alkyl, alkyl C 1-4 represents C1-, C2-, C3- or C4 alkyl, C 1-5 alkyl represents C1-, C2-, C3- alkyl, C4-, or C5, C1-6 alkyl represents C1- alkyl, C2-, C3-, C4-, C5- or C6, C 1-7 alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7 alkyl, alkyl C 1-8 represents C1-, C2-, C3-, C4- alkyl C5-, C6-, C7- or C8-alkyl, alkyl C 1-10 - represents C1-, C2-, C3-, C4- alkyl, C5-, C6-, C7-, C8-, C9- or C10 and C 1-18 alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, alkyl C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18. Further, C 3-4 cycloalkyl represents C3- cycloalkyl or C4, C 3-5 cycloalkyl represents cycloalkyl C3-, C4- or C5-cycloalkyl, cycloalkyl C 3-6 represents C3-, C4-, C5- or cycloalkyl C6, C 3-7 cycloalkyl represents cycloalkyl C3-, C4-, C5-, C6- or C7-, C 3-8 cycloalkyl - represents C3-, C4-, C5-, C6-, C7- or C8 cycloalkyl, cycloalkyl C 4-5 represents C4- or C5 cycloalkyl, C 4-6 cycloalkyl represents C4- cycloalkyl, C5- or C6, C 4-7 cycloalkyl represents C4-, C5-, C6- or C7 cycloalkyl, cycloalkyl C 5-6 represents C5- or C6 cycloalkyl and C 5-7 cycloalkyl represents C5- cycloalkyl, C6- or C7-. With respect to cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are substituted by a heteroatom, S, N, or O. However, the monounsaturated or polyunsaturated cycloalkyls, preferably monounsaturated without a particular ring heteroatom they will be within the term cycloalkyl as long as the Cycloalkyl is not an aromatic system. The alkyl radicals and Cycloalkyl are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF2, CF3 or CH2OH) as well as pyrazolinone, oxopirazolinone, [1,4] -dioxane or dioxolane.

Here, in relation to alkyl and cycloalkyl - a unless expressly defined otherwise - it is understood that the term substituted in the context of this invention means substitution of at least one hydrogen radical with F, Cl, Br, I, NH2, SH or OH, it is understood that "polysubstituted" radicals means that the substitution takes place both in different atoms as several times in the same atom with the same substituent or with different substituents, for example three times on the same atom of C, as in the case of CF_ {3}, or in different places, as in in case of -CH (OH) -CH = CH-CHCl2. The Particularly preferred substituents here are F, Cl and OH. With with respect to cycloalkyl, the hydrogen radical can be substituted also with O-C1-3 alkyl or alkyl C1-3 (in each case monosubstituted or polysubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3, methoxy or ethoxy.

It is understood that the term (CH 2) 3-6 means -CH_ {2} -CH_ {2} -CH_ {2} -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} - Y -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {-}  it is understood that (CH2) 1-4 means -CH_ {2} -, -CH_ {2} -CH_ {2} -, -CH_ {2} -CH_ {2} -CH_ {2} - and -CH 2 -CH 2 -CH 2 -CH 2 -, it is understood that (CH2) 4-5 means -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} - Y -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -, etc.

It is understood that an aryl radical means a ring system with at least one aromatic ring but without heteroatoms even in only one of the rings. The examples are phenyl, naphthyl, fluorantenyl, fluorenyl, tetralinyl or indanyl, in particular fluorenyl 9H or anthracenyl radicals, which can be unsubstituted, monosubstituted or polysubstituted.

It is understood that a heteroaryl radical means a heterocyclic ring system that has at least one non-ring saturated and may contain one or more heteroatoms of the group consisting of nitrogen, oxygen and / or sulfur and can also be monosubstituted or polysubstituted. Can be mentioned examples of the heteroaryl group that are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline

Here, in relation to aryl and heteroaryl, it is understood that substituted means the substitution of the aryl or heteroaryl by R, O, a halogen, preferably F and / or Cl, a CF 3, a CN, a NO 2, an NRR, a C 1-6 alkyl (saturated), a C 1-6 alkoxy, a C 3-8 cycloalkoxy, a C 3-8 cycloalkyl or a C 2-6 alkylene , meaning R hydrogen or
C 1-6 alkyl.

It is understood that the term "salt" means any form of active compound used according to the invention in the that an ionic form is assumed or charged and coupled with a counterion (a cation or an anion) or is in solution. Must also understood as complexes of the active compounds with other molecules and ions, in particular complexes that are complexed through ionic interactions. It especially includes physiologically salts acceptable, which is used equivalent to salts pharmacologically acceptable.

The term "physiologically acceptable salt" means in the context of this invention any salt that is tolerates physiologically (most of the time means no it is especially toxic not caused by the counterion) if used appropriately for a treatment especially if used in, or It applies to humans and / or mammals.

These physiologically acceptable salts can form with cations or bases and it is understood that in the context of this invention means salts of at least one of the compounds used according to the invention - normally an acid (deprotonated) as an anion with at least one preferably inorganic cation, which Physiologically tolerated, especially if used in humans and / or mammals Metal salts are particularly preferred alkaline and alkaline earth, and also those salts of NH4, but in particular (mono) - or (di) sodium salts, (mono) - or (di) potassium, magnesium or calcium.

These physiologically acceptable salts can also be formed with anions or acids it is understood that in the context of this invention mean salts of at least one of the compounds used according to the invention - normally protonated, by example in nitrogen- like the cation with at least one anion that they are physiologically tolerated - especially if used in humans and / or mammals. It is understood by this, in particular, in the context of this invention, the salt formed with a tolerated acid physiologically, that is salts of the particular active compound with organic and inorganic acids that are physiologically tolerated especially if they are used in humans and / or mammals. Examples of salts Physiologically tolerated of particular acids are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, acid methanesulfonic acid, formic acid, acetic acid, oxalic acid, acid succinic, malic acid, tartaric acid, mandelic acid, acid fumaric, lactic acid or citric acid.

It is understood that the term "solvate" according to This invention means any form of active compound according to the invention in which the compound is linked through bonds not covalent to another molecule (more likely a solvent polar) which especially includes hydrates and alcoholates, for example methanolate

Unless stated otherwise, the compounds of the invention include compounds that differ only in the presence of one or more atoms enriched in an isotopic manner. By example, compounds having the present structures except by substituting one carbon for carbon enriched in 13 C or 14 C or 15 N enriched nitrogen are within the scope of this invention.

The invention also covers the use of any prodrug of the compounds described for the invention. Examples of the well-known methods of producing a prodrug of a given active compound are known to those skilled in the art and can be found for example in Krogsgaard-Larsen et al ., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002) .

In a preferred embodiment of the invention the compound according to general formula I is selected from compounds according to the general formula Ia or Ib or any mixture of same.

3

In a preferred embodiment of the invention for a compound according to formula I at least one of R2, R 3 or R 4 represents hydrogen, while at least one of R 2, R 3 or R 4 is different from hydrogen.

In a preferred embodiment of the invention for a compound according to formula I R 7 represents hydrogen.

In a preferred embodiment of the invention for a compound according to formula I R 2, R 3 and R 4 each of them independently represent hydrogen, a linear or branched C 1-6 alkyl group, a halogen atom, or CF 3, preferably R 2, R 3 and R 4 each independently represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3.

In a preferred embodiment of the invention for a compound according to formula I R 5 and R 6 each of they independently represent an alkyl group Linear or branched C 1-6, a halogen atom, or CF 3, preferably R 5 and R 6 each of them independently represent methyl, ethyl, F, Cl, Br and CF_ {3}.

In a preferred embodiment of the invention for a compound according to formula I R2 represents an atom of chlorine at position 4 of the phenyl ring, while R3 and R 4 represent hydrogen.

In a preferred embodiment of the invention for a compound according to formula I R 5 and R 6 each of they represent a chlorine atom in position 2- and 4 of the ring phenyl, while R 7 represents hydrogen.

In a preferred embodiment of the invention for a compound according to formula I R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.

In a very preferred additional aspect of the invention the compound of general formula I is represented by a compound of general formula II

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4

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in the that

quad

R1 represents hydrogen or an alkyl group C 1-4, linear or branched, substituted or not substituted, saturated or unsaturated,

quad

R 12 or R 13 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, SH, NH 2, hydrogen, methyl, ethyl, F, Cl, Br and CF 3,

quad

R 14 or R 15 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, SH, NH 2, methyl, ethyl, F, Cl, Br and CF 3,

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof.

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In a preferred embodiment of the invention the compound according to general formula II is selected from compounds according to the general formula IIa or IIb or any mixture of same

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5

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In a preferred embodiment of the invention for a compound according to formula II R 12 and R 13 each of them independently represent hydrogen, a group linear or branched C 1-6 alkyl, an atom halogen, or CF 3, preferably R 12 and R 13 each of them independently represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3.

In a preferred embodiment of the invention for a compound according to formula II R 14, and R 15 each of them independently represent an alkyl group Linear or branched C 1-6, a halogen atom, or CF 3, preferably R 14 and R 15 each of them independently represent methyl, ethyl, F, Cl, Br and CF_ {3}.

In a preferred embodiment of the invention for a compound according to formula II R 13 represents Cl and R 12 represents hydrogen.

In a preferred embodiment of the invention for a compound according to formula II R 14 and R 15 each of them represents Cl.

In a preferred embodiment of the invention for a compound according to formula II R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.

In another preferred embodiment the compound according to Formula I or II is selected from the group consisting of:

?

acid 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (rac) -5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (R) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (S) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

or any mixture thereof

optionally in the form of an N-oxide corresponding, a corresponding salt or a solvate correspondent.

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In a preferred embodiment of the invention for the manufacture of the medicament, in addition to at least one compound according to either of the general formulas I, Ia, Ib, II, IIa and or IIb, at least one substituted pyrazoline compound according to the general formula X, with

6

in the that

quad

R 16 represents a phenyl group optionally at less monosubstituted,

quad

R 17 represents a phenyl group optionally at less monosubstituted,

quad

R 18 represents a saturated cycloaliphatic group or unsaturated, optionally at least monosubstituted, containing optionally at least one heteroatom as a ring member, which it can be condensed with a cyclic, mono or polycyclic system, optionally at least monosubstituted, or an aryl group or optionally at least monosubstituted heteroaryl, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or a moiety -NR 19 R 20 -,

quad

R 19 and R 20, identical or different, represent a hydrogen atom, a linear aliphatic radical or branched, saturated or unsaturated, optionally at least monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or an aryl group or optionally at least monosubstituted heteroaryl, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted and / or linked through a linear or branched alkylene group, a moiety -SO 2 -R 21 -, or a moiety -NR 22 R 23 -,  with the proviso that R 19 and R 20 do not represent identical hydrogen,

quad

R 21 represents a linear aliphatic group or branched, saturated or unsaturated, optionally at least monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains at least one heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system, or a optionally at least monosubstituted aryl or heteroaryl group, which may be condensed with a cyclic, monocyclic or polycyclic and / or linked through a linear alkylene group or branched,

quad

R 22 and R 23, identical or different, represent a hydrogen atom, a linear aliphatic radical or branched, saturated or unsaturated, optionally at least monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or an aryl group or optionally at least monosubstituted heteroaryl, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted and / or linked through a group linear or branched alkylene,

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof.

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In a preferred embodiment of the invention in the compound according to the general formula X R 16 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group constituted by a linear C 1-6 alkyl group or branched, a linear C 1-6 alkoxy group or branched, a halogen atom, CH2F, CHF2, CF3, CN, OH, NO2, - (C = O) -R ', SH, SR', SOR ', SO2R', NH2, NHR ', NR'R' ', - (C = O) -NH2, - (C = O) -NHR 'and - (C = O) -NR'R' 'in the that R 'and R' 'for each substituent represent independent linear or branched C 1-6 alkyl, preferably R 16 represents a phenyl group, which is optionally substituted by one or more selected substituents from the group consisting of methyl, ethyl, F, Cl, Br and CF 3, plus preferably R 16 represents a phenyl group, which is monosubstituted with a chlorine atom in position 4.

In a preferred embodiment of the invention, the compound according to the general formula XR17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear C1-6 alkyl group or branched, a linear or branched C 1-6 alkoxy group, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R ', SH, SR', SOR ', SO2R', NH2 {, NHR ', NR'R'', - (C = O) -NH_ {2}, - (C = O ) -NHR 'and - (C = O) -NR'R'', in which R' and optionally R '' for each substituent independently represent linear or branched C 1-6 alkyl, preferably R ^ 17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3, more preferably R 17 represents a phenyl group, which is disubstituted with two chlorine atoms in its
position 2 and 4.

In a preferred embodiment of the invention in the compound according to the general formula X R 18 represents a C 3-8 cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, containing optionally at least one heteroatom as a member of the ring, which it can be condensed with a cyclic, monocyclic or optionally at least monosubstituted polycyclic, or a group heteroaryl or aryl of 5 or 6 carbon atoms optionally at less monosubstituted, which may be condensed with a system cyclic, monocyclic or polycyclic optionally at least monosubstituted, or a moiety -NR 19 R 20 -, preferably R 18 represents a cycloaliphatic group C 3-8 saturated, optionally at least monosubstituted, which optionally contains one or more atoms of nitrogen as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or a moiety -NR 19 R 20 -, more preferably R 18 represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, in which each of these groups can be substituted with one or more alkyl groups C 1-6, or a moiety -NR 18 R 19 -.

In a preferred embodiment of the invention in the compound according to the general formula X R 19 and R 20, identical or different, they represent a hydrogen atom, a linear or branched C 1-6 aliphatic radical, saturated or unsaturated, optionally at least substituted, a group C 3-8 cycloaliphatic saturated or unsaturated, optionally at least monosubstituted, which optionally contains the less a heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or a heteroaryl group or aryl of 5 or 6 carbon atoms optionally at least monosubstituted, which may be condensed with a cyclic system, monocyclic or polycyclic optionally at least monosubstituted and / or bonded through a methylene (-CH2 -) or ethylene group (-CH_ {2} -CH_ {2}), a remainder -SO 2 -R 21 -, or a remainder -NR 22 R 23 -, preferably one of these residues R 19 and R 20 represents a hydrogen atom and the other of these residues R 19 and R 20 represents a cycloaliphatic group C 3-8 saturated or unsaturated, optionally at less monosubstituted, which optionally contains at least one heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at less monosubstituted, or a heteroaryl or aryl group of 5 or 6 atoms carbon optionally at least monosubstituted, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, a remainder -SO 2 -R 21 -, or a moiety -NR 22 R 23 -, or R 19 and R 20, identical or different, each of them represents a C 1-6 alkyl group, plus preferably one of these residues R19 and R20 represents a hydrogen atom and the other of these wastes R 19 and R 20 represents a pyrrolidinyl group optionally at least monosubstituted, a piperidinyl group optionally at less monosubstituted, a piperazinyl group optionally at least monosubstituted, a triazolyl group optionally at least monosubstituted, a moiety -SO2 -R21-, or a remainder -NR 22 R 23 -, or R 19 and R 20, identical or different, they represent a methyl group, an ethyl group, a group n-propyl, an isopropyl group, a group n-butyl, a sec-butyl group or a tert-butyl group.

In a preferred embodiment of the invention in the compound according to the general formula X R 21 represents a linear or branched C 1-6 aliphatic group, saturated or unsaturated, optionally at least monosubstituted, a C 3-8 cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, containing optionally at least one heteroatom as a member of the ring, which it can be condensed with a cyclic, monocyclic or polycyclic, or a heteroaryl or aryl group of 5 or 6 atoms of optionally at least monosubstituted carbon, which may be condensed with a cyclic, monocyclic or polycyclic system and / or bonded through a methylene (-CH2 -) or ethylene group (-CH 2 -CH 2), preferably R 21 represents a C 1-6 alkyl group, a group saturated cycloaliphatic, optionally at least monosubstituted, which it can be condensed with a cyclic, monocyclic or polycyclic, or a phenyl group, which is optionally substituted with one or more C 1-6 alkyl groups.

In a preferred embodiment of the invention in the compound according to the general formula X R 22 and R 23, identical or different, they represent a hydrogen atom, a linear or branched C 1-6 aliphatic radical, saturated or unsaturated, optionally at least monosubstituted, a C 3-8 cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, containing optionally at least one heteroatom as a member of the ring, which it can be condensed with a cyclic, monocyclic or optionally at least monosubstituted polycyclic, or an aryl group or heteroaryl of 5 or 6 carbon atoms, optionally at least monosubstituted, which may be condensed with a cyclic system, monocyclic or polycyclic optionally at least monosubstituted and / or bonded through a methylene (-CH2 -) or ethylene group (-CH 2 -CH 2), preferably R 22 and R 23, identical or different, represents a hydrogen atom or a C 1-6 alkyl radical.

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In a preferred embodiment of the invention the compound according to the general formula X is represented by a structure in which

quad

R 16 represents a phenyl ring, which is monosubstituted with a halogen atom, preferably an atom of chlorine, in position 4,

quad

R 17 represents a phenyl ring, which is disubstituted with two halogen atoms, preferably atoms of chlorine, in its position 2 and 4,

quad

R 18 represents a pyrrolidinyl group, a group piperidinyl, a piperazinyl group, a homopiperazinyl group, a morpholinyl group, or a moiety -NR 19 R 20 -,

quad

R 19 represents a hydrogen atom or a group linear or branched C 1-6 alkyl,

quad

R 20 represents an alkyl group C 1-6 linear or branched, a remainder -SO 2 -R 21 -, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a group homopiperazinyl, a morpholinyl group, a triazolyl group, in the that each of the heterocyclic rings may be substituted with one or more, C 1-6 alkyl groups, identical or different, and

quad

R 21 represents a phenyl group, which is optionally substituted with one or more alkyl groups C_ {1-6}, which can be identical or different,

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof.

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In a preferred embodiment of the invention at less a compound according to formula X is selected from the group Constituted by:

N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

(rac) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

(R) -N-Piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

(S) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

[1,2,4] -triazol-4-yl-amide  of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

(4-methyl-piperazin-1-yl) -amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

diethylamide acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

[5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-yl] -piperidine-1-yl-methanone,

N- [5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carbonyl] -4-methylphenylsulfonamide,

optionally in the form of an N-oxide corresponding, a corresponding salt or a solvate correspondent.

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In a preferred embodiment of the use of the combination (A) according to the invention at least the following are used compounds:

?

5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (rac) -5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (R) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid, or

?

acid (S) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

or any mixture thereof and

?

N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide;

?

(rac) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide;

?

(R) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide;

?

(S) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide;

or any mixture thereof

each of them optionally in the form of a Corresponding N-oxide, a corresponding salt or a solvate correspondent.

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Another aspect of the invention is the use of compounds according to general formula I or II or their combination with compounds of the general formula X for the manufacture of a medication for the treatment of risk factors cardiovascular caused by metabolic / eating disorders, especially a combination of consequences of these disorders.

Another aspect of the invention is the use of compounds according to general formula I or II or their combination with compounds of the general formula X for the manufacture of a medication for the treatment of metabolic syndrome, especially in its weight dependent aspects, preferably with the condition (exclusion) of excluding levels of triglycerides

The process to acquire compounds according to the general formula I is illustrated in scheme I given to continuation:

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Scheme I

7

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The reaction of a benzaldehyde compound of general formula III with a pyruvate compound of general formula IV is preferably carried out in the presence of at least one base, more preferably in the presence of a metal hydroxide alkali such as sodium hydroxide or potassium hydroxide or a alkali metal methoxide such as sodium methoxide, are described for example in Synthetic communications, 26 (11), 2229-33, (1996). The respective description is incorporates as reference to this document and is part of the description. Preferably said reaction is carried out in a protic reaction medium such as an alkyl alcohol C 1-4 or mixtures thereof.

The reaction temperature as well as the Reaction duration may vary over a wide range. The Preferred reaction temperatures range from -10 ° C to boiling point of the reaction medium. Reaction times suitable may vary for example from several minutes to several hours.

It is also preferred that the reaction of the benzaldehyde compound of general formula III with a compound of pyruvate of general formula IV is carried out under conditions acid catalyzed, more preferably by putting the mixture at reflux in dichloromethane in the presence of trifluoromethanesulfonate of copper (II) as described, for example, in Synlett, (1), 147-149, 2001. The respective description is incorporates as reference to this document and is part of the description.

The reaction of the compound of general formula (V) with an optionally substituted phenyl hydrazine of the general formula (VI) is preferably carried out in a reaction medium suitable such as C 1-4 alcohols or ethers such as dioxane or tetrahydrofuran or mixtures of at least two of these compounds mentioned above. Also preferably, said reaction can be carried out in the presence of an acid, in which the acid can be organic, such as acetic and / or inorganic acid such as hydrochloric acid. In addition, the reaction can also carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these may be used bases.

The reaction temperature as well as the duration of the reaction may vary over a wide range. The suitable reaction temperatures vary from temperature ambient, that is, approximately 25 ° C to the point of boiling of the reaction medium. Adequate reaction times they can vary for example from several minutes to several hours.

The carboxylic group of the compound of formula general (VII) can be activated by additional reactions by introduction of a suitable leaving group according to the methods conventional techniques well known to those skilled in the art, which lead to a compound according to the general formula (VIIa).

8

Preferably, the compounds of formula general (VI) are transferred in an acid chloride, an anhydride of acid, a mixed anhydride, an alkyl ester C 1-4, an activated ester such as ester p-nitrophenyl. Other well known methods for Acid activation include activation with N, N-dicyclohexylcarbodiimide or hexafluoro phosphate from benzotriazol-N-oxotris (dimethylamino) phosphonium (BOP)).

If said activated compound of general formula (VII) is an acid chloride, preferably prepared by the reaction of the corresponding acid of general formula (VI) with thionyl chloride, or oxalyl chloride, wherein said agent Chlorination is also used as the solvent. Too preferably an additional solvent can be used. The Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform, or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofuran, or dimethoxyethane. You can use the mixtures of two or more solvents of one class or two or more solvents of different kinds. Reaction temperatures Preferred range from 0 ° C to the boiling point of solvents and reaction times from several minutes to several hours.

If said activated compound of general formula (VIIa) is a mixed anhydride, said anhydride can be prepared preferably, for example, by reaction of the corresponding acid of general formula (VIIa) with ethyl chloroformate in the presence of a base such as triethylamine or pyridine, in a solvent suitable.

After that, the activated compound can be reacted with an alkyl alcohol to give rise to compounds according to general formulas I or II where R 1 is a C 1-4 alkyl group, linear or branched, substituted or unsubstituted, saturated or unsaturated.

In addition, as A is represented in the formula General VIIa represents a leaving group, through the reaction with an activating agent, said compound being isolated optionally and / or optionally purified, and at least one compound of general formula (VIIa) is reacted with a compound of general formula R 18 H, in which R 18 represents a moiety -NR 19 R 20 -, in which R 19 and R 20 have the meaning given above for compounds of general formula X, to give a substituted pyrazoline compound of the general formula X, where R 18 represents a -NR 19 R 20 - moiety,

During the processes described above, protection of sensitive groups may be necessary and / or desirable or of the reagents. The introduction of protective groups conventional as well as its elimination can be done by methods well known to those skilled in the art.

If the substituted pyrazoline compounds of general formula I or II are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by usual procedures known to those skilled in the art, for example, methods chromatographic or fractional crystallization with reagents chiral It is also possible to obtain pure stereoisomers through of stereoselective synthesis, especially using bases chiral such as brucine, quinine, (-) - cinconidine, (+) - cinconine or R - (+) - 1-phenylethylamine.

In a process for the preparation of salts of substituted pyrazoline compounds of general formula I or II and stereoisomers thereof, at least one compound of formula general I or II that has at least one basic group is made react with at least one inorganic and / or organic acid, preferably in the presence of a suitable reaction medium. The suitable reaction media include, for example, any of those provided above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are, by example, citric acid, maleic acid, fumaric acid, acid tartaric acid, or derivatives thereof, acid p-toluenesulfonic acid, methanesulfonic acid or acid camphorsulfonic.

In a process for the preparation of salts of substituted pyrazoline compounds of general formula I or II and stereoisomers thereof, at least one compound of formula general I or II having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are, for example, hydroxides, carbonates or alkoxides, which include cations suitable, derived for example from alkali metals, metals alkaline earth or organic cations, for example [NH_ {n} R_-4] +, where n is 0, 1, 2, 3 or 4 and R represents an alkyl radical C 1-4 branched or unbranched. The means of Suitable reactions are, for example, any of those provided previously.

You can also get solvates, preferably hydrates, of the pyrazoline compounds substituted of general formula I or II, of the corresponding stereoisomers, of the corresponding N-oxides or of the corresponding salts thereof by procedures customary known to those skilled in the art.

Compounds of substituted pyrazoline of general formula I or II, comprising rings, saturated, unsaturated or aromatic containing an atom of nitrogen in the form of its N-oxides by well methods known to those skilled in the art.

The purification and isolation of substituted pyrazoline compounds of general formula I or II, of a corresponding stereoisomer, or salt, or N-oxide, or solvate or any intermediate product thereof can be carried out, if desired, by conventional methods known to skilled in the art, for example, chromatographic methods or recrystallization

The substituted pyrazoline compounds of general formula I, Ia, Ib, II, IIa, IIb and X given below, of the corresponding N-oxides or the corresponding salts of the themselves and the corresponding solvates are acceptable toxicologically and therefore are suitable as principles pharmaceutical assets

The medicament according to the present invention can be in any form suitable for application to humans and / or animals, preferably humans that include infants, children and adults, and can be produced by known standard procedures by those skilled in the art. The composition of the medication It may vary depending on the route of administration.

The medicine obtained according to the present invention may, for example, be administered parenterally in combination with conventional injectable liquid vehicles, such as water or suitable alcohols. Excipients may be included conventional pharmaceuticals, such as stabilizing agents, solubilizing agents and buffers, in such compositions injectable These medications can be injected, for example, by intramuscularly, intraperitoneally or via intravenous

Solid oral compositions (which are prefer as liquid forms) can be prepared by methods Conventional mixing, filling or compressing. Can be used repeated mixing operations to distribute the principle active through these compositions using large amounts of fillers. Such operations are conventional in the technique. The tablets can for example be prepared by wet or dry granulation and can optionally be coated according to the methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The mentioned formulations will be prepared using standard methods such as those described in the pharmacopoeias Spanish and American and similar reference texts.

Medications according to the present invention they can also be formulated in compositions for oral administration containing one or more compatible vehicles or excipients physiologically, in solid or liquid form. These compositions may contain conventional ingredients such as bonding, loading agents, lubricants and wetting agents adequate. The compositions can have any shape Convenient, such as tablets, microgranules, capsules, lozenges, aqueous or oily solutions, suspensions,  emulsions, or dry powder forms suitable for your reconstitution with water or other suitable liquid medium before use for immediate or delayed release.

Liquid oral forms for administration may also contain certain additives such as sweeteners, flavorings, preservatives and emulsifiers. They can also non-aqueous liquid compositions be formulated for Oral administration containing edible oils. Such liquid compositions can be conveniently encapsulated, by example in gelatin capsules in a single dose amount.

The compositions of the present invention they can also be administered topically, or through a suppository.

Daily doses for humans and animals can vary depending on factors that are based on the respective species or other factors, such as age, sex, weight or grade of disease among others. Daily doses in humans may be preferably in the range of 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active ingredient to be administered in one or several shots per day.

The present invention is illustrated below. With the help of examples. These illustrations are provided only by way of example and do not limit the general spirit of the present invention.

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Examples

Example 0 represents a compound according to Formula I or II

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Example 0 Acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic a) Acid 4- (4-chlorophenyl) -2-oxo-3-butenoic

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9

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They dissolved p-chlorobenzaldehyde (13.3 g, 95 mmol) and pyruvate ethyl (10 g, 86 mmol) in 150 ml of absolute ethanol in a flask of Three mouths The solution was cooled to 0 ° C and added dropwise. an aqueous solution of NaOH (3.8 g in 45 ml of water) keeping the temperature below or equal to 10 ° C, forming a precipitate yellow-orange color The mixture was stirred reaction for 1 hour at 0 ° C and for another 1.5 hours at temperature ambient (approximately 25 ° C). Then the mixture of reaction was cooled to about 5 ° C and isolated by filtration the insoluble sodium salt of the acid 4- (4-chlorophenyl) -2-oxo-3-butenoic.

The filtrate was left in the refrigerator during night, forming more precipitate that was removed by filtration, it combined with the first fraction of the salt and washed with diethyl ether. Sodium Salt of Acid 4- (4-chlorophenyl) -2-oxo-3-butenoic  It was then treated with a 2N HCl solution, stirred for some minutes and acid separated 4- (4-chlorophenyl) -2-oxo-3-butenoic solid by filtration and dried to give 12.7 g of the product desired (70% of theoretical yield).

IR (KBr, cm -1): 3500-2500, 1719.3, 1686.5, 1603.4, 1587.8, 1081.9.

1 H NMR (CDCl 3, δ): 7.4 (d, J = 8.4Hz, 2H), 7.5 (d, J = 16.1Hz, 1H), 7.6 (d, J = 8.4Hz, 2H), 8.1 (d, J = 16.1Hz, 1H).

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a2) Acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

In an alternative route, it was used instead of ethyl pyruvate, salt CH 3 -C (O) -C (O) -O - Na + (sodium pyruvate) was dissolved with ethanolic water.

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b) Acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

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10

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Acid mixed 4- (4-chlorophenyl) -2-oxo-3-butenoic obtained according to step a, (12.6 g, 60 mmol), hydrochloride 2,4-dichlorophenylhydrazine (12.8 g, 60 mmol) and acid glacial acetic acid (200 ml) under a nitrogen atmosphere and it heated to reflux for 4 hours, cooled to temperature ambient (approximately 25 ° C) and poured on ice, obtaining thus a sticky dough that was extracted with methylene chloride. Be washed the combined methylene chloride fractions with water, dried over sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical performance).

IR (KBr, cm -1): 3200-2200, 1668.4, 1458, 1251.4, 1104.8.

1 H NMR (CDCl 3, δ): 3.3 (dd, 1H), 3.7 (dd, 1H), 5.9 (dd, 1H), 7.09-7.25 (m, 7H).

Examples 1 to 6 represent compounds according to the formula X.

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Example 1 N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide (a) Acid Chloride 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

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eleven

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Acid dissolved 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic (2.5 g, 6.8 mmol) obtained according to step (b) in 4 ml of chloride thionyl under nitrogen atmosphere and heated to reflux for 2.5 hours The excess thionyl chloride was removed from the mixture reaction under reduced pressure and the resulting crude residue (2.6 g) It is used without any further purification.

IR (KBr, cm -1): 1732.3, 1700, 1533.3, 1478.1, 1212.9, 826.6.

Starting from this compound, they can Prepare compounds according to general formulas I and II in which R 1 is a linear C 1-4 alkyl group or branched, reacting this compound with alcohol appropriate alkyl.

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(b) N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide

12

N-aminopiperidine dissolved (0.6 ml, 5.6 mmol) and triethylamine (4 ml) in methylene chloride (25 ml) under nitrogen atmosphere. The resulting mixture was cooled in ice at 0 ° C and a solution of chloride of the acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic obtained in step (b) in methylene chloride (15 ml). It stirred the resulting reaction mixture at room temperature (approximately 25 ° C) overnight. After this, the reaction mixture with water, followed by an aqueous solution saturated and again with water, dried over sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. It crystallized the resulting crude solid in ethanol. The solid was removed crystallized by filtration and the mother liquor was concentrated to give a second fraction of crystallized product. Be combined the two fractions to give a total amount of 1.7 g (57% of theoretical yield) of N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide  which has a melting point of 183-186 ° C.

IR (KBr, cm -1): 3222.9, 2934.9, 1647.4, 1474.7, 1268.3, 815.6.

1 H NMR (CDCl 3, δ): 1.4 (m, 2H), 1.7 (m, 4H), 2.8 (m, 4H), 3.3 (dd, J = 6.1 and 18.3Hz, 1H), 3.7 (dd, J = 12.5 and 18.3 Hz, 1H), 5.7 (dd, J = 6.1 and 12.5 Hz, 1H), 7.0-7.2 (m, 6H), 7.4 (s, 1H).

The compounds according to the following examples 2-6 have been prepared analogously to the process described in Example 1 in combination with Example 0.

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Example 2 [1,2,4] triazol-4-yl amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazol-3-carboxylic- [1,2,4] triazol-4-yl amide

Melting point: 134-138 ° C.

IR (KBr, cm -1): 3448, 1686, 1477, 1243, 1091, 821.

1 H NMR (CDCl 3, δ): 3.1 (dd, J = 6.2 and 17.9Hz, 1H), 3.7 (dd, J = 12.3 and 17.9Hz, 1H), 5.9 (dd, J = 6.2 and 12.3 Hz, 1H), 7.2-7.5 (m, 7H), 8.7 (s, 2H), 12.0 (sa, 1 H).

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Example 3 Hydrochloride (4-methyl-piperazin-1-yl) -amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid

Melting point: 150-155 ° C.

IR (KBr, cm -1): 3433, 1685, 1477, 1296, 1246, 1088, 1014, 825.

1 H NMR (CDCl 3, δ): 2.7 (d, J = 4.2Hz, 3H), 3.0-3.4 (m, 9H), 3.6 (dd, J = 11.9 and 17.9 Hz, 1H), 5.8 (dd, J = 5.5 and 11.9 Hz, 1H), 7.1 (d, J = 8.4Hz, 2H), 7.25 (2d, J = 8.4 and 8.7 Hz, 3H), 7.4 (d, J = 2.2Hz, 1H), 7.5 (d, J = 8.7Hz, 1H), 9.8 (s, 1H), 11.2 (sa).

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Example 4 Acid diethylamide 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid

This compound was obtained in the form of a oil.

IR (film, cm -1): 2974, 1621, 1471, 1274, 1092, 820.

1 H NMR (CDCl 3, δ): 1.2 (m, 6H), 3.3-3.9 (m, 6H), 5.6 (dd, J = 5.8 and 11.7 Hz, 1H), 7-7.25 (m, 7H).

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Example 5 [5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazol-3-yl] -piperidin-1-yl-methanone

Melting point: 105-110 ° C.

IR (KBr, cm -1): 2934, 1622, 1470, 1446, 1266, 1010, 817.

1 H NMR (CDCl 3, δ): 1.7 (m, 6H), 3.4 (dd, J = 5.7 and 17.9Hz, 1H), 3.7 (m, 3H), 3.9 (m, 2H), 5.6 (dd, J = 6.1 and 11.9 Hz, 1H), 7-7.25 (m, 7H).

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Example 6 N- [5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazol-3-carbonyl] -4-methyl-phenylsulfonamide

This compound was obtained as a solid. amorphous.

IR (KBr, cm -1): 1697, 1481, 1436, 1340, 1169, 1074, 853.

1 H NMR (CDCl 3, δ): 2.4 (s, 3H), 3.2 (dd, J = 6.6 and 18.3Hz, 1H), 3.6 (dd, J = 12.8 and 18.3Hz, 1H), 5.8 (dd, J = 6.6 and 12.8Hz, 1H), 7 (d, J = 8.2Hz, 2H), 7.2 (s, 1H), 7.3-7.4 (m, 6H), 8 (d, J = 8.1Hz, 2H), 9 (s, 1H).

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Example 7 N-oxide N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide

N-Piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide (0.15 g, 332) was dissolved
mmol) in 7 ml of dichloromethane in an inert atmosphere of nitrogen gas. The resulting solution was cooled on ice to 0 ° C and m-chloroperbenzoic acid (0.204 g, 0.83 mmol) was added in several portions. After stirring for 15 minutes a control performed by thin layer chromatography showed that no starting material remained. A saturated solution of sodium bicarbonate was then added slowly, the organic phase was separated, washed with water, dried over sodium sulfate and filtered. The filtered solution was evaporated to dryness and the crude product was purified through column chromatography to give 78 mg (50% of theory) of N-piperidinyl-5- (4-chlorophenyl) -1- ( 2,4-Dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide in the form of a white solid having a melting point of 115-120 ° C.

IR (KBr, cm -1): 3202, 1678, 1654, 1474, 1309, 1107.

1 H-NMR (CDCl 3, δ): 1.6 (m, 2H), 1.8-2.0 (m, 4H), 2.55 (m, 2H), 3.3 (dd, J = 6.3 Hz and 18.2 Hz, 1H), 3.7 (m, 3H), 5.8 (dd, J = 6.3 Hz and 12.5 Hz, 1H), 7.0-7.3 (m, 7H), 8.5 (s, 1 HOUR.).

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Data / Pharmacological tests

The compound according to example 0 is an inhibitor of high blood triglyceride levels and, on the other On the other hand, other factors such as insulin, whose levels are reduced - and that contribute to the metabolic syndrome. The Decreased plasma insulin is indicative of an improvement in insulin sensitivity, which is a positive sign for the metabolic syndrome as it increases in obese animal models Diet-induced as the basal insulin used here. This it is probably also a good indication as to the effectiveness of the compound to help a patient suffering from developed diabetes, especially with respect to the syndrome metabolic.

This effect is tested in obese mice. fed a high fat diet. In the following paragraphs The method of this study is described.

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I. In-vivo test for lipid parameters or other important parameters for metabolic syndrome (especially triglycerides) in blood plasma

The study was conducted using male mice (C57BL76J). The mice were divided into 2 groups:

Group I (vehicle: 0.5% HPMC)

Group II (Example 0 to 30 mg / kg / day / p.o.)

The animals of both groups were fed with A high fat diet.

After 28 days of treatment, the animals they were sacrificed and blood samples were taken. They were determined in blood levels of lipid parameters or other parameters important for metabolic syndrome, in this case especially Insulin in the plasma of animals.

The analysis of whole blood samples it was performed according to the methods known in the art and in the case of Insulin was performed with an ELISA based assay ultrasensitive

Plasma insulin for control (Group I) it was 285.7 ± 57.9 (pmol / l) and for the group treated with compound from example 0 (Group II) was 156.4 ± 38.6 (pmol / l). This was statistically significant at p <0.05 using ANOVA factorial.

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II. Study in a rodent model using rodents that show signs or are considered as a model of diabetes developed

The compound according to example 0 is applied to rodents that according to the methods known in the art get develop symptoms similar to the effects of diabetes developed. Compared to the control, the compound according to the Example 0 shows positive results.

Claims (29)

1. Use of a substituted pyrazoline compound of general formula I,

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13

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in the that

quad

R1 represents hydrogen or an alkyl group C 1-4, linear or branched, substituted or not substituted, saturated or unsaturated,

quad

R 2, R 3 and R 4 each of them independently represent hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 for each substituent independently represent alkyl C 1-6 linear or branched,

quad

R 5 and R 6 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, - (C = O) -R 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 R 11, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R11 for each substituent represent independent linear C 1-6 alkyl or branched;

quad

R 7 represents hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 R 11, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R11 for each substituent represent independent linear C 1-6 alkyl or branched;

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof,

quad

for the manufacture of a medicine for treatment of eating disorders, which include obesity or metabolic syndrome in patients with diabetes developed.

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2. Use according to claim 1, characterized in that the eating disorder to be treated in patients with developed diabetes is obesity. 3. Use according to claim 1, characterized in that the eating disorder to be treated in patients with developed diabetes is the metabolic syndrome.

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4. Use according to claim 1, characterized in that the compound according to general formula I is selected from compounds according to general formula Ia or Ib or any mixture thereof

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14

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5. Use according to any one of claims 1 to 4, characterized in that at least one of R 2, R 3 or R 4 represents hydrogen, while at least one of R 2, R 3 or R 4 is different from hydrogen. 6. Use according to any one of claims 1 to 5, characterized in that R 7 represents hydrogen. 7. Use according to any one of claims 1 to 6, characterized in that R 2, R 3 and R 4 each independently represent hydrogen, a C 1-6 alkyl group linear or branched, a halogen atom, or CF 3, preferably R 2, R 3 and R 4 each independently represent hydrogen, methyl, ethyl, F, Cl , Br and CF_ {3}. Use according to any one of claims 1 to 7, characterized in that R 5 and R 6 each independently represent a linear or branched C 1-6 alkyl group, a halogen atom , or CF 3, preferably R 5 and R 6 each independently represent methyl, ethyl, F, Cl, Br and CF 3. 9. Use according to any one of claims 1 to 8, characterized in that R2 represents a chlorine atom at position 4 of the phenyl ring, while R3 and R4 represent hydrogen. 10. Use according to any one of claims 1 to 9, characterized in that R 5 and R 6 each represents a chlorine atom in position 2 and 4 of the phenyl ring, while R <+> 7} represents hydrogen. 11. Use according to any one of claims 1 to 10, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.

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12. Use according to one or more of claims 1 to 11, characterized in that the compound according to general formula I is selected from a compound of general formula II

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fifteen

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in the that

quad

R1 represents hydrogen or an alkyl group C 1-4, linear or branched, substituted or not substituted, saturated or unsaturated,

quad

R 12 or R 13 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, SH, NH 2, hydrogen, methyl, ethyl, F, Cl, Br and CF 3,

quad

R 14 or R 15 each of them in a manner independently represent a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, SH, NH 2, methyl, ethyl, F, Cl, Br and CF 3,

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof.

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13. Use according to claim 12, characterized in that the compound according to general formula II is selected from compounds according to general formula IIa or IIb or any mixture thereof

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16

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14. Use according to any of claims 12 or 13 characterized in that R 12 and R 13 each independently represent hydrogen, a linear or branched C 1-6 alkyl group, a halogen atom , or CF 3, preferably R 12 and R 13 each independently represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3. 15. Use according to any one of claims 12, 13 or 14, characterized in that R 14, and R 15 each independently represent a linear or branched C 1-6 alkyl group, a halogen atom, or CF 3, preferably R 14 and R 15 each independently represent methyl, ethyl, F, Cl, Br and CF 3. 16. Use according to any one of claims 12 to 15, characterized in that R 13 represents Cl and R 12 represents hydrogen. 17. Use according to any one of claims 12 to 16, characterized in that R 14 and R 15 each represents Cl. 18. Use according to any one of claims 12 to 17, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 19. Use according to one or more of the claims 1 to 16, is selected from the group consisting of:

?

acid 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (rac) -5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (R) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (S) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

or any mixture thereof optionally in the form of an N-oxide corresponding, a corresponding salt or a solvate correspondent.

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20. Use according to any one of claims 1 to 19, characterized in that in addition to at least one compound according to any of the general formulas I, Ia, Ib, II, IIa and / or IIb at least one substituted pyrazoline compound according to the general formula X, 17 in the that

quad

R 16 represents a phenyl group optionally at less monosubstituted,

quad

R 17 represents a phenyl group optionally at less monosubstituted,

quad

R 18 represents a saturated cycloaliphatic group or unsaturated, optionally at least monosubstituted, containing optionally at least one heteroatom as a member of the ring, which it can be condensed with a cyclic, monocyclic or optionally at least monosubstituted polycyclic, or an aryl group or optionally at least monosubstituted heteroaryl, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or a remainder -NR 19 R 20 -,

quad

R 19 and R 20, identical or different, represent a hydrogen atom, a linear aliphatic radical or branched, saturated or unsaturated, optionally at least monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or an aryl group or optionally at least monosubstituted heteroaryl, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted and / or linked through a group linear or branched alkylene, a residue -SO 2 -R 21 -, or a moiety -NR 22 R 23 -, with the proviso that R 19 and R 20 do not represent identical hydrogen,

quad

R 21 represents a linear aliphatic group or branched, saturated or unsaturated, optionally at least monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system, or a optionally at least monosubstituted aryl or heteroaryl group, which it can be condensed with a cyclic, monocyclic or polycyclic and / or linked through a linear alkylene group or branched,

quad

R 22 and R 23, identical or different, represent a hydrogen atom, a linear aliphatic radical or branched, saturated or unsaturated, optionally at least monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or an aryl group or optionally at least monosubstituted heteroaryl, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted and / or linked through a group linear or branched alkylene,

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof.

21. Use according to claim 20, characterized in that in the compound according to the general formula XR16 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a C1-6 alkyl group linear or branched, a linear or branched C 1-6 alkoxy group, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R ', SH, SR', SOR ', SO_2R', NH2 {NHR ', NR'R'', - (C = O) -NH_2, - ( C = O) -NHR 'and - (C = O) -NR'R''in which R' and R '' for each substituent independently represent linear or branched C 1-6 alkyl, preferably R ^ 16 represents a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3, more preferably R 16 represents a phenyl group, which It is monosubstituted with a chlorine atom in position 4. 22. Use according to any of claims 20 or 21, characterized in that in the compound according to the general formula XR17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a C_ alkyl group {1-6} linear or branched, a linear or branched C1-6 alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, NO2 , - (C = O) -R ', SH, SR', SOR ', SO_2R', NH_ {2}, NHR ', NR'R'', - (C = O) -NH_ {2 }, - (C = O) -NHR 'and - (C = O) -NR'R'', in which R' and optionally R '' for each substituent independently represent linear C 1-6 alkyl or branched, preferably R 17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3, more preferably R 17 } represents a phenyl group, which is disubstituted with two chlorine atoms in position 2 and 4. 23. Use according to any of claims 20 to 22, characterized in that the compound according to the general formula XR18 represents a saturated or unsaturated C 3-8 cycloaliphatic group, optionally at least monosubstituted, optionally containing at least a heteroatom as a member of the ring, which may be condensed with an optionally at least monosubstituted cyclic, monocyclic or polycyclic system, or an optionally at least monosubstituted heteroaryl or aryl group of 5 or 6 carbon atoms, which may be condensed with a cyclic system , optionally at least mono-substituted monocyclic or polycyclic, or a -NR 19 R 20 -, preferably R 18 represents a saturated C 3-8 cycloaliphatic group, optionally at least monosubstituted, containing optionally one or more nitrogen atoms as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system optionally at least monosubstituted, or a moiety -NR 19 R 20 -, more preferably R 18 represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, in which each of these groups may be substituted with one or more C 1-6 alkyl groups, or a -NR 18 R 19 - moiety. 24. Use according to any of claims 20 to 23, wherein in the compound according to general formula XR ^ {19} and {20} R, identical or different, represent a hydrogen atom, aliphatic radical C 1-6 { linear or branched, saturated or unsaturated, optionally at least substituted, a saturated or unsaturated C 3-8 cycloaliphatic group, optionally at least monosubstituted, optionally containing at least one heteroatom as a ring member, which may be condensed with a optionally at least monosubstituted cyclic, monocyclic or polycyclic system, or an optionally at least monosubstituted heteroaryl or aryl group of 5 or 6 carbon atoms, which may be condensed with an optionally at least monosubstituted cyclic, monocyclic or polycyclic system and through a methylene (-CH2-) or ethylene (-CH2 -CH2), a moiety -SO2 -R21-, or a -NR ^ moiety 22 R 23 -, preferably one of these residues R 19 and R ^ {20} represents a hydrogen atom and the other of these residues R19 and R20 represents a saturated or unsaturated C3-8 cycloaliphatic group, optionally at least monosubstituted, optionally containing at least one heteroatom as a member of the ring, which may be condensed with an optionally at least monosubstituted cyclic, monocyclic or polycyclic system, or an optionally at least monosubstituted heteroaryl or aryl group of 5 or 6 carbon atoms, which may be condensed with a cyclic system, optionally at least mono-substituted monocyclic or polycyclic, a moiety -SO2 -R21-, or a moiety -NR22R23-, or R19 and R20 , identical or different, each represents a C 1-6 alkyl group, more preferably one of these residues R 19 and R 20 represents a hydrogen atom and the other of these residues R 19 and R 20 represents an optionally at least monosubstituted pyrrolidinyl group, an optionally piperidinyl group at least monosubstituted te, an optionally at least monosubstituted piperazinyl group, an optionally at least monosubstituted triazolyl group, a -SO 2 -R 21 - moiety, or a -NR 22 R 23 moiety -, or R 19 and R 20, identical or different, represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group or a tert-butyl group. 25. Use according to any of claims 20 to 24, characterized in that in the compound according to the general formula XR21 represents a linear or branched, saturated or unsaturated C1-6 aliphatic group, optionally at least monosubstituted, a C 3-8 saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, optionally containing at least one heteroatom as a member of the ring, which may be condensed with a cyclic, monocyclic or polycyclic system, or a heteroaryl or aryl group of 5 or 6 optionally at least monosubstituted carbon atoms, which may be condensed with a cyclic, monocyclic or polycyclic system and / or linked through a methylene (-CH2-) or ethylene (-CH2 -CH_) group {2}, preferably R21 represents a C1-6 alkyl group, a saturated cycloaliphatic group, optionally at least monosubstituted, which may be fused to a cyclic, monocyclic or polycyclic system, or a phenyl group, that which is optionally substituted with one or more C 1-6 alkyl groups. 26. Use according to any of claims 20 to 25, wherein in the compound according to general formula XR ^ {22} and {23} R, identical or different, represent a hydrogen atom, an aliphatic C 1- { 6} linear or branched, saturated or unsaturated, optionally at least monosubstituted, a C 3-8 cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, optionally containing at least one heteroatom as a ring member, which may be condensed with an optionally at least monosubstituted cyclic, monocyclic or polycyclic system, or an aryl or heteroaryl group of 5 or 6 carbon atoms, optionally at least monosubstituted, which may be condensed with an optionally at least monosubstituted cyclic, monocyclic or polycyclic system linked through a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2) group, preferably R 22 and R 23, identical or different, represent an atom of hydrogen or a C 1-6 alkyl radical.

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27. Use according to any of claims 20 to 26, characterized in that the compound according to the general formula X is represented by a structure in which

quad

R 16 represents a phenyl ring, which is monosubstituted with a halogen atom, preferably an atom of chlorine, in position 4,

quad

R 17 represents a phenyl ring, which is disubstituted with two halogen atoms, preferably atoms of chlorine, in its position 2 and 4,

quad

R 18 represents a pyrrolidinyl group, a group piperidinyl, a piperazinyl group, a homopiperazinyl group, a morpholinyl group, or a moiety -NR 19 R 20 -,

quad

R 19 represents a hydrogen atom or a group linear or branched C 1-6 alkyl,

quad

R 20 represents an alkyl group C 1-6 linear or branched, a remainder -SO 2 -R 21 -, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a group homopiperazinyl, a morpholinyl group, a triazolyl group, in the that each of the heterocyclic rings may be substituted with one or more, identical or different, alkyl groups C_ {1-6}, and

quad

R 21 represents a phenyl group, which is optionally substituted with one or more alkyl groups C_ {1-6}, which can be identical or different,

quad

optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof.

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28. Use according to any of claims 20 to 27, characterized in that at least one compound according to formula X is selected from the group consisting of:

N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

(rac) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

(R) -N-Piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

(S) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,

[1,2,4] -triazol-4-yl-amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

(4-methyl-piperazin-1-yl) -amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

diethylamide acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

[5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-yl] -piperidine-1-yl-methanone,

N- [5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carbonyl] -4-methylphenylsulfonamide,

optionally in the form of an N-oxide corresponding, a corresponding salt or a solvate correspondent.

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29. Use according to any of claims 20 to 28, characterized in that at least the following compounds are used:

?

acid 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (rac) -5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (R) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

?

acid (S) -5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid,

or any mixture thereof and

?

N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide;

?

(rac) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide;

?

(R) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide; or

?

(S) -N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide;

or any mixture thereof each of them optionally in the form of a Corresponding N-oxide, a corresponding salt or a solvate correspondent.