ES2348374A1 - Pleckstrin-based fusion protein and method for monitoring of enzyme activities by fret - Google Patents

Abstract

Oral pharmaceutical formulations that they comprise substituted pyrazoline compounds.

The present invention relates to formulations oral pharmaceuticals comprising pyrazoline compound substituted, in addition to its use for the preparation of a medicine for the treatment of humans and animals.

Description

Oral pharmaceutical formulations that they comprise substituted pyrazoline compounds.

The present invention relates to formulations Oral pharmaceuticals comprising pyrazoline compounds substituted, in addition to its use for the preparation of a medicine for the treatment of humans and animals.

Cannabinoids are compounds that are derived from the Cannabis sativa plant that is commonly known as marijuana. The most active chemical compound of natural cannabinoids is tetrahydrocannabinol (THC), particularly Δ9 -THC.

These natural cannabinoids, in addition to their synthetic analogs, enhance their physiological effects through binding to specific G-protein coupled receptors, the called cannabinoid receptors.

Currently, they have been identified and cloned two different types of receptors that bind both to natural cannabinoids as synthetic. These receivers, which CB_ {1} and CB_ {2} are designated, participate in a variety of physiological or pathophysiological processes in humans and animals, for example, system related processes central nervous, the immune system, the cardiovascular system,  the endocrine system, the respiratory system, the tract gastrointestinal or with reproduction, as described by example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991; Consroe and Sandyk, in Marijuana / Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.

Therefore, compounds that have a high binding affinity for these cannabinoid receptors and that are suitable for modulating these receptors are useful in prevention and / or the treatment of disorders related to recipients of cannabinoids

In particular, the CB_ {1} receiver participates in many different disorders related to ingestion of foods, such as bulimia or obesity, including obesity associated with type II diabetes (non-insulin dependent diabetes) and therefore, suitable compounds can be used to regulate this receptor in the prophylaxis and / or treatment of these disorders.

Therefore, an object of the present invention was to provide appropriate pharmaceutical formulations for novel compounds for use as active ingredients in medicines. In particular, these active principles must be suitable for modulation of cannabinoid receptors, more particularly for the modulation of the receptors of cannabinoids 1 (CB1).

This object was achieved by providing the substituted pyrazoline compounds of general formula I provided then its stereoisomers, corresponding salts and corresponding solvates thereof.

It has been found that these compounds have a high affinity for cannabinoid receptors, particularly for the CB1 receptor, and acting as modulators, by example, antagonists, inverse agonists or agonists of these receivers Therefore, they are suitable for prophylaxis and / or treatment of various system related disorders central nervous, the immune system, the cardiovascular system,  the endocrine system, the respiratory system, the tract gastrointestinal or eating disorders or with reproduction in humans and / or animals, preferably in humans including infants, children and the elderly.

Therefore, in one of its aspects this invention relates to substituted pyrazoline compounds of general formula I,

one

in the that

R 1 represents a phenyl group optionally at least monosubstituted,

R2 represents a phenyl group optionally at least monosubstituted,

R 3 represents a cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, which optionally contains at least one heteroatom as a member of ring, which can be condensed with a cyclic, mono or polycyclic, at least monosubstituted, or R3 represents a group aryl or heteroaryl optionally at least monosubstituted, which it can be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or R3 represents a moiety -NR 4 R 5,

R 4 and R 5, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, 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, at least monosubstituted, or an aryl or heteroaryl group optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a linear or branched alkylene group, a remainder -SO2 -R6, or a remainder -NR 7 R 8,

R 6 represents an aliphatic, linear 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 ring member, which may be condensed with a cyclic, mono or polycyclic system, or a group aryl or heteroaryl optionally at least monosubstituted, which can  be condensed with a cyclic, mono or polycyclic system and / or bound through a linear or branched alkylene group,

R 7 and R 8, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, 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, at least monosubstituted, or an aryl or heteroaryl group optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a linear or branched alkylene group,

with the condition of

R 4 and R 5 do not both represent an atom of hydrogen, and

than if one of the residues R 4 and R 5 represents a hydrogen atom or an alkyl group, which is optionally at least monosubstituted with an alkoxy group, a alkoxyalkoxy group, a halogen atom or a phenyl group, the another of these residues R 4 and R 5 does not represent a group pyridyl-2-yl, which is optionally monosubstituted in position 5, a group pyridyl-5-yl, which is optionally monosubstituted in position 2, a group pyrimidyl-5-yl, which is optionally monosubstituted in position 2, a group pyridaz-3-yl, which is optionally monosubstituted in position 6, a group pirazin-5-ilo, which is optionally monosubstituted in position 2, a group tien-2-yl, which is optionally monosubstituted in position 5, a group tien-2-yl, which is optionally at least monosubstituted in position 4, a benzyl group, which is optionally monosubstituted in position 4 of the ring, a phenethyl group, which is optionally monosubstituted in the ring position 4, an optionally mono phenyl group, di o trisubstituted, a disubstituted phenyl group, in which the two substituents together form a chain -OCH2O-, -OCH2CH2O- or -CH2CH2O-, which is optionally substituted with one or more halogen atoms or one or two groups methyl, a -NH-phenyl moiety, in which the group phenyl may be monosubstituted in position 4, and

than if one of the residues R 4 and R 5 represents an alkynyl group, the other of these R 4 residues and R 5 does not represent a phenyl group, which is optionally replaced in position 4, and

than if one of the residues R 4 and R 5 represents a hydrogen atom or an aliphatic, linear or radical branched, saturated or unsaturated, unsubstituted or substituted, the another of these residues R 4 and R 5 does not represent a group unsubstituted or substituted thiazole or a group [1,3,4] thiadiazole not substituted or substituted

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;

I

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at least one compound of formula (II),

2

in the that

R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched,

R 2 ', R 3' and R 4 'independently each other 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,

R 5 'and R 6' independently of each other represent 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, 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 R 11 'for each substituent represents independently linear C 1-6 alkyl or branched;

R 7 'represents hydrogen, a linear or branched C 1-6 alkyl group, a linear or branched C 1-6 alkoxy group, a halogen atom, CHF 2, 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 10'11', where R 10 ' and optionally R 11 'for each substituent independently represents linear or branched C 1-6 alkyl;

with the condition of

if R 1 'and R 7' are H and R 5 'and R 6 'both represent C1 in positions 3 and 4 of the ring of phenyl, none of R 2 ', R 3' and R 4 'can represent F at position 4 of the phenyl ring if the other two of R 2 ', R 3' and R 4 'both represent H;

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;

I

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at least one compound of formula (III)

3

in the that

R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched,

R 12, R 13, R 14 or R 15 independently of each other they represent 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, SH, NH 2, hydrogen, methyl, ethyl, F, Cl, Br and CF 3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a solvate

corresponding thereof,

characterized in that the pharmaceutical composition is in any of the pharmaceutical forms (a), (b), (c), (d) or (e) and, therefore, includes:

a) 0.05% to 0.5% by weight of the principle active of a surfactant and optionally one or more excipients additional pharmacists; or

b) an additive that ensures a penetration of water inside the core of the preparation and a release polymer controlled; or

c) at least one additive that ensures a water penetration into the core of the preparation and at least a hydrogel forming polymer; or

d) a nucleus formed by an inert nucleus, a water soluble inert polymer and optionally excipients pharmaceutically stable; or

e) an inert core, with

(aa)

a first layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

(bb)

a second layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable.

It has been found that the compounds of substituted pyrazoline of general formula I, the stereoisomers of the same, the N-oxides thereof, the corresponding salts and the corresponding solvates have a high affinity for cannabinoid receptors, particularly by the receptors of cannabinoids 1 (CB1), that is, they are selective ligands for the CB1 receptor and act as modulators, for example, antagonists, inverse agonists or agonists of these receptors. Therefore, this also applies to the formulations of the invention comprising these compounds. In particular, these Pyrazoline compounds show little or no development of tolerance during treatment, particularly with respect to  food intake, that is, if the treatment is interrupted for a given period of time and then continue subsequently, the pyrazoline compounds used according to the invention will again show the desired effect. After finishing the treatment with pyrazoline compounds is found to The positive influence on body weight continues.

Compounds according to formulas II or III (specifically example 18) are inhibitors of high levels of blood triglycerides Again, this clearly applies also to the formulations of the invention comprising these compounds.

In addition, all these pyrazoline compounds show a relatively weak affinity for the Herg channel, for therefore, for these compounds a low risk of prolongation of the QT interval.

In short, pyrazoline compounds used according to the invention are distinguished by a broad spectrum of beneficial effects, while at the same time show relatively few unwanted effects, that is, effects that do not contribute positively to or even interfere with the patient well-being In general, this effect can also be observed with the pharmaceutical formulations according to the present invention.

A very preferred aspect of the present invention relates to a pharmaceutical composition for the oral administration comprising at least one compound of substituted pyrazoline of general formula I,

4

in the that

R 1 represents a phenyl group optionally at least monosubstituted,

R2 represents a phenyl group optionally at least monosubstituted,

R 3 represents a cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, which optionally contains at least one heteroatom as a member of ring, which can be condensed with a cyclic, mono or polycyclic, at least monosubstituted, or R3 represents a group aryl or heteroaryl optionally at least monosubstituted, which it can be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or R3 represents a moiety -NR 4 R 5,

R 4 and R 5, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, 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, at least monosubstituted, or an aryl or heteroaryl group optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a linear or branched alkylene group, a remainder -SO2 -R6, or a remainder -NR 7 R 8,

R 6 represents an aliphatic, linear 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 ring member, which may be condensed with a cyclic, mono or polycyclic system, or a group aryl or heteroaryl optionally at least monosubstituted, which can  be condensed with a cyclic, mono or polycyclic system and / or bound through a linear or branched alkylene group,

R 7 and R 8, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, 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, at least monosubstituted, or an aryl or heteroaryl group optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a linear or branched alkylene group,

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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The compounds according to formula I have a high affinity for cannabinoid receptors, particularly for the CB1 receptor, and show a marked and prolonged effect in body weight.

Particularly preferably, they apply The following conditions (exclusions) for compounds of General formula I pyrazoline given above:

that R 4 and R 5 do not both represent a hydrogen atom, and

than if one of the residues R 4 and R 5 represents a hydrogen atom or an alkyl group, which is optionally at least monosubstituted with an alkoxy group, a alkoxyalkoxy group, a halogen atom or a phenyl group, the another of these residues R 4 and R 5 does not represent a group pyridyl-2-yl, which is optionally monosubstituted in position 5, a group pyridyl-5-yl, which is optionally monosubstituted in position 2, a group pyrimidyl-5-yl, which is optionally monosubstituted in position 2, a group pyridaz-3-yl, which is optionally monosubstituted in position 6, a group pirazin-5-ilo, which is optionally monosubstituted in position 2, a group tien-2-yl, which is optionally monosubstituted in position 5, a group tien-2-yl, which is optionally at least monosubstituted in position 4, a benzyl group, which is optionally monosubstituted in position 4 of the ring, a phenethyl group, which is optionally monosubstituted in the ring position 4, an optionally mono phenyl group, di o trisubstituted, a disubstituted phenyl group, in which the two substituents together form a chain -OCH2O-, -OCH2CH2O- or -CH2CH2O-, which is optionally substituted with one or more halogen atoms or one or two groups methyl, a -NH-phenyl moiety, in which the group phenyl may be monosubstituted in position 4, and

than if one of the residues R 4 and R 5 represents an alkynyl group, the other of these R 4 residues and R 5 does not represent a phenyl group, which is optionally replaced in position 4, and

than if one of the residues R 4 and R 5 represents a hydrogen atom or an aliphatic, linear or radical branched, saturated or unsaturated, unsubstituted or substituted, the another of these residues R 4 and R 5 does not represent a group unsubstituted or substituted thiazole or a group [1,3,4] thiadiazole not substituted or substituted.

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A mono or polycyclic cyclic system according to the present invention means a cyclic hydrocarbon mono system or polycyclic that can be saturated, unsaturated or aromatic. If he cyclic system is polycyclic, each of the different rings it can show a different degree of saturation, that is, it can be saturated, unsaturated or aromatic. Optionally each of the mono or polycyclic cyclic system rings may contain one or more, preferably 1, 2 or 3, heteroatoms as ring members, that may be identical or different and that may preferably be selected from the group consisting of N, O, S and P, more referrably from the group consisting of N, O S. Preferably, the polycyclic cyclic system may comprise Two rings that are condensed. The rings of the cyclic system mono or polycyclic are preferably 5 or 6 members.

The term "condensate" according to the present invention means that a ring or cyclic system is attached to another ring or cyclic system, in which the terms "voided" or "anelated" are also used by experts in the art to designate this kind of union.

If one or more of the waste R 3 -R 8 represents or comprises a group saturated or unsaturated cycloaliphatic, which optionally contains the minus a heteroatom as a ring member, which is replaced by one or more, for example, 1, 2, 3 or 4, substituents, unless define otherwise, each of the substituents can be independently selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, C 1-6 alkoxy branched or unbranched, C 1-6 alkyl branched or unbranched, perfluoroalkoxy C 1-4 branched or unbranched, C 1-4 perfluoroalkyl branched or unbranched branched, oxo, amino, carboxyl, amido, cyano, nitro, -SO2 NH2, -CO-alkyl C 1-4, -SO-alkyl C 1-4, -SC 2 -alkyl C_ {1-4}, -NH-SO2 -alkyl C 1-4, in which the alkyl C_ {1-4} can, in each case, be branched or not branched, and a phenyl group, more preferably selected from the group consisting of hydroxyl, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, oxo, CF 3 and a phenyl group.

If one or more of the waste R 3 -R 8 represents or comprises a group cycloaliphatic, which contains one or more heteroatoms as members of ring, unless otherwise defined, each of these heteroatoms can preferably be selected from the group that consists of N, O and S. Preferably, a cycloaliphatic group can contain 1, 2 or 3 selected heteroatoms regardless of the group consisting of N, O and S as members ring

Saturated or unsaturated cycloaliphatic groups, optionally at least monosubstituted, which optionally contain at least one heteroatom as a ring member can be selected preferably from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl and morpholinyl

If one or more of the waste R 3 -R 8 comprises a mono or cyclic system polycyclic, which is substituted by one or more, for example, 1, 2, 3, 4 or 5 substituents, unless otherwise defined, each of the substituents can be independently selected from group consisting of hydroxyl, fluorine, chlorine, bromine, alkoxy C 1-6 branched or unbranched, alkyl C 1-6 branched or unbranched, C 1-4 perfluoroalkoxy branched or unbranched branched, branched C 1-4 perfluoroalkyl or unbranched, amino, carboxyl, oxo, amido, cyano, nitro, -SO2 NH2, -CO-alkyl C 1-4, -SO-alkyl C 1-4, -SO 2 -alkyl C_ {1-4}, -NH-SO2 -alkyl C 1-4, in which the alkyl C_ {1-4} can, in each case, be branched or not branched, and a phenyl group, more preferably selected from the group consisting of hydroxyl, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF 3, oxo and a phenyl group.

If one or more of the residues R 1 -R 8 represents or comprises an aryl group, including a phenyl group, which is substituted by one or more, for example, 1, 2, 3, 4 or 5 substituents, unless otherwise defined, each of the substituents can be independently selected from the group consisting of a halogen atom (eg, F, Cl, Br, I), a linear C 1-6 alkyl group or branched, a linear or branched C 1-6 alkoxy group, a formyl group, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-C 1-6 alkyl group, a cyano group, a nitro group, a carboxyl group, a group -CO-O-C 1-6 alkyl, a moiety -CO-NR A R B, a moiety -CO-NH-NR-C R D, a -SH, a group -S-C 1-6 alkyl, a group -SO-C 1-6 alkyl, a group -SO 2 -C 1-6 alkyl }, a group - (C 1-6 alkylene) -S-C 1-6 alkyl, a group - (C 1-6 alkylene) -SO-C 1-6 alkyl, a group - (C 1-6 alkylene) - SO 2 -C 1-6 alkyl, a moiety -NH 2, a NHR 'or an NR'R''moiety, wherein R' and R '' independently represent a linear or branched C 1-6 alkyl group, a C 1-6 alkyl group substituted by one or more hydroxyl groups and a group - (C 1-6 alkylene) -
NR E R F,

in which R A, R B, identical or different, they represent hydrogen or an alkyl group C 1-6, or R A and R B together with the atom of nitrogen that forms a bridge form a saturated cyclic system, mono or bicyclic, 3-10 membered heterocyclic, which may be at least monosubstituted by one or more groups C 1-6 alkyl, identical or different, and / or that they may contain at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a member of ring,

R C, R D, identical or different, they represent a hydrogen atom, an alkyl group C_ {1-6}, a group -CO-O-alkyl C 1-6, a cycloalkyl group C 3-8, a group (rent C 1-6) - cycloalkyl C 3-8, a group (rent C 1-6) -O-alkyl C 1-6 or an alkyl group C_ {1-6} substituted with one or more groups hydroxyl, or R C, R D together with the nitrogen atom that bridges form a saturated cyclic system, mono or bicyclic, 3-10 membered heterocyclic, which they may be at least monosubstituted by one or more substituents independently selected from the group consisting of group C 1-6 alkyl, a group -CO-C 1-6 alkyl, a -CO-O-alkyl C_ {1-6}, a group -CO-NH-alkyl C_ {1-6}, a group -CS-NH-alkyl an oxo group, a C 1-6 alkyl group substituted with one or more hydroxyl groups, a group (C 1-6 alkylene) -O-C 1-6 alkyl and a group -CO-NH2 and / or which may contain at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a ring member, and

in which R E, R F, identical or different, they represent hydrogen or an alkyl group C 1-6, or R E and R F together with the atom of nitrogen that forms a bridge form a saturated cyclic system, mono or bicyclic, 3-10 membered heterocyclic, which may be at least monosubstituted by one or more, identical or different C 1-6 alkyl groups and / or which may contain at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a member of ring.

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Preferred aryl groups, which may be optionally at least monosubstituted, they are phenyl and naphthyl.

If one or more of the waste R 3 -R 8 represents or comprises a group heteroaryl, which is substituted by one or more, for example, 1, 2, 3, 4 or 5 substituents, unless otherwise defined, each of the substituents can be independently selected from group consisting of a halogen atom (for example, F, Cl, Br, I), a linear or branched C 1-6 alkyl group, a linear or branched C 1-6 alkoxy group, a formyl group, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-alkyl group C 1-6, a cyano group, a carboxyl group, a -CO-O-alkyl group C_ {1-6}, a remainder -CO-NR A R B, a remainder -CO-NH-NR C R D, a group -S-C 1-6 alkyl, a group -SO-C 1-6 alkyl, a group -SO2 -C 1-6 alkyl, a group - (rent C 1-6) - S-alkyl C 1-6, a group - (rent C 1-6) - SO-alkyl C 1-6, a group - (rent C 1-6) - SO 2 -alkyl C 1-6, an alkyl group C 1-6 substituted by one or more hydroxyl groups and a group - (rent C 1-6) - NR E R F,

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in which R A, R B, identical or different, they represent hydrogen or an alkyl group C 1-6, or R A and R B together with the atom of nitrogen that forms a bridge form a saturated cyclic system, mono or bicyclic, 3-10 membered heterocyclic, which may be at least monosubstituted by one or more groups C 1-6 alkyl, identical or different, and / or that they may contain at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a member of ring,

R C, R D, identical or different, they represent a hydrogen atom, an alkyl group C_ {1-6}, a group -CO-O-alkyl C 1-6, a cycloalkyl group C 3-8, a group (rent C 1-6) - cycloalkyl C 3-8, a group (rent C 1-6) -O-alkyl C 1-6 or an alkyl group C_ {1-6} substituted with one or more groups hydroxyl, or R C, R D together with the nitrogen atom that bridges form a saturated cyclic system, mono or bicyclic, 3-10 membered heterocyclic, which they may be at least monosubstituted by one or more substituents independently selected from the group consisting of group C 1-6 alkyl, a group -CO-C 1-6 alkyl, a group -CO-O-alkyl C_ {1-6}, a group -CO-NH-alkyl C_ {1-6}, a group -CS-NH-alkyl C 1-6, an oxo group, an alkyl group C 1-6 substituted with one or more hydroxyl groups,  a group (rent C 1-6) -O-C 1-6 alkyl and a -CO-NH2 and / or which may contain at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a ring member, and

in which R E, R F, identical or different, they represent hydrogen or an alkyl group C 1-6, or R E and R F together with the atom of nitrogen that forms a bridge form a saturated cyclic system, mono or bicyclic, 3-10 membered heterocyclic, which may be at least monosubstituted by one or more, identical or different C 1-6 alkyl groups and / or which may contain at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a member of ring,

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Heteroatoms, which are present as ring members in the heteroaryl radical, may, unless otherwise defined, independently selected from the group It consists of nitrogen, oxygen and sulfur. Preferably a heteroaryl radical may comprise 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.

Suitable heteroaryl groups, which may be optionally at least monosubstituted, can be selected preferably from the group consisting of thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzo [1,2,5] -thiodiazolyl, benzo [b] thiophenyl, benzo [b] furanyl, imidazo [2,1-b] thiazolyl, triazolyl, and pyrazolyl, more preferably selected from the group that consists of thienyl, benzo [1,2,5] -thiodiazolyl, benzo [b] thiophenyl, imidazo [2,1-b] thiazolyl, triazolyl and pyrazolyl

If one or more of the residues R 4 -R 8 represents or comprises a linear or branched, saturated or unsaturated aliphatic group such as an alkyl group, which is substituted by one or more, for example, 1, 2, 3, 4 or 5 substituents, unless otherwise defined, each of the substituents may be independently selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, branched or unbranched C 1-4 alkoxy, C 1-4 branched or unbranched perfluoroalkoxy, C 1-4 branched or unbranched perfluoroalkyl, amino, carboxyl, amido, cyano, nitro, SO 2 NH 2,
-CO-C 1-4 alkyl, -SO-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, -NH-SO 2 -C 1-4 alkyl , in which the C 1-4 alkyl can, in each case, be branched or unbranched, and a phenyl group, more preferably selected from the group consisting of hydroxyl, F, Cl, Br, methoxy, ethoxy, CF 3 and a phenyl group.

Linear or branched aliphatic groups, saturated or unsaturated, preferred, 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.

If any of the waste R 4 -R 8 represents or comprises a group linear or branched alkylene, said alkylene group can preferably selected from the group consisting of methylene - (CH 2) -, ethylene - (CH 2 -CH 2) -, n-propylene- (CH2 -CH2 -CH2) - or iso-propylene - (- C (CH 3) 2) -.

Pyrazoline compounds are preferred substitutes of general formula I provided above, in the that

R 1 represents a phenyl group optionally at least monosubstituted,

R2 represents a phenyl group optionally at least monosubstituted,

R 3 represents a cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, which optionally contains at least one heteroatom as a member of ring, which can be condensed with a cyclic, mono or polycyclic, at least monosubstituted, or R3, represents a group aryl or heteroaryl optionally at least monosubstituted, which it can be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or R3 represents a moiety -NR 4 R 5,

R 4 and R 5, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, 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, at least monosubstituted, or an aryl or heteroaryl group optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a linear or branched alkylene group, a remainder -SO2 -R6, or a remainder -NR 7 R 8,

R 6 represents an aliphatic, linear 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 ring member, which may be condensed with a cyclic, mono or polycyclic system, or a group aryl or heteroaryl optionally at least monosubstituted, which can  be condensed with a cyclic, mono or polycyclic system and / or bound through a linear or branched alkylene group,

R 7 and R 8, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, 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, at least monosubstituted, or an aryl or heteroaryl group optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a linear or branched alkylene group,

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,

in which the following conditions (exclusions):

that R 4 and R 5 do not both represent a hydrogen atom, and that if one of the residues R 4 and R 5 represents a hydrogen atom or a linear aliphatic group or branched, saturated or unsaturated, substituted or unsubstituted, the another of these residues R 4 and R 5 does not represent a group substituted or unsubstituted pyridyl, a substituted pyrimidyl group or unsubstituted, a substituted or unsubstituted pyridazyl group, a substituted or unsubstituted pyrazinyl group, a thienyl group substituted or unsubstituted, a substituted or unsubstituted benzyl group substituted, a substituted or unsubstituted phenethyl group, a group substituted or unsubstituted phenyl, a substituted or unsubstituted phenyl group substituted, which is condensed (attached) to at least one ring or cyclic system, optionally substituted, a remainder -NH-phenyl, in which the phenyl group may be at least monosubstituted, an unsubstituted thiazole group or substituted, or a group [1,3,4] unsubstituted thiadiazole or replaced.

Compounds of substituted pyrazoline of general formula I provided above, in which R 1 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a group linear or branched C 1-6 alkyl, a group linear or branched C 1-6 alkoxy, an atom of halogen, CH2F, CHF2, CF3, CN, OH, NO2, - (C = O) -R ', SH, SR', SOR ', SO_2R', NH_ {2}, NHR ', NR'R' ', - (C = O) -NH2, - (C = O) -NHR 'and - (C = O) -NR'R' ', in the that R 'and R' 'for each substituent independently represent linear or branched C 1-6 alkyl, preferably R 1 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 1 represents a phenyl group, which is substituted with a chlorine atom in position 4, and R2 -R8 have the meaning given above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any reason of mixture, or a corresponding N-oxide thereof, or a salt corresponding thereof, or a corresponding solvate of the same.

Compounds of substituted pyrazoline of general formula I provided above, in which R2 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a group linear or branched C 1-6 alkyl, a group linear or branched C 1-6 alkoxy, an atom of halogen, CH2F, CHF2, CF3, CN, OH, NO2, - (C = O) -R ', SH, SR', SOR ', SO_2R', NH_ {2}, NHR ', NR'R' ', - (C = O) -NH2, - (C = O) -NHR 'and - (C = O) -NR'R' 'in the that R 'and R' 'for each substituent independently represent linear or branched C 1-6 alkyl, preferably R2 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 R2 a phenyl group, which is disubstituted with two chlorine atoms in positions 2 and 4, and R1 and R 3 -R 8 have the meaning given above, 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.

Preference is also given to compounds of substituted pyrazoline of general formula I provided above, in which R 3 represents a group C 3-8 cycloaliphatic, saturated or unsaturated, optionally at least monosubstituted, which optionally contains at least one heteroatom as a ring member, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or R3 represents an aryl or heteroaryl group 5 or 6 members, optionally at least monosubstituted, which can be condensed with a cyclic, mono or polycyclic system, by less monosubstituted, or R3 represents a moiety -NR 4 R 5, preferably R 3 represents a group C 3-8 saturated cycloaliphatic, optionally at less monosubstituted, optionally containing one or more atoms of nitrogen as ring members, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or R 3 represents a -NR 4 R 5 moiety, more preferably R 3 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 R 3 represents a moiety -NR 4 R 5 and R 1, R 2 and R 4 -R 8 have the meaning given above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any reason of mixture, or a corresponding N-oxide thereof, or a salt corresponding thereof, or a corresponding solvate of the same.

In addition, the substituted pyrazoline compounds of the general formula I given above, in which R 4 and R 5, identical or different, represent a hydrogen atom, a C 1-6 aliphatic radical are preferred , unbranched 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 a cyclic, mono or polycyclic system, at least monosubstituted, or a 5 or 6 membered aryl or heteroaryl group, optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or attached to through a methylene group
(-CH 2 -) or ethylene (-CH 2 -CH 2) -, a moiety -SO 2 -R 6, or a moiety -NR 7 R ^ { 8, preferably one of these residues R 4 and R 5 represents a hydrogen atom and the other of these residues R 4 and R 5 represents 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 a cyclic, mono or polycyclic system, at least monosubstituted, or an aryl or heteroaryl group of 5 or 6 members, optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, a moiety -SO2 -R6, or a moiety -NR7R ^ 8, or R 4 and R 5, identical or different, each represents a C 1-6 alkyl group, more preferably one of the residues R 4 and R 5 represents a hydrogen atom and the other of these residues R 4 and R 5 represents an optional pyrrolidinyl group at least one monosubstituted entity, an optionally at least monosubstituted piperidinyl group, an optionally at least monosubstituted piperazinyl group, an optionally at least monosubstituted triazolyl group, a -SO2 -R6 moiety, or a -NR2 moiety 7 R 8, or R 4 and R 5, 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, and R 1 -R 3 and R 6 -R 8 have the meaning given above, 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 thereof, or a corresponding salt of the same, or a corresponding solvate thereof.

Compounds of substituted pyrazoline of general formula I provided above, in which R 6 represents an aliphatic group C 1-6, linear or branched, saturated or unsaturated, optionally at least monosubstituted, a group cycloaliphatic, saturated or unsaturated, optionally at least monosubstituted, optionally containing at least one heteroatom as a ring member, which may be condensed with a system cyclic, mono or polycyclic, or an aryl or heteroaryl group of 5 or 6 members, optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system and / or attached to through a methylene (-CH2 -) or ethylene group (-CH 2 -CH 2) -, preferably R 6 represents a C 1-6 alkyl group, a group saturated cycloaliphatic, optionally at least monosubstituted, which it can be condensed with a cyclic, mono or polycyclic system, or a phenyl group, which is optionally substituted with one or more C 1-6 alkyl groups, and R 1 -R 5, R 7 and R 8 have the meaning given above, 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 an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof.

Pyrazoline compounds are also preferred. substitutes of general formula I provided above, in the that R 7 and R 8, identical or different, represent an atom of hydrogen, a C 1-6 aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, a cycloaliphatic group, saturated 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, at least monosubstituted, or an aryl or heteroaryl group of 5 or 6 members, optionally at least monosubstituted, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted and / or linked through a methylene group (-CH2 -) or ethylene (-CH2 -CH2) -, preferably represent a hydrogen atom or an alkyl radical C 1-6, and R 1 -R 6 have the meaning provided above, 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 an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof.

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Particularly preferred are the compounds of general formula I given below,

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5

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in the that

R 1 represents a phenyl ring, which is monosubstituted with a halogen atom, preferably an atom of chlorine, in position 4,

R2 represents a phenyl ring, which is disubstituted with two halogen atoms, preferably atoms of chlorine, in its positions 2 and 4,

R 3 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a group homopiperazinyl, a morpholinyl group, or a moiety -NR 4 R 5,

R 4 represents a hydrogen atom or a linear or branched C 1-6 alkyl group,

R 5 represents an alkyl group C 1-6 linear or branched, a group pyrrolidinyl, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, in which each of the heterocyclic rings they can be substituted with one or more alkyl groups C_ {1-6}, identical or different, or a remainder -SO2 -R6, and

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

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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Compounds are more particularly preferred of substituted pyrazoline selected from the group consisting in:

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,

acid diethylamide 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] -piperidin-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, or a corresponding salt, or a solvate correspondent.

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In another aspect, the present invention also provides a process for the preparation of compounds of substituted pyrazoline of general formula I, according to which it is made reacting at least one benzaldehyde compound of the general formula IV

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6

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in which R1 has the meaning given above, with a pyruvate compound of general formula (V)

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7

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in which G represents an OR group, R being a branched C 1-6 alkyl radical or unbranched, preferably an ethyl radical, or G represents a group O - K with K being a cation, preferably a cation monovalent, more preferably an alkali metal cation, even more preferably a sodium cation, to give a compound of general formula (SAW)

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8

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in which R1 has the meaning provided above, which is optionally isolated and / or optionally it is purified, and that is reacted with a optionally substituted phenylhydrazine of formula (VII)

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9

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or with a corresponding salt of the same, in which R2 has the meaning given above, under inert atmosphere, to give a compound of formula (VIII)

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10

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in which R1 and R2 have the meaning given above, which is optionally isolated and / or optionally purified, and optionally transferred under an inert atmosphere to a compound of formula (IX)

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eleven

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in which the R 1 substituents and R2 have the meaning given above and A represents a leaving group, by reaction with an agent activating, optionally isolating and / or optionally purifying said compound, and at least one compound of general formula (VI) is reacts with a compound of the general formula R3H, in the that R 3 represents a -NR 4 R 5 moiety, wherein R 4 and R 5 have the meaning given above, to give a substituted pyrazoline compound of general formula I, in the that R 3 represents a remainder -NR 4 R 5,

and / or at least one compound of the general formula (IX) is reacted with a compound of general formula R 3 H, in which R 3 has the meaning given above to give a compound of general formula (I) provided above, which is optionally isolated and / or optionally purified.

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The procedure is also illustrated in the Scheme I provided below:

Scheme I

12

The reaction of the benzaldehyde compound of formula IV with a pyruvate compound of formula V is brought to preferably carried out in the presence of at least one base, plus preferably in the presence of an alkali metal hydroxide, such such as sodium hydroxide or potassium hydroxide or a methoxide of alkali metal, such as sodium methoxide, as described, by 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, sodium pyruvate can be used as the pyruvate compound. Preferably, said reaction is carried out in a protic reaction medium such as an alcohol C 1-4 alkyl or mixtures thereof. Too mixtures of such alcohols with water can be used, for example, ethanol / water

The reaction temperature as well as the duration of the reaction, it can 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 to carry out the reaction. of the benzaldehyde compound of formula IV with a compound of pyruvate of formula V under acid catalyzed conditions, plus preferably refluxing the mixture in dichloromethane in presence of copper (II) trifluoromethanesulfonate as describes, for example, in Synlett, (1), 147-149, 2001. The respective description is incorporated as a reference to the present document and form part of the description.

The reaction of the compound of formula (VI) with a substituted phenylhydrazine of formula (VII) is carried out preferably in a suitable reaction medium, such as alcohols or C 1-4 ethers, such as dioxane or tetrahydrofuran or mixtures of at least two of these compounds previously mentioned. Also preferably, said reaction it can be carried out in the presence of an acid, whereby 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, methoxide sodium or sodium ethoxide, or a mixture of At least two of these bases.

The reaction temperature as well as the duration of the reaction, it can vary over a wide range. The Preferred reaction temperatures range 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 (VIII) can be activated for subsequent reactions by introduction of a suitable leaving group according to methods Conventionals well known to those skilled in the art. Preferably, the compounds of formula (VIII) are transferred to an acid chloride, an acid anhydride, a mixed anhydride, a C 1-4 alkyl ester, an activated ester such as p-nitrophenyl ester. Other methods well Known for acid activation include activation with N, N-dicyclohexylcarbodiimide or hexafluorophosphate benzotriazol-N-oxotris (dimethylamino) phosphonium (BOP)).

If said activated compound of formula (IX) in an acid chloride, is preferably prepared by reaction of the corresponding acid of formula (VIII) with thionyl or oxalyl chloride, whereby said Chlorination is also used as a solvent. Preferably, an additional solvent can also be used. Solvents Suitable 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. They can also mixtures of two or more solvents of a class or two are used or more solvents of different kinds. Reaction temperature preferred ranges from 0 ° C to the boiling point of solvent and reaction times from several minutes to several hours.

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

The reaction of the compound of the general formula (IX) with a compound of general formula HR3 to give compounds of general formula I, in which R 3 represents a -NR 4 R 5 moiety is preferably carried out in the presence of a base such as triethylamine, in a reaction medium such as methylene chloride The temperature is preferably in the range from 0 ° C to the boiling point of the medium of reaction. The reaction time can vary widely interval, for example, from several hours to several days.

The reaction of the compound of the general formula (IX) with a compound of the general formula HR 3 to give compounds of the general formula I, in which R 3 represents a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, optionally containing at least one heteroatom as a ring member, which may be condensed with a cyclic, mono or polycyclic system, optionally at least monosubstituted, or an optionally at least monosubstituted aryl or heteroaryl group, which may be condensed with a cyclic system, mono or polycyclic, optionally at least monosubstituted, can be carried out according to conventional methods well known to those skilled in the art, for example Pascual, A., J. Prakt Chem., 1999, 341 (7), 695-700; Lin, S. et al ., Heterocycles, 2001, 55 (2), 265-277; Rao, P. et al ., J. Org. Chem., 2000, 65 (22), 7323-7344, Pearson DE and Buehler, CA, Synthesis, 1972, 533-542 and the references cited therein. The respective descriptions are incorporated by reference to this document and form part of this description.

Preferably said reaction is carried out. in the presence of a Lewis acid, which is preferably selected of the group consisting of FeCl 3, ZnCl 2 and AlCl 3, in a suitable reaction medium such as toluene, benzene, tetrahydrofuran or similar reaction media. The temperature is preferably in the range of from 0 ° C to the point of boiling of the reaction medium, more preferably from 15 up to 25 ° C. The reaction time can vary widely interval, for example, from several minutes to several hours.

The aforementioned reactions that assume the synthesis of the ring of 4,5-dihydro-pyrazole or the reaction of a compound comprising said ring are carried out under a inert atmosphere, preferably nitrogen or argon, to avoid oxidation of the cyclic system. During the procedures described previously it may be necessary and / or desirable to protect sensitive groups or reagents. The introduction of groups Conventional protectors, in addition to their removal, can be carried out by methods well known to those skilled in the technique.

If the substituted pyrazoline compounds of general formula (I) 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 chiral reagents. It is also possible to obtain pure stereoisomers through the stereoselective synthesis.

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In another aspect the present invention relates to the compound

13

optionally in the form of one of 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, in particular as a product intermediate in a process to prepare compounds of substituted pyrazoline of general formula (I).

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In a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula (I) and stereoisomers thereof, in which at least one compound of general formula (I) 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.

Still in an additional aspect this invention also provides a process for the preparation of salts of substituted pyrazoline compounds of the general formula (I) or stereoisomers thereof, in which at least one compound of general formula (I) having at least one acidic group it is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. The right bases they are, for example, hydroxides, carbonates or alkoxides, which include suitable cations, derived for example from alkali metals, alkaline earth metals 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, 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, 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.

Those skilled in the art understand that the term substituted pyrazoline compounds as used herein should be understood to also encompass derivatives such as ethers, esters and complexes of these compounds. The term "derivatives" as used in this application is defined herein with the meaning of a chemical compound that has undergone a chemical derivation from an active compound to change (improve for pharmaceutical use) any of its properties. physicochemical, especially a so-called prodrug, for example, its esters and ethers. Examples of well-known methods for 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 Drug Design and Discovery, Taylor & Francis (April 2002 ). The respective description is incorporated as a reference to this document and is part of the description.

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

The substituted pyrazoline compounds of general formula (I) given below, its stereoisomers, the corresponding N-oxides, the corresponding salts of the themselves and the corresponding solvates are toxicologically acceptable and therefore suitable as active ingredients Pharmacists for the preparation of medicines.

It has been found that the compounds of substituted pyrazoline of general formula I provided to then the stereoisomers thereof, the N-oxides of the same, the corresponding salts and the solvates corresponding have a high affinity for the receptors of cannabinoids, particularly by cannabinoid receptors 1 (CB1), that is, are selective ligands for the receptor CB1 and act as modulators, for example, antagonists, Inverse agonists or agonists of these receptors. In particular, these pyrazoline compounds show little or no development of tolerance during treatment, particularly with respect to food intake, that is, if the treatment is interrupted for a given period of time and then continue subsequently, the pyrazoline compounds used according to the invention will again show the desired effect. After finishing the treatment with pyrazoline compounds is found to The positive influence on body weight continues.

In addition, these pyrazoline compounds show a relatively weak affinity for the Herg channel, therefore, to these compounds are expected a low risk of prolongation of the QT interval

In short, pyrazoline compounds used according to the invention are distinguished by a broad spectrum of beneficial effects, while at the same time show relatively few unwanted effects, that is, effects that do not contribute positively to or even interfere with the patient well-being

In another preferred aspect of the invention, the invention relates to a pharmaceutical composition for the oral administration comprising at least one compound of substituted pyrazoline of general formula II

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14

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in the that

R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched,

R 2 ', R 3' and R 4 'independently each other 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,

R 5 'and R 6' independently of each other represent 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, 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 R 11 'for each substituent represents independently linear C 1-6 alkyl or branched;

R 7 'represents hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, an atom of halogen, CH2F, CHF2, CF3, CN, OH, NO2, - (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 R 11 'for each substituent independently represents linear or branched C 1-6 alkyl;

with the condition of

if R 1 'and R 7' are H and R 5 'and R 6 'both represent Cl at positions 3 and 4 of the ring of phenyl, none of R 2 ', R 3' and R 4 'can represent F at position 4 of the phenyl ring if the other two of R 2 ', R 3' and R 4 'both represent H; optionally in 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 and nanoparticles for the production of a medication for prophylaxis and / or treatment of disorders related to the cannabinoid receptor system.

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These compounds according to formula I had a surprising effect on blood levels of substances relevant to the diet, for example triglycerides.

With respect to the compounds general formula II, linear or branched, saturated aliphatic groups are preferred  or unsaturated, which may be substituted by one or more substituents, may preferably be selected from the group that It consists of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 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, the radicals alkyl and cycloalkyl are understood to mean hydrocarbons saturated and unsaturated (but not aromatic), branched, not branched and cyclic, which may not be substituted or be mono or polysubstituted. In these radicals, alkyl C 1-2 represents C1 or C2 alkyl, alkyl C 1-3 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, C4 alkyl or C5, C 1-6 alkyl represents C1, C2 alkyl, 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, C5, C6 alkyl, C7 or C8, C 1-10 alkyl represents C1 alkyl, C2, C3, C4, C5, C6, C7, C8, C9 or C10 and alkyl C 1-18 represents C1, C2, C3, C4, C5 alkyl, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 or C18. In addition, C 3-4 cycloalkyl represents C3 or C4 cycloalkyl, C 3-5 cycloalkyl represents C3, C4 or C5 cycloalkyl, cycloalkyl C 3-6 represents C3, C4, C5 or C6 cycloalkyl, C 3-7 cycloalkyl represents C3 cycloalkyl, 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, C 5-6 cycloalkyl represents C5 or C6 cycloalkyl and C5-7 cycloalkyl represents C5, C6 or C7 cycloalkyl. With respect to cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or 0. However, mono or polyunsaturated cycloalkyl, preferably monounsaturated, without a heteroatom in the ring, also in particular, they fall within the term cycloalkyl always that the cycloalkyl is not an aromatic system. The radicals alkyl 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.

In this document, in relation to alkyl and cycloalkyl, unless expressly defined Otherwise, the term substituted in the context of this invention is understand what the replacement of at least one radical means hydrogen by F, Cl, Br, I, NH2, SH or OH, it being understood that "polysubstituted" radicals mean that substitution it has an effect on different or the same atoms several times with the same or different substituents, for example three times in the same C atom, as in the case of CF 3, or in different places as in the case of -CH (OH) -CH = CH-CHCl2. Substituents Particularly preferred herein are F, Cl and OH. With respect to cycloalkyl, the hydrogen radical can also replaced by 0 (C 1-3 alkyl) or C 1-3 alkyl (in each case mono or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3, methoxy or ethoxy.

The term (CH 2) 3-6 it should be understood that it 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_ {-}  (CH2) 1-4 should be understood as meaning -CH_ {2} -, -CH_ {2} -CH_ {2} -, -CH_ {2} -CH_ {2} -CH_ {2} - and -CH 2 -CH 2 -CH 2 -CH 2 -, (CH 2) 4 -5 should be understood that it means -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} - Y -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -, etc.

An aryl radical is understood to mean cyclic systems with at least one aromatic ring but without heteroatoms not even in one of the rings. Examples are phenyl, naphthyl, fluorantenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may not be substituted or be mono or polysubstituted.

A heteroaryl radical is understood to mean heterocyclic cyclic systems that have at least one ring unsaturated and may contain one or more heteroatoms of the group that It consists of nitrogen, oxygen and / or sulfur and may also be mono or polysubstituted. Examples that can be mentioned from the group of the heteroaryls 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.

In this document, in relation to aryl and heteroaryl, substituted means substitution of the aryl or heteroaryl by R, OR, a halogen, preferably F and / or Cl, a CF 3, a CN, a NO 2, an NRR, an alkyl C 1-6 (saturated), an alkoxy C 1-6, a cycloalkoxy C 3-8, a C 3-8 cycloalkyl or a C 2-6 alkylene.

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

In a preferred embodiment of the invention for a compound according to formula II, R 2 ', R 3 and R 4 independently of each other represent hydrogen, an alkyl group C 1-6 linear or branched, a halogen atom or CF 3, preferably R 2 ', R 3' and R 4 ' independently of each other they 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 5 'and R 6' independently of each other they represent an alkyl group C 1-6 linear or branched, a halogen atom or CF 3, preferably R 5 'and R 6' independently together they represent methyl, ethyl, F, Cl, Br and CF 3.

In a preferred embodiment of the invention for a compound according to formula II, R 2 'represents an atom of chlorine in position 4 of the phenyl ring, while R 3 'and R 4' represent hydrogen.

In a preferred embodiment of the invention for a compound according to formula II, R 5 'and R 6' each represents chlorine atoms in positions 2 and 4 of the phenyl ring, while R 7 'represents hydrogen.

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

In a very preferred aspect, the present invention invention relates to a pharmaceutical composition for oral administration comprising at least one compound of general formula II represented by a compound of general formula III

fifteen

in the that

R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched,

R 12 or R 13 independently of each other represent 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, SH, NH2, hydrogen, methyl, ethyl, F, Cl, Br and CF 3,

R 14 or R 15 independently of each other represent 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, SH, NH2, methyl, ethyl, F, Cl, Br and CF 3,

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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These compounds according to formula II had a surprising effect on blood levels of substances relevant to the diet, for example triglycerides.

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

In a preferred embodiment of the invention for a compound according to formula III, R 14 and R 15 independently of each other they represent an alkyl group C 1-6 linear or branched, a halogen atom or CF 3, preferably R 14 and R 15 independently together they represent methyl, ethyl, F, Cl, Br and CF 3.

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

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

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

In another preferred embodiment, the compound according to formula II or III is selected from the group consisting in:

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

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

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Another preferred embodiment of the invention also covers any prodrug of the compounds of the invention described above, in addition to any medicament comprising this and any use thereof; especially that it includes its esters and ethers. Those skilled in the art know examples of well known methods for producing a prodrug of a given active compound and can be found, for example, in Krogsgaard-Larsen et al ., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002).

In another aspect, the present invention also provides a process for the preparation of compounds of substituted pyrazoline of general formula II or III, in which R 1 'is hydrogen, given above, in which at least a benzaldehyde compound of general formula IV '

16

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wherein R 2 ', R 3' and R 4 'have the meaning mentioned above, it is done react with a pyruvate compound of the general formula (V ')

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17

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in which G represents an OR group, R being a branched C 1-6 alkyl radical or unbranched, or G represents a group O - K with K being a cation, preferably an inorganic cation, more preferably a cation alkali metal, more preferably sodium, to give a compound of general formula (SAW')

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18

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which is optionally isolated and / or optionally it is purified, and that is reacted with a optionally substituted phenylhydrazine of formula (VII ')

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19

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or with a corresponding salt of the same, in which R 5 ', R 6' and R 7 'have the meaning mentioned above, under inert atmosphere, to give a compound of formula (VIII ')

twenty

wherein R 2 ', R 3', R 4 ', R 5', R 6 'and R 7' have the meaning provided above, which is optionally isolated and / or optionally it is purified, and optionally it is esterified to give a alkyl ester if in the substituted pyrazoline compound of general formula I or II according to the invention R 1 'is a group C 1-4 alkyl - linear or branched.

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The process according to the invention is also illustrated in scheme I provided below:

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Scheme I

twenty-one

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The reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula V '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, such as describes, 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 duration of the reaction, it can 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.

Also preferably, the reaction of benzaldehyde compound of general formula III with a compound of pyruvate of general formula V 'is carried out under conditions acid catalyzed, more preferably refluxing the dichloromethane mixture 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 the general formula (VI ') with an optionally substituted phenylhydrazine of the formula general (VII ') is preferably carried out in a medium of suitable reaction such as alcohols or ethers C 1-4 such as dioxane or tetrahydrofuran or mixtures of at least two of these compounds above mentioned. Also preferably, said reaction can be carried out. carried out in the presence of an acid, whereby the acid can be organic, such as acetic and / or inorganic acid, such as acid hydrochloric. In addition, the reaction can also be carried out in presence of a base such as piperidine, piperazine, hydroxide sodium, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these can also be used bases.

The reaction temperature as well as the duration of the reaction, it can vary over a wide range. The suitable reaction temperatures range 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 (VIII ') can be activated for subsequent reactions by introducing a suitable leaving group according to methods Conventionals well known to those skilled in the art. Preferably the compounds of general formula (VIII ') are transferred to an acid chloride, an acid anhydride, a mixed anhydride, a C 1-4 alkyl ester or a activated ester such as a p-nitrophenyl ester. Other well known methods for acid activation include activation with N, N-dicyclohexylcarbodiimide or hexafluorophosphate benzotriazol-N-oxotris (dimethylamino) phosphonium (BOP)).

If said activated compound of general formula (VIII ') is an acid chloride, preferably prepared by the reaction of the corresponding acid of general formula (VIII ') with thionyl chloride or oxalyl chloride, said said also being used chlorinating agent as solvent. Preferably you can also an additional solvent be used. Suitable solvents include hydrocarbons such as benzene, toluene or xylene, hydrocarbons halogenates such as dichloromethane, chloroform or tetrachloride carbon, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane Mixtures of two or more may also be used. solvents of one class or two or more solvents of different lessons. The preferred reaction temperature ranges from 0 ° C to the boiling point of the solvent and the reaction times from several minutes to several hours.

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

After this, the activated compound can be made react with an alkyl alcohol to reach compounds according to the general formulas II or III, R 1 'being an alkyl group C 1-4 linear or branched.

During the procedures described previously it may be necessary and / or desirable to protect sensitive groups or reagents. The introduction of groups Conventional protectors, in addition to their removal, can be carried out by methods well known to those skilled in the technique.

If the pyrazoline compounds themselves Substitutes of general formula II or III 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, chromatographic methods or fractional crystallization with chiral reagents. It is also possible to obtain stereoisomers pure through stereoselective synthesis.

In a further aspect, the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula II or III and stereoisomers thereof, in which at least one compound of general formula II or III having at least one basic group is reacts 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.

Still in an additional aspect, the present invention provides a process for the preparation of salts of substituted pyrazoline compounds of general formula II or III or stereoisomers thereof, in which at least one compound of general formula II or III having at least one acidic group is reacts with one or more suitable bases, preferably in presence of a suitable reaction medium. The right bases they are, for example, hydroxides, carbonates or alkoxides, which include suitable cations, derived for example from alkali metals, alkaline earth metals 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 II or III, 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 II or III, 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 II or III of the invention, of a corresponding stereoisomer, or salt, or N-oxide, or solvate or any intermediate thereof it can be carried out, if desired, by conventional methods known to those skilled in the art, for example, methods chromatographic or recrystallization.

In another preferable aspect of the present invention, the pharmaceutical composition according to the present invention It is suitable for modulation (regulation) of receptors cannabinoids, preferably of cannabinoid receptors 1 (CB1), for the prophylaxis and / or treatment of disorders of the central nervous system, immune system disorders, cardiovascular system disorders, system disorders endocrine, respiratory system disorders, disorders of the gastrointestinal tract or reproductive disorders.

Particularly, preferably said Pharmaceutical composition is suitable for prophylaxis and / or the Psychosis treatment.

In addition, particularly preferably said pharmaceutical composition is suitable for prophylaxis and / or the treatment of eating disorders, preferably bulimia, anorexia, cachexia, obesity and / or diabetes Type II mellitus (non-insulin dependent diabetes), plus preferably obesity. The medicament of the invention also seems to be active in the prophylaxis and / or treatment of disorders of appetite, for example, the pyrazoline compounds of the formula General I also reduce the desire to eat sweets.

In addition, particularly preferably said pharmaceutical composition is suitable for prophylaxis and / or cancer treatment, preferably for prophylaxis and / or treatment of one or more types of cancers selected from the group which consists of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, cancer liver, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, intestinal cancer and prostate cancer, more preferably for the prophylaxis and / or treatment of one or more types of cancers selected from the group consisting of cancer of colon, bowel cancer and prostate cancer.

Particularly preferably said Pharmaceutical composition is suitable for prophylaxis and / or the treatment of alcoholism and / or alcohol addiction, abuse of nicotine and / or smoking, drug abuse and / or drug addiction and / or abuse of drugs and / or drug dependence, preferably drug abuse and / or drug addiction and / or abuse of nicotine and / or smoking.

Medications and / or drugs that are frequently subject to abuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.

The pharmaceutical composition is also suitable. for the prophylaxis and / or treatment of one or more of the disorders selected from the group consisting of bone disorders, preferably osteoporosis (for example, associated osteoporosis with a genetic predisposition, sex hormone deficit or aging), bone disease associated with cancer or disease Paget's bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, disorders spinocerebellar, cognitive disorders, head trauma, head trauma, stroke, seizures panic, peripheral neuropathy, inflammation, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremors, disorders compulsive, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, movement disorders induced by medications, dystonia, endotoxémic shock, hemorrhagic shock, hypotension, insomnia, immune disorders, plaques sclera, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for the potentiation of the analgesic effect of narcotic and non-narcotic pain relievers, or to influence the intestinal transit.

In an embodiment of the composition pharmaceutical according to the invention, the medicament is for the regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, especially stroke, of disorders of the cardiovascular system and disorders of the food intake, preferably bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

In an embodiment of the composition pharmaceutical according to the invention, the composition is for the prophylaxis and / or treatment of nervous system disorders central, immune system disorders, system disorders cardiovascular, endocrine system disorders, disorders of the respiratory system, gastrointestinal tract disorders or reproductive disorders

In an embodiment of the composition pharmaceutical according to the invention, the composition is for the modulation of cannabinoid receptors, preferably those cannabinoid 1 (CB1) receptors, for prophylaxis and / or treatment of central nervous system disorders, disorders of the immune system, disorders of the cardiovascular system, endocrine system disorders, system disorders respiratory, gastrointestinal tract disorders or disorders players.

The daily dosage for humans and Animals may vary depending on factors that are based on the respective species or other factors, such as age, sex, weight or degree of illness, etc. Dosage daily for humans can preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active ingredient that is going to administered during one or several intakes per day.

In a preferred aspect of the present invention, the pharmaceutical composition is in any of the following pharmaceutical forms (a), (b), (d) or (e) and, therefore, understands:

a) 0.05% to 0.5% by weight of the principle active of a surfactant and optionally one or more excipients additional pharmacists; or

b) an additive that ensures a penetration of water inside the core of the preparation and a release polymer controlled; or

d) a nucleus formed by an inert nucleus, a water soluble inert polymer and optionally excipients pharmaceutically stable; or

e) an inert core, with

(aa)

a first layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

(bb)

a second layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable.

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In a very preferred aspect of the present invention, the pharmaceutical composition is in the pharmaceutical form (a) and, therefore, includes:

a) 0.05% to 0.5% by weight of the principle active of a surfactant and optionally one or more excipients Additional pharmacists

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In a preferred aspect of the present invention in the pharmaceutical form (a), the pharmaceutical composition understands:

from 0.5% to 40% by weight of compound of formula (I), (II) or (III)

from 0.05% to 0.5% by weight of sodium alkylsulfate, and

from 2.5% to 10% by weight of disintegrant.

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In a preferred embodiment of the invention in the pharmaceutical form (a), the pharmaceutical composition understands:

from 0.5% to 40% by weight of compound of formula (I), (II) or (III)

from 0.1% to 0.4% by weight of sodium lauryl sulfate,

from 5% to 8% in weight of cross-linked sodium carboxymethyl cellulose,

from 1% to 10% in binder weight,

from 0.2% to 5% by weight of lubricant,

and a diluent in an amount sufficient to give 100%.

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In a preferred embodiment of the invention, in the pharmaceutical form (a) the surfactant is added to the water purified in the procedure.

In a preferred embodiment of the invention, in the pharmaceutical form (a) the composition is in the form of capsules, microgranules, granules, tablets, sachets, powders, tablets oblong, gels, particulate systems such as granules, microgranules, multiparticles and the like, optionally compressed to give tablets or fill in capsules.

In a preferred embodiment of the invention, in the pharmaceutical form (a) the composition is in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase

compound formula (I), (II) or (III)

30% starch of corn

60.78% of lactose monohydrate mesh 200

2.53% of povidone K 30

5 of cross-linked sodium carboxymethyl cellulose

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Granulation

0.1% of sodium lauryl sulfate

water QS

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External phase

1% stearate magnesium

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In a preferred embodiment of the invention, in the pharmaceutical form (a) the composition is in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase

compound formula (I), (II), (III)

30% starch of corn

55.49% of lactose monohydrate mesh 200

2.53% of povidone K 30

5 of cross-linked sodium carboxymethyl cellulose

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Granulation

0.1% of sodium lauryl sulfate

water QS

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External phase

1% stearate magnesium

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In a preferred embodiment of the invention, in the pharmaceutical form (a) the composition is in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase

compound formula (I), (II) or (III)

30% starch of corn

43.73% of lactose monohydrate mesh 200

2.53% of povidone K 30

5 of cross-linked sodium carboxymethyl cellulose

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Granulation

0.1% of sodium lauryl sulfate

water QS

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External phase

1% stearate magnesium

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Another preferred aspect of the invention is refers to a procedure for the preparation of a composition Pharmaceutical in the pharmaceutical form (a) in which:

to)

be mix the active substance according to formulas I, II or III and the surfactant at room temperature, optionally with a diluent, a binder and / or a coloring agent;

b)

the mixture is moistened with purified water;

C)

the The resulting wet mass is dried and classified; Y optionally

d)

be added to the dried grains a lubricant an agent non-stick, a flow agent, a coloring agent and / or a flavoring agent

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In a preferred embodiment of the procedure for the preparation of a pharmaceutical composition in the form pharmaceutical (a) the surfactant is incorporated in step b) in place of in stage a).

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (b) and, by Therefore, it includes:

b) an additive that ensures a penetration of water inside the core of the preparation and a release polymer controlled.

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A very preferred separate aspect of the invention relates to a sustained release preparation of hydrogel type comprising (1) at least one of the compounds of formulas I, II or III, (2) at least one additive that ensures a water penetration into the core of the preparation and (3) at minus one hydrogel forming polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the controlled release polymer is a sustained release polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the sustained release polymer is based on a soluble polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the sustained release polymer is based on an insoluble polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the sustained release polymer is based on a matrix forming polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the insoluble polymer is based on alkyl cellulose, preferably ethyl cellulose.

In a preferred embodiment of the invention in the pharmaceutical form (b) the soluble polymer is based on a derivative of cellulose.

In a preferred embodiment of the invention in the pharmaceutical form (b) the cellulose derivative is hydroxypropylmethylcellulose or hydroxypropylcellulose.

In a preferred embodiment of the invention in the pharmaceutical form (b) the matrix forming polymer is a hydrogel forming polymer.

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (c) and, by Therefore, it includes:

c) at least one additive that ensures a water penetration into the core of the preparation and at least a hydrogel forming polymer

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In a preferred embodiment of the invention the pharmaceutical form (c) comprises

(1) at least one compound of formulas I, II or III, (2) at least one additive that ensures water penetration within the core of the preparation and (3) at least one polymer hydrogel former, in which said preparation may undergo a substantially complete gelation during its permanence in the upper digestive tract, including the stomach and intestine thin, and can release the drug in the lower digestive tract, including the colon

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In a preferred embodiment of the invention, in the pharmaceutical form (c) said additive that ensures penetration of water inside the core of the preparation is at least one additive which has a solubility such that the volume of water required for dissolving 1 gram of said additive is not more than 5 ml.

In a preferred embodiment of the invention in the pharmaceutical form (c), said additive that ensures a water penetration into the core of the preparation is at least an additive that has a solubility such that the volume of water required to dissolve 1 gram of said additive is not more than 4 ml.

In a preferred embodiment of the invention in the pharmaceutical form (c), said hydrogel forming polymer is or either a polymer that has an average molecular weight not less than 2,000,000 or a polymer having a viscosity not less than 1000 cps as measured at 1% concentration in water at 25 ° C, or a mixture of two or more of these polymers.

In a preferred embodiment of the invention in the pharmaceutical form (c), said hydrogel forming polymer includes at least one polyethylene oxide.

In a preferred embodiment of the invention the Pharmaceutical form (c) comprises (1) at least one compound of formulas I, II or III in an amount not exceeding 85% by weight based on the total preparation, (2) at least one additive that ensures a penetration of water into the core of the preparation in a amount from 5 to 80% by weight based on the preparation total, and (3) at least one hydrogel-forming polymer in a amount from 10 to 95% by weight based on the total preparation

In a preferred embodiment of the invention the Pharmaceutical form (c) comprises (1) at least one compound of formula (I), (II) or (III) in an amount not exceeding 80% by weight based on the total preparation, (2) at least one additive that ensures a penetration of water into the core of the preparation in a amount from 5 to 60% by weight based on the preparation total, and (3) at least one hydrogel-forming polymer in a amount from 15 to 90% by weight based on the total preparation

In a preferred embodiment of the invention, in the pharmaceutical form (a), the release of the active substance is pH controlled.

In a preferred embodiment of the invention, in the pharmaceutical form (a), the release of the active substance is controlled by a polymer whose solution depends on the pH.

In a preferred embodiment of the invention, in the pharmaceutical form (c), the polymer is a polymer resistant to gastric juices, such as methyl esters of acid copolymerized methacrylic / methacrylic acid.

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In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (d) and, by Therefore, it includes:

d) a nucleus formed by an inert nucleus, a water soluble inert polymer and optionally excipients pharmaceutically acceptable.

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In a preferred embodiment of the invention, in the pharmaceutical form (d), the water soluble polymer comprises hydroxypropylmethylcellulose or hydroxypropylcellulose.

In a preferred embodiment of the invention the Pharmaceutical form (d) has an enteric coating.

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (e) and, by Therefore, it includes:

(e) an inert core, with

(aa)

a first layer containing a compound of formula (I), (II), or (III), and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

(bb)

a second layer containing a compound of formula (I), (II), or (III), and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable.

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In a preferred embodiment of the invention, in The pharmaceutical form (e), the release of the active substance is controlled.

In a preferred embodiment of the invention, in the pharmaceutical form (e), the controlled release depends on the pH

In a preferred embodiment of the invention, in the pharmaceutical form (e), the controlled release dependent on the pH is ensured by an enteric polymer.

In a preferred embodiment of the invention, in the pharmaceutical form (e), the enteric polymer is a polymer resistant to gastric juices, such as methyl esters of copolymerized methacrylic acid / methacrylic acid.

In a preferred embodiment of the invention, in the pharmaceutical form (e), the controlled release formulation It is a sustained release formulation.

Another preferred aspect of the invention is a Pharmaceutical composition for oral administration of a compound  of formula (I), (II) or (III), or a mixture thereof, for administration in the form of oblong tablets, gels, systems particulates such as granules, microgranules, multiparticles and similar, optionally compressed to give tablets or refill in capsules

In general, pharmaceutical compositions according to the present invention can also be formulated containing in addition one or more vehicles or physiologically excipients compatible, in solid or liquid form. These compositions can additionally also contain conventional components, such as binding agents, fillers, lubricants and agents acceptable humectants. The compositions can take -if it is suitable - any convenient way, such as tablets, microgranules, multiparticles, capsules, lozenges, oblong tablets, aqueous or oily solutions, suspensions, emulsions, or dry powder forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or sustained release.

The pharmaceutical excipients that can be used for the pharmaceutical composition according to the present invention especially include a diluent, a binder and a lubricant. You can also add a fluidity agent, an agent non-stick and, optionally, a coloring agent and / or an agent flavoring

A study of the effects of incorporating agents humectants showed that a low concentration of surfactant, such as sodium alkyl sulfate, increases the wettability considerably. It was found that by incorporating a surfactant in the formulation, the formulation dissolves quickly and completely and with Good reproducibility of the results. According to this invention, sodium alkyl sulfate is understood to mean a (C8-C12) alkyl sodium sulfate, by example sodium octylsulfate or, preferably, lauryl sulfate sodium.

The diluent used in the composition of the present invention can be one or more compounds that can densify the active ingredient to give the desired mass. The Preferred diluents are inorganic phosphates such as phosphates of calcium; sugars such as hydrated or anhydrous lactose, or mannitol; and cellulose or cellulose derivatives such as, by example, microcrystalline cellulose, starch, corn starch or pregelatinized starch. Very particularly preferred are the lactose monohydrate, mannitol, microcrystalline cellulose and starch of corn, used alone or in a mixture, for example a mixture of lactose monohydrate and corn starch.

The binder used in the composition of the present invention can be one or more compounds that can densify a compound of formula (I), turning it into particles larger and denser with better fluidity properties. The Preferred binders are alginic acid or sodium alginate; the cellulose and cellulose derivatives, such as carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose or sodium methylcellulose; jelly; acrylic acid polymers; and povidone for example povidone K 30, which is a very particularly preferred binder. The binder is present in a proportion of 1% to 10% by weight in the pharmaceutical composition according to the invention.

The lubricant used in the composition of the The present invention can be one or more compounds that can avoid the problems associated with the preparation of dry forms, such as adhesion and / or seizure problems that occur in the machines during compression or filling. Lubricants Preferred are fatty acids or fatty acid derivatives such such as calcium stearate, glyceryl monostearate, glyceryl palmitosterate, magnesium stearate, lauryl sulfate sodium, sodium stearyl fumarate, zinc stearate or acid stearic; hydrogenated vegetable oils, for example, hydrogenated castor; polyalkylene glycols, especially polyethylene glycol; sodium benzoate; or talcum powder According to this invention magnesium stearate is preferred. The lubricant is present in a proportion of 0.2% to 5% by weight in the composition pharmaceutical according to the invention.

The non-stick agent that can be used in The composition of the present invention may be one or more compounds that can reduce the sticky character of the formulation, for example, avoiding adhesion to surfaces metallic Preferred non-stick agents are compounds that They contain silicon, for example silica or talc. The agent Non-stick may be present in a proportion of 0 to 5% in weight in the pharmaceutical composition according to the invention.

The fluidity agent that can be used in the Composition of the present invention may be one or more compounds which can allow the fluidity of the prepared formulation. The Preferred flow agents are silicon-containing compounds, for example anhydrous colloidal silica or precipitated silica. The agent of fluidity can be present in a proportion of 0 to 15% in weight in the pharmaceutical composition according to the invention.

The disintegrating agent is understood to mean cellulose or cellulose derivatives, such as carboxymethyl cellulose of sodium or cross-linked sodium carboxymethyl cellulose, crospovidone, pregelatinized starch or sodium carboxymethyl starch, the cross-linked sodium carboxymethyl cellulose a disintegrating agent favorite.

When it is not explicitly mentioned Otherwise, the percentage by weight of excipients and additives It always refers to the active substance.

According to the present invention, the compositions Pharmaceuticals can be prepared by wet granulation or through a layered procedure.

Therefore, for the granulation procedure wet, the internal phase is mixed at room temperature, the active substance, diluent, binder, agent disintegrant, sodium alkyl sulfate and, optionally, the agent dye and then moisten with the granulation liquid. The Wet mass obtained is dried and then classified. Then I know add to the dry grains classified the component or components of the external phase, specifically the lubricant, possibly the non-stick agent, the flow agent and, if it is appropriate, the coloring agent and / or the flavoring agent.

The layered procedure is characterized because to a spherical core of sugar / inert starch a first is applied layer containing a mixture of the active substance, the diluent, the binder, disintegrating agent, sodium alkyl sulfate and, optionally, the coloring agent, optionally followed by a second insulation layer formed by water soluble polymers and compatible excipients. Finally, a layer is applied that It consists of an enteric coating.

As a result of extensive studies on Sustained release of a drug, the inventors of the present invention also discovered that the release of a drug in the colon, which has a low water content, can be achieved providing a preparation adapted to absorb water within its core to undergo substantially gelling complete during its permanence in the upper digestive tract, such as in the stomach and small intestine, and then move in gel form towards the lower digestive tract. The The present invention was achieved based on the previous finding.

Therefore, another aspect of the present invention refers to a sustained release preparation of type hydrogel comprising (1) at least one drug, (2) an additive that provides a penetration of water into the core of the preparation, and (3) a hydrogel forming polymer, whose preparation undergoes complete gelation during permanence in the upper digestive tract, such as in the stomach and in the small intestine, and that can release a drug in the colon.

The term "gelation substantially complete "of the preparation as used herein descriptive refers to the state in which no less than about 70%, preferably not less than about 80%, of the Preparation is gelled.

Since even the colon can be used as an absorption site, the sustained release preparation of the present invention prolongs the period of drug absorption to a remarkable point and, therefore, guarantees a stable level of blood drug Therefore, the preparation of the present invention absorbs water during its permanence in the tract upper digestive to experience gelation substantially complete and then moves into the tract lower digestive, constantly wearing its surface, and it maintains drug release with additional wear on the lower digestive tract, with the result that a sustained and sufficient absorption of the drug even in the colon where there is little water available.

The sustained release preparation of the The present invention is described in more detail at continuation.

The drug or drugs that can be used in the preparation according to the present invention are not particularly limited in type, provided they are used for a system of sustained release.

In order that these drugs can easily absorbed in the colon, which has a low content in water, it is preferable to improve its solubilities in advance. They can known techniques are used to improve the solubility of a drug that can be applied in the preparation of hydrogels. Between such techniques (solubilization treatment) can be mentioned the method comprising adding a surfactant (for example, polyoxyethylene-hydrogenated castor oils, higher fatty acid esters of polyoxyethylene sorbitan, polyoxypropylene glycols of polyoxyethylene, sucrose fatty acid esters, etc.) and the method comprising preparing a solid dispersion of the drug and a solubilizing agent such as a polymer (for example, a water soluble polymer such as hypromellose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc. or a enteric polymer such as carboxymethylcellulose (CMEC), phthalate of hypromellose (HPMCP), methyl acid methacrylate copolymer methacrylic (Eudragit L and S; the trade name of Rhom & Haas Co.), etc.). When the drug is a basic substance, the method comprises adding an organic acid such as citric acid, acid Tartaric or similar. If necessary, the method implies formation of a soluble salt or the method comprises the formation of a clathrate using cyclodextrin or the like. These procedures for solubilization they can be modified as necessary to the particular drug

The additive to allow water to penetrate into the core of the preparation according to the present invention (this additive to ensure water penetration into the core of preparation will hereinafter be referred to as "hydrophilic base") is such that the amount of water required to dissolve 1 g of the hydrophilic base not exceeding 5 ml and preferably not exceeding 4 ml at the temperature of 20 +/- 5 ° C. The higher the solubility of the hydrophilic base in water, the more effective the base will be to allow water to enter the core of the preparation. The hydrophilic base includes, among others, highly hydrophilic polymers such as polyethylene glycol (PEG; for example, PEG400, PEG1500, PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and Fats Co.) and polyvinylpyrrolidone (PVP; for example, PVP K30, the trade name of BASF), sugar alcohols such as D-sorbitol, xylitol, etc., sugars such as sucrose, anhydrous maltose, D-fructose, dextran (for example dextran 40), glucose, etc., surfactants such as polyoxyethylene -hydrogenated castor oil (HCO; for example, Cremophor RH40 produced by BASF, HCO-40 and HCO-60 produced by Nikko Chemicals Co.), polyoxyethylene-polyoxypropylene glycol (for example, Pluronic F68 produced by Asahi Denka Kogyo KK), ester of high molecular weight fatty acids of polyoxyethylene sorbitan (Tween; for example, Tween 80 produced by Kanto Kagaku KK), etc .; salts such as sodium chloride, magnesium chloride, etc., organic acids such as citric acid, tartaric acid, etc .; amino acids such as glycine, beta-alanine, lysine hydrochloride, etc .; and amino sugars such as meglumine.

Preferred are PEG6000, PVP, D-sorbitol, etc.

The proportion of such hydrophilic base depends on the characteristics of the drug (solubility, therapeutic efficacy, etc.) and drug content, solubility of the base itself hydrophilic, characteristics of the hydrogel forming polymer used, the patient's condition at the time of administration and of other factors. However, the proportion may be preferably at a level sufficient to achieve a substantially complete gelation during the permanence of the Preparation in the upper digestive tract. The preparation remains in the upper digestive tract for a period different that depends on the species and the individual, but on approximately 2 hours after administration in the case of dogs and about 4 to 5 hours after administration in the case of human beings (Br. J. clin. Pharmac, (1988) 26, 435-443). For administration to beings human, the proportion may preferably be at a level enough to achieve substantially complete gelation in about 4 to 5 hours after administration. By therefore, usually the proportion of hydrophilic base is approximately 5-80% by weight and preferably of approximately 5-60% by weight based on the total weight of the preparation.

If the hydrophilic content is too high small, the necessary gelation does not occur inside the nucleus of the preparation, so that the release of drug in the colon. On the other hand, when the content in base hydrophilic is excessive, gelation occurs in a longer time short, but the resulting gel is so fragile that the release of drug is too fast, thus failing to ensure a sustained release sufficient. In addition, because the amount of base is large, the product becomes bulky.

The hydrogel forming polymer mentioned previously must have physical properties, including viscosity in the gelled state, which allow the preparation of the present invention more or less maintain its shape during its journey to the lower digestive tract, specifically to the colon, resisting the contractile forces of the associated digestive tract With the digestion of food.

The hydrogel-forming polymer that can be used in the preparation of the present invention is preferably a polymer that shows a high viscosity in gelation. For example, a polymer showing a viscosity of not less than 1000 cps in 1% aqueous solution (at 25 ° C) is particularly preferred.

The properties of the polymer depend on its weight molecular. The hydrogel forming polymer that can be used in the present invention is preferably a weight substance comparatively high molecular, specifically a polymer that It has an average molecular weight of not less than 2 x 10 <6> and more preferably of not less than 4 x 10 <6>.

Among such polymers are poly (oxide of ethylene) (POE) having a molecular weight of not less than 2 x 10 <6> [for example, Polyox WSR-303 (weight Average molecular: 7x10 <6>; viscosity: 7500-10000 cps, 1% in H2O, 25 ° C), Polyox WSR Coagulant (average molecular weight: 5 x 10 <6>; viscosity: 5500-7500 cps, under the same conditions as before), Polyox WSR-301 (average molecular weight: 4 x 10 <6>; viscosity: 1650-5500 cps, in the same conditions as before), Polyox WSR-N-60K (average molecular weight: 2 x 10 <6>; viscosity: 2000-4000 cps, 2% in H2O, 25ºC), all of them are trade names of Union Carbide Co.]; hypromellose (HPMC) [for example, Metolose 90SH100000 (viscosity: 4100-5600 cps., 1% in H2O, 20 ° C), Metolose 90SH50000 (viscosity: 2900-3900 cps, in the same conditions as before), Metolose 90SH30000 (viscosity: 25000-35000 cps, 2% in H2O, 20ºC), all of them are trade names of Shin-Etsu Chemicals Co.]; sodium carboxymethyl cellulose (CMC-Na) [for example, Sanlose F-150MC (average molecular weight: 2 x 10 <5>; viscosity: 1200-1800 cps, 1% in H2O, 25 ° C), Sanlose F-1000MC (average molecular weight: 42 x 10 <4>; viscosity: 8000-12000 cps, in same conditions as before), Sanlose F-300MC (weight Average molecular: 3 x 10 <5>; viscosity: 2500-3000 cps, under the same conditions as before), all of them are trade names of Nippon Seishi Co., Ltd.]; hydroxyethylcellulose (HEC) [eg, HEC Daicel SE850 (weight Average molecular: 148 x 10 <4>; viscosity: 2400-3000 cps, 1% in H2O, 25 ° C), HEC Daicel SE900 (average molecular weight: 156 x 10 <4>; viscosity: 4000-5000 cps, under the same conditions as before), all of them are trade names of Daicel Chemical Industries]; carboxyvinyl polymers [eg, Carbopol 940 (average molecular weight: approximately 25 x 10 <5>; B.F. Goodrich Chemical Co.) and etcetera.

Preferred is a POE that has a weight molecular average of not less than 2 x 10 <6>. If required a continuous release of the drug for a long time, by example longer than 12 hours, a polymer having a higher molecular weight, preferably an average molecular weight of not less than 4 x 10 <6>, or a higher viscosity, preferably a viscosity of not less than 3000 cps at a 1% concentration in water at 25 ° C.

The above hydrogel forming polymer can used alone, or two or more class (s) of the above hydrogel-forming polymers in admixture. 0 for the present invention the mixture of two can be suitably used or more kinds of any polymer, mixture that has characteristics suitable for the present invention.

In order to guarantee a release of the drug in the human colon, it is necessary that a part of the preparation that has undergone gelation in the colon, even at the latest at least 6-8 hours, preferably at least 12 hours, after administration.

In order to provide a preparation of hydrogel type having such properties, although it depends on the volume of preparation, type of polymer and properties and the amount of the drug and additive to ensure a water penetration into the preparation core, normally prefers that the preparation contains 10-95% in weight (preferably 15-90% by weight) of hydrogel forming polymer based on the weighing preparation less than 600 mg, and that a preparation contains not less than 70 mg per preparation and preferably not less than 100 mg per Preparation of hydrogel forming polymer. If the amount of this  polymer is below the level mentioned above, the Preparation will not admit wear to the digestive tract during a long enough time and you may not get enough sustained release

As for the base types and proportions hydrophilic and hydrogel forming polymer (the latter is referred to in hereinafter as a hydrogel forming base), its usefulness has been established with the following experiments.

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

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

The daily dosage for humans and Animals may vary depending on factors that are based on the respective species or other factors, such as age, sex, weight or degree of illness, etc. Dosage daily for humans can preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active ingredient that is going to administered during one or several intakes per day.

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Pharmacological methods I. In vitro determination of affinity for CB1 / CB2 receptors

In-vitro determination of the affinity of the substituted pyrazoline compounds of the invention by the CB1 / CB2 receptors is carried out as described in the publication of Ruth A. Ross, Heather C. Brockie et al ., "Agonist-inverse agonist characterization at CB_ {1} and CB_ {2} cannabinoid receptors of L-759633, L759656 and AM630", British Journal of Pharmacology, 126, 665-672, (1999), in which Transfected human CB 1 and CB 2 receptors from Receptor Biology, Inc. are used. The radioligand used for both receptors is [3 H] -CP55940. The respective parts are incorporated by reference to this document and are part of this description.

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II. In vivo bioassay system to determine cannabinoid activity Mouse tetrad model

It is known that substances with affinity for cannabinoid receptors produce a wide range of effects Pharmacological It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in Mice produces analgesia, hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has an affinity for cannabinoid receptors, since all these effects are common for various kinds of active agents in the nervous system central. However, the substances that show all these effects, that is, the substances that are active in this model called tetrad, they are considered to have affinity for cannabinoid receptors It has also been shown that cannabinoid receptor antagonists are extremely effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.

The tetrad model is described, for example, in the publication of AC Howlett et al , International Union of Pharmacology XXVII. Classification of Cannabinoid Receptors, Pharmacol Rev 54, 161-202, 2002 and David R. Compton et al ., " In-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A): Inhibition of Tetrahydrocannbinol-induced Responses and Apparent Agonist Activity", J. Pharmacol. Exp. Ther. 277, 2, 586-594, 1996. The corresponding parts of the description are incorporated by reference to this document.

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Material and methods

In all the following experiments they are used NMRI male mice weighing 20-30 g (They would, Barcelona, Spain).

Before the tests in the procedures behavioral behaviors then the mice acclimatize to the experimental environment. Control values prior to treatment were determined to measure analgesia using hot plate latency (in seconds), rectal temperature, sedation and catalepsy.

In order to determine agonist activity of the substance to be tested, mice are injected via intravenous the substance to be tested or the vehicle alone. fifteen minutes after injection, analgesia latency is measured in hot plate. 20 minutes after the injection the rectal temperature, sedation and catalepsy.

In order to determine the activity antagonist, the identical procedure is used as for determination of agonist effects, but with the difference of that the substance to be evaluated to determine its activity antagonist is injected 5 minutes before intravenous injection of 1.25 mg / kg of Win-55,212, a known agonist of the cannabinoid receptor.

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Hot plate analgesia

Hot plate analgesia is determined according to the method described in Woolfe D. et al . "The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307, 1944. The respective description is incorporated as a reference to this document and is part of this description.

The mice are placed on a hot plate (Harvard analgesimeter) at 55 ± 0.5 ° C until they show a painful sensation, licking its legs or jumping, and registers the time for these sensations to occur. This reading is consider as the baseline value (B). The maximum time limit that mice are allowed to remain on the hot plate in absence of any painful response is 40 seconds with the In order to avoid skin lesions. This period is called time. limit (PC).

Fifteen minutes after the administration of the substance to be tested, the mice are placed back on the hot plate and the procedure is repeated above described This period is called post-treatment reading. (PT).

The degree of analgesia is calculated from the formula:

MPE% of analgesia = (PT-B) / (PC-B) x 100

MPE = maximum possible effect.

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Determination of sedation and ataxia

Sedation and ataxia are determined according to the method described in Desmet LKC et al . "Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975. The respective description is incorporated by reference to this document and forms part of this description.

The scoring system chosen is

0:

no ataxia;

one:

doubtful;

2:

obvious tranquility and silence;

3:

pronounced ataxia;

before, in addition to after treatment.

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The percentage of sedation is determined according to the formula:

% sedation = arithmetic mean / 3 x 100

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Hypothermia

Hypothermia is determined according to the method described in David R. Compton et al . " In-vivo Characterization of a Specific Cannabinoid Antagonist Receptor (SR141716A) Inhibition of Tetrahydrocannbinol-induced Responses and Apparent Agonist Activity", J. Pharmacol Exp Ther. 277, 2, 586-594, 1966. The respective description is incorporated by reference to this document and forms part of this description.

Rectal temperatures are determined initials with a thermometer (Yello Springs Instruments Co., Panlabs)  and a thermistor probe inserted 25 mm before the administration of the substance to be tested. Temperature rectal is measured again 20 minutes after administration of the substances to be tested. The temperature difference is calculate for each animal, so that the differences ≥ -2 ° C is They consider that they represent activity.

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Catalepsy

Catalepsy is determined according to the method described in Alpermann HG et al . "Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is incorporated by reference to this document and forms part of this description.

The cataleptic effect of the substance that is going to be tested is evaluated according to the duration of the catalepsy, putting the animals head down with their legs on top of the wood block.

The scoring system chosen is:

Catalepsy during:

more than 60 seconds = 6; 50 -60 seconds = 5, 40-50 seconds = 4, 30-40 seconds = 3, 20-30 seconds = 2, 5-10 seconds = 1, and less than 5 seconds = 0.

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The percentage of catalepsy is determined according to the following formula:

% of catalepsy = arithmetic mean / 6 X 100

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III. In vivo tests to determine activity against obesity

In vivo tests to determine the activity against obesity of the pyrazoline compounds of the invention are carried out as described in the publication of G. Colombo et al ., "Appetite Suppression and Weight Loss after the Cannabinoid Antagonist SR 141716 "; Life Sciences, 63 (8), 113-117, (1998). The respective part of the description is incorporated as a reference to this document and is part of this description.

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IV. In vivo tests to determine antidepressant activity

In vivo tests to determine the antidepressant activity of the pyrazoline compounds of the invention in the forced swimming test are carried out as described in the publication of ET Tzavara et al ., "The CB1 receptor antagonist SR141716A selectively increases monoaminargic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions "; Br. J. Pharmacol. 2003, 138 (4): 544: 53. The respective part of the description is incorporated as a reference to this document and is part of this description.

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V. In vivo tests for the regulation of triglycerides in blood plasma

The study was conducted using male mice six weeks of life B6 Lep ob / ob, obtained from Charles River (France). The mice were divided into 3 groups: I (control), II (vehicle), III (example 18).

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Groups I:

Group I animals received the diet Standard (D-12450B, Research Diets, NJ, States United).

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Group II:

The animals of groups II and III were fed a high fat diet (D-12492, Research Diets, NJ, United States), in both cases for 7 weeks (References 1 and 2).

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At the end of the feeding period of 7 weeks, the treatment period began (14 days): the mice Group II received the vehicle (10 ml / kg / day, po, of the aqueous solution of acacia gum, 5% w / v). Group III are administered 30 mg / kg / day, po, of the compound of the acid invention 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic  according to Example 18. Group I did not receive any treatment. The three groups of mice had the same diet as in the period previous.

At the end of the 14 day treatment period, blood triglyceride levels of the animals.

The analysis of whole blood samples was performed using "Lipid panel" test strips and the photometric system Analyzer Cardio-Check Test System, from PA Instruments Polymer Technology Systems Indianapolis, IN-46268, United States (distributed in Spain by Novalab Ibérica S.A.L., Madrid, Spain).

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 1 1 mg gelatin capsule

A gelatin capsule was prepared by wet granulation and it had the following composition:

Internal phase

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

51 mg starch of corn

103.33 mg of lactose monohydrate mesh 200

4.3 mg of povidone K 30

8.5 mg of cross-linked sodium carboxymethyl cellulose

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Granulation

0.17 mg of sodium lauryl sulfate

purified water QS (how much is enough)

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External phase

1.7 mg of magnesium stearate

Up to 170 mg is completed for one capsule of opaque white jelly size 3.

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Example 2 10 mg gelatin capsule

A gelatin capsule was prepared by wet granulation and it had the following composition:

10 mg of compound N- [5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazol-3-carbonyl] -4-methyl-phenylsulfonamide

51 mg starch of corn

94.33 mg of lactose monohydrate mesh 200

4.3 mg of povidone K 30

8.5 mg of cross-linked sodium carboxymethyl cellulose

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Granulation

0.17 mg of sodium lauryl sulfate

purified water QS

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External phase

1.7 mg of magnesium stearate

Up to 170 mg is completed for one capsule of opaque white jelly size 3.

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Example 3 30 mg gelatin capsule

A gelatin capsule was prepared by wet granulation and it had the following composition:

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

51 mg starch of corn

74.33 mg of lactose monohydrate mesh 200

4.3 mg of povidone K 30

8.5 mg of cross-linked sodium carboxymethyl cellulose

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Granulation

0.17 mg of sodium lauryl sulfate

purified water QS

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External phase

1.7 mg of magnesium stearate

Up to 170 mg is completed for one capsule of opaque white jelly size 3.

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Example 4 30 mg gelatin capsule

A gelatin capsule was prepared by wet granulation and it had the following composition:

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

51 mg starch of corn

73.65 mg of lactose monohydrate mesh 200

4.3 mg of povidone K 30

8.5 mg of cross-linked sodium carboxymethyl cellulose

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Granulation

0.85 mg of sodium lauryl sulfate

purified water QS

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External phase

1.7 mg of magnesium stearate

Up to 170 mg is completed for one capsule of opaque white jelly size 3.

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Example 5 1 mg tablet

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

50 mg of starch of corn

130 mg of lactose monohydrate mesh 200

6 mg of 6 cP hypromellose

10 mg of cross-linked sodium carboxymethyl cellulose

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Granulation

1 mg of sodium lauryl sulfate

purified water QS

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External phase

2 mg of magnesium stearate

Up to 200 mg for one tablet is completed.

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Example 6 10 mg tablet Internal phase

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

50 mg of starch of corn

211.5 mg of lactose monohydrate mesh 200

9 mg of 6 cP hypromellose

15 mg of sodium carboxymethyl starch

1.5 mg of sodium lauryl sulfate

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Granulation

purified water QS

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External phase

3 mg of magnesium stearate

Up to 300 mg is completed for one tablet.

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Example 7 30 mg tablet Internal phase

30 mg of N-oxide compound N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide

80 mg of starch of corn

252 mg of lactose monohydrate mesh 200

12 mg of povidone K 30

20 mg of cross-linked sodium carboxymethyl cellulose

2 mg of sodium lauryl sulfate

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Granulation

purified water QS

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External phase

4 mg of magnesium stearate

Up to 400 mg is completed for one tablet.

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Example 8 Microgranules

In 580 g of deionized water 75 g are dispersed of [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 (10.6%) and 70 g of hypromellose, 20 mg of carboxymethylcellulose crosslinked sodium (2.8%) and 1 mg of sodium lauryl sulfate (0.14%). Be introduce 490 g of uniform, inert sugar / starch spheres (composition according to the US Pharmacopoeia) in an apparatus of fluidized bed and the previously obtained dispersion is sprayed on the spheres After spraying, the spheres dry before applying the second layer.

In 350 g of deionized water 52 g are dispersed of hypromellose and 7 g of titanium dioxide and the aqueous dispersion resulting is sprayed on the spheres obtained in the stage previous. After spraying, the spheres were dried before of applying the third layer of enteric coating.

In 280 g of deionized water 290 g are dispersed of a copolymer of methacrylic acid (aqueous suspension type C) of the USP (US Pharmacopoeia), 13 g of triethyl citrate and 38.5 g of talc and the resulting aqueous dispersion is sprayed on the spheres obtained in the previous stage. After applying this final enteric coating layer dried the spheres (microgranules).

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Example 9

In a solvent mixture (dichloromethane-methanol) dissolved [1,2,4] triazol-4-yl amide acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid (CPTA), Tween 80 and CMEC and the solution was spray dried using a spray dryer. The dried mixture was mixed with POLYOX303 and the resulting composition was compression molded using an oil press at a compression pressure of 0.8 ton / punch to provide tablets (SR (sustained release)) that each measured 8.0 mm in diameter and weighed 171.6 mg (content in CPTA: 65 mg). Separately, CPTA and TC-5E in a solvent mixture (dichloromethane-methanol) and using a Hi-Coater (Coater), this component of Immediate release (QR; CPTA: 15 mg) was coated on the SR component (CPTA: 65 mg) to provide tablets that they weighed 194.1 mg each (CPTA: 80 mg).

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Example 10 30 mg tablet Internal phase

30 mg of acid 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxylic 80 mg cornstarch

252 mg of lactose monohydrate mesh 200

12 mg of povidone K 30

20 mg of cross-linked sodium carboxymethyl cellulose

2 mg of sodium lauryl sulfate

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Granulation

purified water QS

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External phase

4 mg of magnesium stearate

Up to 400 mg was completed for one tablet.

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Example 11 N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide a) Acid 4- (4-chlorophenyl) -2-oxo-3-butenoic

22

In a three-mouth flask they dissolved p-chlorobenzaldehyde (13.3 g, 95 mmol) and pyruvate of ethyl (10 g, 86 mmol) in 150 ml of absolute ethanol. The solution was cooled with ice to 0 ° C and added dropwise an aqueous solution of NaOH (3.8 g in 45 mL of water), maintaining the temperature below or equal to 10 ° C, by which formed an orange yellow precipitate. Mix The reaction was stirred for 1 hour at 0 ° C and additionally during 1.5 hours at room temperature (approximately 25 ° C). After, the reaction mixture was cooled to about 5 ° C and isolated the insoluble sodium salt of acid 4- (4-chlorophenyl) -2-oxo-3-butenoic by filtration

The filtrate was left in the refrigerator during night, whereby more precipitate formed, which separated by filtration, 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 a few minutes and separated by acid filtration 4- (4-chlorophenyl) -2-oxo-3-butenoic solid and dried to give 12.7 g of the desired product (70% of theoretical performance).

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

2. 3

The acid was 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 glacial acetic acid (200 mL) under a nitrogen atmosphere and it heated at reflux for 4 hours, cooled to temperature ambient (about 25 ° C) and added to ice water, whereby a sticky dough was obtained which was extracted with methylene chloride Methylene Chloride Fractions combined, washed with water, dried with sodium sulfate, dried filtered and evaporated to dryness to give a yellow solid pale (12.7 g, 57% of theoretical yield).

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).

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c) Acid Chloride 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxylic

24

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

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

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d) N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide [this compound can also be referred to as acid piperidin-1-ylamide 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid or as 1- (2,4-Dichlorophenyl) -5- (4-chlorophenyl) -4,5-dihydro-N- (piperidin-1-yl) -1H-pyrazol-3-carboxamide]

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25

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Under nitrogen atmosphere, they dissolved N-aminopiperidine (0.6 mL, 5.6 mmol) and triethylamine (4 mL) in methylene chloride (25 mL). Mix resulting was cooled with ice to 0 ° C and a drop was added dropwise.  acid chloride solution 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic  obtained in step (c) in methylene chloride (15 mL). Mix resulting reaction was stirred at room temperature (approximately 25 ° C) overnight. Then the mixture of reaction was washed with water, followed by an aqueous solution saturated sodium bicarbonate, then again with water, it dried over sodium sulfate, filtered and evaporated to dryness in a rotary evaporator. The resulting crude solid crystallized from ethanol. The crystallized solid was filtered off and the mother waters were concentrated to give a second fraction of crystallized product The two fractions were combined 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 procedure described in example 1.

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Example 12 [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

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, 1H).

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Example 13 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 8.7Hz, 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 14 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 an 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 15 [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 16 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 17 N-oxide N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide

Under nitrogen gas as an inert atmosphere it dissolved N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide  (0.15 g, 332 mmol) in 7 mL of dichloromethane. Dissolution resulting was cooled with ice to 0 ° C and acid was added m-chloroperbenzoic acid (0.204 g, 0.83 mmol) in several portions. After stirring for 15 minutes, a control by thin layer chromatography medium showed that there was no material left of departure. Then a saturated solution was slowly added of sodium bicarbonate, the organic phase was separated, washed with water, dried over sodium sulfate and filtered. Dissolution filtered was evaporated to dryness and the crude product was purified by column chromatography giving 78 mg (50% of theoretical yield) of N-oxide N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide in the form of a white solid that had 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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Example 18 Acid 5- (4-? -Phenyl-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid

The preparation of example 18 has already been described in Example 11 following steps a) and b).

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Pharmacological data I. In vitro determination of affinity for CB1 / CB2 receptors

The affinity of the compounds of substituted pyrazoline of the invention by the receptors CB1 / CB2, as described above. Some of The values obtained are given in the following table I:

TABLE I

26

As can be seen from the values provided in table 1, the pyrazoline compounds of the invention are particularly suitable for regulating the receiver of CB_ {1}.

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II. In vivo bioassay system to determine cannabinoid activity

The determination of cannabinoid activity is determined as described above. Some of the values obtained are given in the following table II:

TABLE II

27

i.v. intravenous

A: proof of hot plate

B: hypothermia

C: catalepsy

D: sedation

As can be seen from the values provided in table II, the pyrazoline compounds of the invention show an antagonistic effect.

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III. In vivo tests to determine activity against obesity

In vivo tests to determine activity against obesity were carried out as described above, whereby four different groups of 10 rats each were treated as follows:

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Group I :

The group was treated with a vehicle, specifically gum arabic (5% by weight) in water.

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Group II :

The second group of rats was treated with the compound N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide of the invention according to example 1. Said compound was administered intraperitoneally to rats for a period of 14 days in a daily dose of (10 mg / kg body weight).

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Group III :

The third group of rats was treated with amphetamine, an active ingredient known to reduce appetite. Said compound was administered intraperitoneally to the rats. over a period of 14 days at a daily dose of (5 mg / kg of body weight).

As can be seen from Figure 1, body weight decreases due to compound administration of the invention according to example 11 and this effect is also observed after the treatment is finished.

Figure 2 shows the reduction of ingestion of food due to the administration of the compound of the invention according to example 11.

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IV. In vivo test to determine antidepressant activity

In vivo tests to determine the antidepressant activity of the pyrazoline compounds of the invention in the forced swimming test were carried out as described above. In particular, the compound according to example 11 had positive effects with respect to the immobilization time and fighting time.

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V. In vivo test for the regulation of triglycerides in blood plasma

The compounds according to formula II (specifically example 18) are inhibitors of levels high blood triglycerides. This effect has been demonstrated in obese mice fed a diet high in fat

The results obtained were the following:

28

The results showed that mice Group II who received a diet high in fat they had blood triglyceride levels significantly higher than Control Group I. However, the administration of the compound according to Example 18 (Group III) improved blood triglyceride levels, which were not different from the levels of Group I who received a diet standard.

Claims (49)

1. Pharmaceutical composition for oral administration comprising at least one compound of formula (I): 31 in the that R 1 represents a phenyl group optionally at least monosubstituted, R2 represents a phenyl group optionally at least monosubstituted, R 3 represents a cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, which optionally contains at least one heteroatom as a member of ring, which can be condensed with a cyclic, mono or polycyclic, at least monosubstituted, or R3 represents a group aryl or heteroaryl optionally at least monosubstituted, which can be condensed with a cyclic, mono or polycyclic system, by less monosubstituted, or R3 represents a moiety -NR 4 R 5, R 4 and R 5, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a ring member, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or an aryl or heteroaryl group optionally at less monosubstituted, which may be condensed with a system cyclic, mono or polycyclic, at least monosubstituted and / or attached to through a linear or branched alkylene group, a moiety -SO 2 -R 6, or a moiety -NR 7 R 8, R 6 represents an aliphatic, linear 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 ring member, which may be condensed with a cyclic, mono or polycyclic system, or a group aryl or heteroaryl optionally at least monosubstituted, which can be condensed with a cyclic, mono or polycyclic system and / or bound through a linear or branched alkylene group, R 7 and R 8, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a ring member, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or an aryl or heteroaryl group optionally at less monosubstituted, which may be condensed with a system cyclic, mono or polycyclic, at least monosubstituted and / or attached to through a linear or branched alkylene group, with the condition of R 4 and R 5 do not both represent an atom of hydrogen, and than if one of the residues R 4 and R 5 represents a hydrogen atom or an alkyl group, which is optionally at least monosubstituted with an alkoxy group, a alkoxyalkoxy group, a halogen atom or a phenyl group, the another of these residues R 4 and R 5 does not represent a group pyridyl-2-yl, which is optionally monosubstituted in position 5, a group pyridyl-5-yl, which is optionally monosubstituted in position 2, a group pyrimidyl-5-yl, which is optionally monosubstituted in position 2, a group pyridaz-3-yl, which is optionally monosubstituted in position 6, a group pirazin-5-ilo, which is optionally monosubstituted in position 2, a group tien-2-yl, which is optionally monosubstituted in position 5, a group tien-2-yl, which is optionally at least monosubstituted in position 4, a benzyl group, which is optionally monosubstituted in position 4 of the ring, a group phenethyl, which is optionally monosubstituted at position 4 of the ring, an optionally mono, di or trisubstituted phenyl group, a disubstituted phenyl group, in which the two substituents form together a string -OCH_2 O-, -OCH_ {2} CH2 O- or -CH2CH2O-, which is optionally substituted with one or more halogen atoms or one or two methyl groups, a moiety -NH-phenyl, in which the phenyl group may be monosubstituted in position 4, and that if one of the waste R 4 and R 5 represents an alkynyl group, the other of these residues R 4 and R 5 does not represent a phenyl group, which is optionally substituted in position 4, and than if one of the residues R 4 and R 5 represents a hydrogen atom or an aliphatic, linear or radical branched, saturated or unsaturated, unsubstituted or substituted, the another of these residues R 4 and R 5 does not represent a group unsubstituted or substituted thiazole or a group [1,3,4] thiadiazole not substituted or substituted 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; I at least one compound of formula (II),

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32

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in the that R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched, R 2 ', R 3' and R 4 'independently each other 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 linear or branched C 1-6 alkyl, R 5 'and R 6' independently of each other represent 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, NO 2, - (C = O) -R 10 ', SH, SR 10', SOR 10 ', NH 2, NHR 10', NR 10'11 ', - (C = O) -NH 2, - (C = O) -NHR 10 'and - (C = O) -NR 10 'R 11', in which R 10 'and optionally R 11 'for each substituent represents independently linear C 1-6 alkyl or branched; 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 R 11 'for each substituent represents independently linear C 1-6 alkyl or branched;

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with the condition of if R 1 'and R 7' are H and R 5 'and R 6 'both represent Cl at positions 3 and 4 of the ring of phenyl, none of R 2 ', R 3' and R 4 'can represent F at position 4 of the phenyl ring if the other two of R 2 ', R 3' and R 4 'both represent H; 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; I at least one compound of formula (III) 33 in the that R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched, R 12, R 13, R 14 or R 15 independently of each other they represent 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, SH, NH 2, hydrogen, methyl, ethyl, F, Cl, Br and CF 3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof, characterized in that the pharmaceutical composition is in any of the pharmaceutical forms (a), (b), (c), (d) or (e) and, therefore, comprises: a) 0.05% to 0.5% by weight of the principle active of a surfactant and optionally one or more excipients additional pharmacists; or b) an additive that ensures a penetration of water inside the core of the preparation and a release polymer controlled; or c) at least one additive that ensures a water penetration into the core of the preparation and at least a hydrogel forming polymer; or d) a nucleus formed by an inert nucleus, a water soluble inert polymer and optionally excipients pharmaceutically stable; or e) an inert core, with

(aa)

a first layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

(bb)

a second layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable.

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2. Pharmaceutical composition according to claim 1, characterized in that the composition comprises at least one compound of formula (I). 3. Pharmaceutical composition according to claim 2, characterized in that the compound of formula (I) is a compound in which: R 1 represents a phenyl group optionally at least monosubstituted, R2 represents a phenyl group optionally at least monosubstituted, R 3 represents a cycloaliphatic group saturated or unsaturated, optionally at least monosubstituted, which optionally contains at least one heteroatom as a member of ring, which can be condensed with a cyclic, mono or polycyclic, at least monosubstituted, or R3 represents a group aryl or heteroaryl optionally at least monosubstituted, which can be condensed with a cyclic, mono or polycyclic system, by less monosubstituted, or R3 represents a moiety -NR 4 R 5, R 4 and R 5, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a ring member, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or an aryl or heteroaryl group optionally at less monosubstituted, which may be condensed with a system cyclic, mono or polycyclic, at least monosubstituted and / or attached to through a linear or branched alkylene group, a moiety -SO 2 -R 6, or a moiety -NR 7 R 8, R 6 represents an aliphatic, linear 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 ring member, which may be condensed with a cyclic, mono or polycyclic system, or a group aryl or heteroaryl optionally at least monosubstituted, which can be condensed with a cyclic, mono or polycyclic system and / or bound through a linear or branched alkylene group, R 7 and R 8, identical or different, they represent a hydrogen atom, an aliphatic radical, not branched or branched, saturated or unsaturated, optionally at less monosubstituted, a saturated or unsaturated cycloaliphatic group, optionally at least monosubstituted, which optionally contains the less a heteroatom as a ring member, which may be condensed with a cyclic, mono or polycyclic system, at least monosubstituted, or an aryl or heteroaryl group optionally at less monosubstituted, which may be condensed with a system cyclic, mono or polycyclic, at least monosubstituted and / or attached to through a linear or branched alkylene group, 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 with the following conditions: that if R 4 and R 5 do not both represent a hydrogen atom, and that if one of the residues R 4 and R 5 represents a hydrogen atom or a linear aliphatic group or branched, saturated or unsaturated, substituted or unsubstituted, the other of these residues R 4 and R 5 does not represent a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidyl group, a substituted pyridazyl group or unsubstituted, a substituted or unsubstituted pyrazinyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted phenethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group , which is condensed (bound) to at least one optionally substituted ring or cyclic system, a -NH-phenyl moiety, in which the phenyl group may be at
monosubstituted nos, an unsubstituted or substituted thiazole group, or an unsubstituted or substituted thiadiazole [1,3,4] group.

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4. Pharmaceutical composition according to claims 2 or 3, characterized in that the compound of formula (I) is a compound in which R 1 represents a phenyl ring, which is monosubstituted with a halogen atom, preferably an atom of chlorine, in position 4,

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R2 represents a phenyl ring, which is disubstituted with two halogen atoms, preferably atoms of chlorine, in its positions 2 and 4, R 3 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a group homopiperazinyl, a morpholinyl group, or a moiety -NR 4 R 5, R 4 represents a hydrogen atom or a linear or branched C 1-6 alkyl group, R 5 represents an alkyl group C 1-6 linear or branched, a group pyrrolidinyl, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, in which each of the heterocyclic rings they can be substituted with one or more alkyl groups C_ {1-6}, identical or different, or a remainder -SO2 -R6, and R 6 represents a phenyl group, which is optionally substituted with one or more alkyl groups C_ {1-6}, which can be identical or different, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any reason of mixture, or a corresponding N-oxide thereof, or a salt corresponding thereof, or a corresponding solvate of the same, and from 0.05% to 0.5% by weight of the active substance of at less a surfactant and optionally one or more excipients pharmaceutically acceptable.

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5. Pharmaceutical composition according to claims 2, 3 or 4, characterized in that the compound of formula (I) is a compound selected from 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, acid diethylamide 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-1H-pyrazol-3-yl] -piperidin-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, or a corresponding salt, or a solvate correspondent.

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6. Pharmaceutical composition according to claim 1, characterized in that the composition comprises at least one compound of formula (II), 3. 4 in the that

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R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched, R 2 ', R 3' and R 4 'independently each other 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, R 5 'and R 6' independently of each other represent a linear C 1-6 alkyl group or branched, a linear C 1-6 alkoxy group or branched, a halogen atom, CH2F, CHF2, CF3CN, 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 R 11' for each substituent independently represents alkyl C 1-6 linear or branched; 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 R 11 'for each substituent represents independently linear C 1-6 alkyl or branched; with the condition of if R 1 'and R 7' are H and R 5 'and R 6 'both represent Cl at positions 3 and 4 of the ring of phenyl, none of R 2 ', R 3' and R 4 'can represent F at position 4 of the phenyl ring if the other two of R 2 ', R 3' and R 4 'both represent H; 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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7. Pharmaceutical composition according to claim 1, characterized in that the composition comprises at least one compound of formula (III) 35 in the that R 1 'represents hydrogen or an alkyl group C 1-4 linear or branched, R 12, R 13, R 14 or R 15 independently of each other they represent 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, SH, NH 2, hydrogen, methyl, ethyl, F, Cl, Br and CF 3.

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8. Pharmaceutical composition according to claim 7, characterized in that the compound of formula (III) is selected from: acid 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid, optionally in the form of your racemate or one of its enantiomers; a corresponding N-oxide; a salt corresponding or a corresponding solvate.

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9. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is in any of the following pharmaceutical forms (a), (b), (d) or (e) and, therefore, comprises: a) 0.05% to 0.5% by weight of the principle active of a surfactant and optionally one or more excipients additional pharmacists; or b) an additive that ensures a penetration of water inside the core of the preparation and a release polymer controlled; or d) a nucleus formed by an inert nucleus, a water soluble inert polymer and optionally excipients pharmaceutically stable; or e) an inert core, with

(aa)

a first layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

(bb)

a second layer containing a compound of formula (I), (II), or (III) and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable.

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10. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is in the pharmaceutical form (a) and therefore comprises: a) 0.05% to 0.5% by weight of the principle active of a surfactant and optionally one or more excipients Additional pharmacists

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11. Pharmaceutical composition according to claim 10 comprising:

from 0.5% to 40% by weight of compound of formula (I), (II) or (III)

from 0.05% to 0.5% by weight of sodium alkylsulfate, and

from 2.5% to 10% by weight of disintegrant.

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12. Pharmaceutical composition according to claim 10 containing:

from 0.5% to 40% by weight of compound of formula (I), (II) or (III)

from 0.1% to 0.4% by weight of sodium lauryl sulfate,

from 5% to 8% in weight of cross-linked sodium carboxymethyl cellulose,

from 1% to 10% in binder weight,

from 0.2% to 5% by weight of lubricant,

and a diluent in an amount sufficient to give 100%.

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13. Pharmaceutical composition according to a any one of claims 10 to 12, wherein the Surfactant is added to the purified water in the process. 14. Pharmaceutical composition according to a any of claims 10 to 13 in the form of capsules, microgranules, granules, tablets, sachets, powders, tablets oblong, gels, particulate systems such as granules, microgranules, multiparticles and the like, optionally compressed to give tablets or fill in capsules.

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15. Pharmaceutical composition according to claims 10 to 14 in the form of a gelatin capsule and which It has the following formulation, expressed in percentages in weight: Internal phase

compound formula (I), (II) or (III)

30% starch of corn

60.78% of lactose monohydrate mesh 200

2.53% of povidone K 30

5 of cross-linked sodium carboxymethyl cellulose

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Granulation

0.1% of sodium lauryl sulfate

water QS

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External phase

1% stearate magnesium

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16. Pharmaceutical composition according to claims 10 to 14 in the form of a gelatin capsule and which It has the following formulation, expressed in percentages in weight: Internal phase

compound formula (I), (II), (III)

30% starch of corn

55.49% of lactose monohydrate mesh 200

2.53% of povidone K 30

5 of cross-linked sodium carboxymethyl cellulose

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Granulation

0.1% of sodium lauryl sulfate

water QS

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External phase

1% stearate magnesium

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17. Pharmaceutical composition according to claims 10 to 14 in the form of a gelatin capsule and which It has the following formulation, expressed in percentages in weight: Internal phase

compound formula (I), (II) or (III)

30% starch of corn

43.73% of lactose monohydrate mesh 200

2.53% of povidone K 30

5 of cross-linked sodium carboxymethyl cellulose

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Granulation

0.1% of sodium lauryl sulfate

water QS

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External phase

1% stearate magnesium

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18. Method for the preparation of a pharmaceutical composition according to any one of claims 10 to 17, characterized in that: a) the active substance is mixed according to formulas I, II or III and the surfactant at room temperature, optionally with a diluent, a binder and / or an agent Colorant; b) the mixture is moistened with water purified; c) the resulting wet mass is dried and classify; and optionally d) a classified grains are added to lubricant a non-stick agent, a flow agent, an agent colorant and / or a flavoring agent.

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19. Method according to claim 18 for the preparation of a pharmaceutical composition according to any one of claims 1 to 10, characterized in that the surfactant is incorporated in step b) instead of in step a). 20. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is in the pharmaceutical form (b) and therefore comprises: b) an additive that ensures a penetration of water inside the core of the preparation and a release polymer controlled.

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21. Controlled release formulation according to claim 20, wherein the controlled release polymer It is a sustained release polymer. 22. Controlled release formulation according to claim 21, wherein the sustained release polymer It is based on a soluble polymer. 23. Controlled release formulation according to claim 21, wherein the sustained release polymer It is based on an insoluble polymer. 24. Controlled release formulation according to claim 22 or 23, wherein the release polymer Sustained is based on a matrix forming polymer. 25. Controlled release formulation according to claim 23, wherein the insoluble polymer is based on alkyl cellulose, preferably ethyl cellulose. 26. Controlled release formulation according to claim 22, wherein the soluble polymer is based on a cellulose derivative. 27. Controlled release formulation according to claim 26, wherein the cellulose derivative is hydroxypropylmethylcellulose or hydroxypropylcellulose. 28. Controlled release formulation according to claim 24, wherein the matrix forming polymer is a hydrogel forming polymer. 29. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is in the pharmaceutical form (c) and therefore comprises: (c) at least one additive that ensures a water penetration into the core of the preparation and at least a hydrogel forming polymer.

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30. Preparation of sustained release type hydrogel according to claim 29 comprising (1) at least one composed of formulas I, II or III, (2) at least one additive that ensures water penetration into the core of the preparation and (3) at least one hydrogel-forming polymer, wherein said preparation may undergo substantial gelation complete during its permanence in the upper digestive tract, including the stomach and small intestine, and can release the drug in the lower digestive tract, including the colon. 31. Preparation of sustained release type hydrogel according to claim 30, wherein said additive which ensures water penetration into the core of the preparation It is at least one additive that has a solubility such that the volume of water required to dissolve 1 gram of said additive is not more than 5 ml. 32. Preparation of sustained release type hydrogel according to claim 31, wherein said additive which ensures water penetration into the core of the preparation It is at least one additive that has a solubility such that the volume of water required to dissolve 1 gram of said additive is not more than 4 ml. 33. Preparation of sustained release type hydrogel according to claim 29, wherein said polymer Hydrogel former is either a polymer that has a weight molecular average not less than 2,000,000 or a polymer that it has a viscosity of not less than 1000 cps as measured at 1% concentration in water at 25 ° C, or a mixture of two or more of these polymers 34. Preparation of sustained release type hydrogel according to claim 29, wherein said polymer Hydrogel former includes at least one polyethylene oxide. 35. Preparation of sustained release type hydrogel according to any one of claims 29 to 36, which comprises (1) at least one compound of formulas I, II, III in a amount not exceeding 85% by weight based on the total preparation, (2) at least one additive that ensures water penetration into of the preparation core in an amount from 5 to 80% by weight based on the total preparation, and (3) at least one hydrogel forming polymer in an amount of from 10 to 95% by weight based on total preparation. 36. Preparation of sustained release type hydrogel according to any one of claims 29 to 35, which comprises (1) at least one compound of formula I, II, III in a amount not exceeding 80% by weight based on the total preparation, (2) at least one additive that ensures water penetration into of the preparation core in an amount from 5 to 60% by weight based on total preparation, and (3) at least one hydrogel forming polymer in an amount from 15 to 90% by weight based on total preparation. 37. Controlled release formulation according to claim 20, wherein the release of the active ingredient It is controlled by pH. 38. Controlled release formulation according to claim 37, wherein the release of the active ingredient It is controlled by a polymer whose solution depends on the pH. 39. Controlled release formulation according to claim 38, wherein the polymer is a polymer resistant to gastric juices, such as methyl esters of copolymerized methacrylic acid / methacrylic acid. 40. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is in the pharmaceutical form (d) and therefore comprises: d) a nucleus formed by an inert nucleus, a water soluble inert polymer and optionally excipients pharmaceutically acceptable.

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41. Preparation according to claim 40, in which the water soluble polymer comprises hydroxypropylmethylcellulose or hydroxypropylcellulose. 42. Preparation according to claim 40 that It has an enteric coating. 43. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is in the pharmaceutical form (e) and therefore comprises: (e) an inert core, with

(aa)

a first layer containing a compound of formula (I), (II), or (III), and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

(bb)

a second layer containing a compound of formula (I), (II), or (III), and optionally an inert polymer water soluble and optionally one or more excipients pharmaceutically acceptable;

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44. Formulation according to claim 43 in the that the release of the active substance is controlled. 45. Formulation according to claim 44 in the that controlled release depends on pH. 46. Formulation according to claim 45, in which the pH dependent controlled release is assured by an enteric polymer. 47. Formulation according to claim 46, in which the enteric polymer is a juice resistant polymer gastric, such as methacrylic acid / acid methyl esters copolymerized methacrylic. 48. Formulation according to claim 44, in which the controlled release formulation is a formulation of sustained release 49. Pharmaceutical composition for administration oral of a compound of formula (I), (II) or (III), or a mixture of the same, for administration in the form of oblong tablets, gels, particulate systems such as granules, microgranules, multiparticles and the like, optionally compressed to give tablets or filled in capsules.