ES2336883B1 - SUBSTITUTED PIRAZOLINE COMPOUNDS, WITH A DEFAULT STEREOCHEMISTRY, FOR THE REDUCTION OF TRIGLICERIDS IN BLOOD. - Google Patents

Abstract

Substituted pyrazoline compounds, with a default stereochemistry, for the reduction of triglycerides in blood.

The present invention relates to compounds of substituted pyrazoline, methods for its preparation, medications comprising these compounds, as well as their use for the preparation of a medicine for the treatment of humans and animals.

Description

Substituted pyrazoline compounds, with a default stereochemistry, for the reduction of triglycerides in blood.

The present invention relates to compounds of substituted pyrazoline, methods for its preparation, medications which comprise these compounds, in addition to their use for preparation of a medicament for the treatment of humans and animals.

Triglycerides are the chemical form in which there is most of the fat in the food in addition to the organism. Triglycerides are found in the blood plasma and, associated with cholesterol, they form plasma lipids. The triglycerides in the blood plasma come from fats consumed directly or that are synthesized from, for example, hydrates carbon Ingestion of unnecessary food becomes triglycerides and is transported to fat cells for storage. An elevated triglyceride level can also be consequence of disease states, such as diabetes mellitus without treating. An excess of triglycerides in the plasma (hypertriglyceridemia) is related to the appearance of coronary heart disease and possibly other disorders.

Therefore, compounds that have a effect on triglycerides, especially in blood plasma They are useful for the prevention and / or treatment of disorders related.

Therefore, it was an object of the present invention provide novel compounds for use as active ingredients in medicines, which are suitable for regulation, and in particular for reducing levels of triglyceride levels in the blood plasma.

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

It has been found that these compounds have a marked effect on the level of triglycerides in plasma blood

Therefore, in one of its aspects this invention relates to a substituted pyrazoline compound of General Formula

one

at that

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

R2, R3 and R4, independently each other, they represent hydrogen, an alkyl group C 1-6 linear or branched, an alkoxy group C 1-6 linear or branched, a halogen atom, CH 2 F, CHF 2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 represent, independently for each substituent, 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 represent, independently for each substituent, 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 RU, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R 11 represent, independently for each substituent, linear C 1-6 alkyl or branched;

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

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

with the condition of

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

These compounds had a surprising effect. on blood levels of relevant dietary substances, by example triglycerides.

Another aspect of the present invention relates to to a substituted pyrazoline compound of the general formula

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2

at that

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

R2, R3 and R4, independently each other, they 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 represent, independently for each substituent, 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 RU, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R 11 represent, independently for each substituent, 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 represent, independently for each linear, C 1-6 alkyl or substituent or branched;

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

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

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

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, 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, cycloalkyl 4-6 represents C4, C5 cycloalkyl or C6, cycloalkyl 4-7 represents cycloalkyl C4, C5, C6 or C7, cycloalkyl 5-6 represents C5 or C6 cycloalkyl and 5-7 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 O. However, mono or polyunsaturated cycloalkyls, preferably monounsaturated, without a heteroatom in the ring, also in particular, they are included within the term cycloalkyl provided that cycloalkyl is not an aromatic system. The alkyl and cycloalkyl radicals 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 the substitution has effect on different or on 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. Particularly preferred substituents herein they are F, Cl and OH. With respect to cycloalkyl, the hydrogen radical it can also be substituted by O (alkyl C_ 1-3) or C 1-3 alkyl (en 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_ {-} (CH 2) 1-4 it should be understood that means -CH_ {2} -, -CH_ {2} -CH_ {2} -, -CH_ {2} -CH_ {2} -CH_ {2} - and -CH 2 -CH 2 -CH 2 -CH 2 -, (CH2) 4-5 it should be understood that it means -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} - and -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 systems that have at least one aromatic ring and they may contain one or more heteroatoms of the group consisting of nitrogen, oxygen and / or sulfur and may also be mono or polysubstituted Examples that can be mentioned from the group of 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.

The term "salt" should be understood as means any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is it couples with a counterion (a cation or anion) or is in solution. This also means the compound complexes active with other molecules and ions, particularly complexes that complex through ionic interactions. Especially this covers any "physiologically acceptable salt".

The term "physiologically acceptable salt" which should be understood as equivalent and interchangeable with "salt physiologically acceptable "means in the context of this invention any salt that is physiologically tolerated (the largest part of the time meaning that it is not toxic, especially not produced by the counterion) if properly used with or Applies to humans and / or mammals.

These physiologically acceptable salts can be formed with cations or bases and in the context of this invention It should be understood that it means salts of at least one of the compounds used according to the invention, usually an acid (deprotonated), as an anion with at least one cation, preferably inorganic, which is physiologically tolerated, especially if Used with humans and / or mammals. They prefer particularly the salts of alkali metals and metals alkaline earth and also those with NH4, but in particular salts of (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium

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

The term "solvate" according to this invention It should be understood that it means any form of the active compound according to the invention in which this compound has attached to it through a non-covalent bond another molecule (most likely a polar solvent) including especially hydrates (mono and multihydrates) and alcoholates, for example, methanolate and ethanolate

Unless stated otherwise, the Compounds of the invention are also intended to include the compounds. which differ only in the presence of one or more enriched atoms isotopically For example they are within the scope of this invention the compounds having the present structures except for the replacement of a hydrogen with a deuterium or a tritium or the substitution of a carbon for a carbon enriched in 13 C or 14 C or nitrogen enriched in 15 N.

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

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

In a preferred embodiment of the invention for a compound according to formula I R 2, R 3 and R 4 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 I 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 with each other, they represent methyl, ethyl, F, Cl, Br and CF 3.

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

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

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

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

3

at that

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

R 12 or R 13, independently between yes, they 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 one another, represent a linear or branched C 1-6 alkyl group, a C 1-6 alkoxy group
linear 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 an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof.

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

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

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

In another preferred embodiment the compound according to Formula I or II is:

acid (R) -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.

Another preferred embodiment of the invention also covers any prodrug of the compounds of the invention described above as well as any medicament comprising this and any use thereof; in particular including 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 Drugdesign and Discovery, Taylor & Francis (April 2002) .

In another preferred embodiment of the invention, they also cover mixtures of the compounds of the invention (according to formulas I and II) described above with their opposite enantiomer corresponding according to formula XX

4

in any suitable reason (excluding a racemic mixture), as well as any combination and medication that includes this and any use of it describe to continuation.

In another aspect the present invention it also provides a procedure for the preparation of substituted pyrazoline compound of general formula I or II, in the that R1 is hydrogen, given above, in that at least a benzaldehyde compound of general formula III

5

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 (IV)

6

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 of an alkali metal, more preferably sodium, to give a compound of general formula (V)

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7

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which is optionally isolated and / or purifies, and that is reacted with a phenylhydrazine optionally substituted general formula (SAW)

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8

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

9

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

This follows from the addition of a base chiral

The process of the invention is also illustrated in scheme I, given below:

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Scheme I

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10

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

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 IV 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 included in this document as a reference and is part of the description.

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

The reaction temperature as well as the Reaction duration may 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 (VII) can be activated for additional reactions by the introduction of a suitable leaving group according to methods Conventionals well known to those skilled in the art. Preferably, the compounds of general formula (VII) are transferred into an acid chloride, a mixed anhydride, a C 1-4 alkyl ester, an activated ester such as 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 (VII) is an acid chloride, preferably prepared by reaction of the corresponding acid of general formula (VII) with thionyl chloride or oxalyl chloride, wherein said Chlorination is also used as the solvent. Can also be used preferably an additional solvent. Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane. Mixtures of two or more solvents of one class or two or more solvents of different classes The preferred reaction temperature has a range from 0 ° C to the boiling point of the solvent and reaction times from several minutes to several hours.

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

After this, the activated compound can reacted with an alkyl alcohol to give compounds according to the general formula VIIa which are equivalent of compounds of general formula I being R1 being an alkyl group C 1-4 linear or branched substituted or not replaced.

Finally, compounds VII or VIIa are treated with a suitable chiral base, preferably (+) - cinconine or R - (+) - 1-phenylethylamine, to give compounds according to the general formula I.

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 or II are obtained themselves in the form of a mixture of stereoisomers, in particular enantiomers or diastereomers, said mixtures can be separated by procedures customary used by those skilled in the art, for example, Chromatographic methods or crystallization with chiral reagents. It is also possible to obtain pure stereoisomers through the stereoselective synthesis.

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

In yet another additional aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of the general formula I or II or stereoisomers thereof, in which at least one compound of general formula I or II with at least one acid group is reacts with one or more suitable bases, preferably in presence of a suitable reaction medium. The appropriate bases 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 R4-n] +, 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.

The solvates, preferably hydrates, of the substituted pyrazoline compounds of general formula I or II, of the corresponding stereoisomers of the N-oxides corresponding or corresponding salts thereof they can also be obtained by usual procedures known by Those skilled in the art.

A substituted pyrazoline compound of the formula general I or II, which comprises a nitrogen atom containing saturated, unsaturated or aromatic rings can also be obtained in the form of their N-oxides by well known methods of experts in the art.

Purification and isolation of the compound substituted pyrazoline of the invention of general formula I or II, of a corresponding stereoisomer, or salt, or solvate or any intermediate product thereof can, if necessary, be taken to carried out by conventional methods known to those skilled in the technique, for example chromatographic methods or recrystallization.

As a reference on stereochemistry and usual methods for separation, reference is made to Eliel and Wilen, Stereochemistry of organic Compounds, John Wiley & Sons Inc., 1994, included by reference. Preferred methods include MPLC, HPLC, simulated mobile lot and printed polymers.

The substituted pyrazoline compounds of general formula I and II provided below, their stereoisomers, their corresponding N-oxides, salts corresponding of them and their corresponding solvates are toxicologically acceptable and are therefore suitable as active ingredients for the preparation of medicines.

It has been found that the pyrazoline compound substituted by general formula (I) and (II) given below, stereoisomers thereof, N-oxides thereof, salts corresponding and corresponding solvates have the property of regulate triglyceride levels in blood plasma.

It has been found that the compounds of substituted pyrazoline of general formula X provided to then stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have a high affinity for cannabinoid receptors, particularly those cannabinoid 1 receptors (CBÇ_ {1}), that is, they are antagonists on these receptors. In particular, these compounds of pyrazoline show little or no tolerance development during treatment, particularly with regard to ingestion food. After finishing the treatment with the compounds of pyrazoline, a decrease in body weight is found with regarding levels prior to treatment.

Therefore, another aspect of the present invention a medicament comprising at least one compound of substituted pyrazoline of general formula I or II according to the invention and optionally one or more pharmaceutically excipients acceptable.

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Therefore, another aspect of the present invention refers to a medicament comprising at least one compound of substituted pyrazoline of general formula I

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eleven

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at that

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

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, 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 represent, independently for each substituent, alkyl C 1-6 linear or branched,

R 5, R 6 and R 7, independently each other, they 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 10, SH, SR 10, SOR 10, NH 2, NHR 10, NR 10 RU, - (C = O) -NH 2, - (C = O) -NHR 10 and - (C = O) -NR 10 R 11, in which R 10 and optionally R 11 represent, independently for each substituent, linear C 1-6 alkyl or branched;

optionally in the form of an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof;

and optionally one or more excipients pharmaceutically acceptable.

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Another aspect of the present invention relates to to a medicament comprising at least one pyrazoline compound substituted of general formula I

12

at that

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

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 represent, independently for each substituent, alkyl C 1-6 linear or branched,

R 5, R 6 and R 7, independently each other, they 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 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 represent, independently for each substituent, linear C 1-6 alkyl or branched;

optionally in the form of an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof;

and optionally one or more excipients pharmaceutically acceptable.

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

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

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In one embodiment of the medication according to the invention for the compound according to formula I, at least one of R 2, R 3 or R 4 represents hydrogen, while at minus one of R2, R3 or R4 is different from hydrogen.

In one embodiment of the medication according to the invention for the compound according to formula I, at least one of R 5, R 6 or R 7 represents hydrogen, while at minus one R 5, R 6 or R 7 is different from hydrogen.

In one embodiment of the medication according to the invention for the compound according to formula I, R2, R3 and R 4 independently represent each other hydrogen, a group linear or branched C 1-6 alkyl, an atom of halogen, 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 one embodiment of the medication according to the invention for the compound according to formula I, R 5, R 6 and R 7, independently of each other, represents hydrogen, a linear or branched C 1-6 alkyl group, a halogen atom, or CF 3, preferably R 5, R 6 and R 7, independently of each other, represents hydrogen, methyl, ethyl, F, Cl, Br and CF 3.

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In one embodiment of the medication according to the invention for the compound according to formula I, R2 represents a chlorine atom at position 4 of the phenyl ring, while that R 3 and R 4 represent hydrogen.

In one embodiment of the medication according to the invention for the compound according to formula I, R 5 and R 6 each represents a chlorine atom in positions 2 and 4 of the phenyl ring, while R 7 represents hydrogen.

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

In one embodiment of the medication according to the invention the compound according to formula I is represented by a compound of general formula (II)

13

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at that

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

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 the form of an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof.

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

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

In one embodiment of the medication according to the invention for the compound according to formula II, R 13 represents Cl and R 12 represents hydrogen.

In one embodiment of the medication according to the invention for the compound according to formula II, R 14 and R 15 each represent Cl.

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

In one embodiment of the medication according to the invention the compound according to formulas I or II is selected from group consisting of:

acid (R) -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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In one embodiment of the medications according to the invention the medicine is for the regulation of the levels of triglycerides in blood plasma and for prophylaxis and / or the treatment of disorders of the central nervous system, in particular strokes, system disorders cardiovascular and food ingestion disorders, preferably bulimia, anorexia, cachexia, obesity and / or diabetes Type II mellitus (non-insulin dependent diabetes), preferably obesity and diabetes

In an embodiment of the medicament comprising the compound according to formula I or II, according to the invention the medication is for 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.

In one embodiment of the medications according to the Invention the medication is for the prophylaxis and / or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity.

In one embodiment of the medications according to the Invention the medication is for the prophylaxis and / or treatment of psychosis

In one embodiment of the medications according to the Invention the medication is for prophylaxis and / or treatment of alcoholism and / or alcohol addiction, nicotine abuse and / or smoking, drug abuse and / or drug addiction and / or drug abuse and / or drug dependence, preferably drug abuse and / or drug addiction and / or abuse of nicotine and / or smoking.

In one embodiment of the medications according to the Invention the medication is for the prophylaxis and / or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, disorders neurodegenerative, cerebellar disorders, disorders spinocerebellar, cognitive disorders, head trauma, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud, tremors, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of cancer brain, bone cancer, lip cancer, mouth cancer, cancer esophagus, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, cancer lung, breast cancer, skin cancer, colon cancer, cancer intestinal and prostate cancer, more preferably for prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of colon cancer, cancer intestinal and prostate cancer; induced movement disorders for 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.

Particularly preferably, said Medications are suitable for prophylaxis and / or treatment of alcoholism, drug abuse and / or medication abuse, preferably drug abuse and for the treatment of obesity.

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

The medicament according to the present invention can be in any form suitable for application to humans and / or animals, preferably humans, including infants, children and adults and can be produced by usual procedures used by Those skilled in the art. The composition of the medication can vary depending on the route of administration.

The medicament of the present invention can, for example, administered parenterally in combination with conventional injectable liquid vehicles, such as water or suitable alcohols. Pharmaceutical excipients may be included. conventional, such as stabilizing agents, agents solubilizers and buffers, in such injectable compositions. These medications can be injected, for example, intramuscularly, intraperitoneally or intravenously.

Solid oral compositions (which are preferred, as well as liquids) can be prepared by methods Conventional mixing, filling or tablet manufacturing. Repeated mixing operations can be used to distribute the agent through those compositions that use a lot of filters. Such operations are conventional in the art. The tablets can, for example, be prepared by granulation in wet or dry and can be optionally coated according to the methods well known in usual pharmaceutical practice, in particular With an enteric coating.

The mentioned formulations will be prepared using usual methods such as those described or referred to in Spanish and American pharmacopoeias and in reference texts Similar.

Medications according to the present invention they can also be formulated in compositions that can be administered orally, containing one or more vehicles or excipients physiologically compatible, in solid or liquid form. These compositions may contain conventional components, such as binding agents, fillers, lubricants and wetting agents acceptable. The compositions can take any form convenient, such as tablets, microgranules, capsules, lozenges, 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.

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 be administered during one or several intake per day.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention (and optionally one or more excipients pharmaceutically acceptable), for the preparation of a medicine for the regulation of triglyceride levels in plasma blood and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention (and optionally one or more excipients pharmaceutically acceptable) for the preparation of a medicine for the prophylaxis and / or treatment of system disorders central nervous, immune system disorders, disorders of the cardiovascular system, endocrine system disorders, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention (and optionally one or more excipients pharmaceutically acceptable), for the preparation of a medicine for the prophylaxis and / or treatment of ingestion disorders of food, preferably bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention (and optionally one or more excipients pharmaceutically acceptable), for the preparation of a medicine for the prophylaxis and / or treatment of psychosis.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention (and optionally one or more excipients pharmaceutically acceptable), for the preparation of a medicine for the prophylaxis and / or treatment of alcoholism and / or the alcohol addiction, nicotine abuse and / or smoking, abuse of drugs and / or drug addiction and / or drug abuse and / or Drug dependence, preferably drug abuse and / or drug addiction and / or nicotine abuse and / or smoking.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for prophylaxis and / or treatment. of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, head trauma, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's disease, disease Alzheimer's disease, Raynaud's disease, tremors, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, bone disorders including osteoporosis or Paget's bone disease; cancer, preferably for the prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, Bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, intestinal cancer and prostate cancer, more preferably for prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of colon cancer, intestinal cancer and prostate cancer; medication-induced movement disorders, dystonia, endotoxémic shock, hemorrhagic shock, hypotension, insomnia, immunological disorders, sclera plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiating the analgesic effect of narcotic analgesics and not narcotics, or to influence traffic
intestinal.

Another preferred aspect of the invention is a method for regulating triglyceride levels in the blood plasma, a method for the treatment of disorders of the central nervous system, in particular accidents cerebrovascular disorders of the cardiovascular system or of food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes, which comprises administering to a subject, preferably a human being, a therapeutically effective amount of one or more of the substituted pyrazoline compounds or mixtures such as those described in this document.

Another preferred aspect of the invention is a method for treating nervous system disorders central, immune system disorders, system disorders cardiovascular, endocrine system disorders, disorders of the respiratory system, gastrointestinal tract disorders or reproductive disorders, which includes administering to a subject, preferably a human being, a therapeutically effective amount of one or more of the substituted pyrazoline compounds or mixtures as described in this document.

Another preferred aspect of the invention is a method for the treatment of psychosis, which comprises administering to a subject, preferably a human being, an amount therapeutically effective of one or more of the pyrazoline compounds substituted or mixtures such as those described herein document.

Another preferred aspect of the invention is a method for the treatment of alcoholism and / or addiction to alcohol, nicotine abuse and / or smoking, drug abuse and / or drug addiction and / or drug abuse and / or drug dependence, preferably drug abuse and / or drug addiction and / or abuse of nicotine and / or smoking, which includes administering to a subject, preferably a human being, a therapeutically effective amount of one or more of the substituted pyrazoline compounds or mixtures as described in this document.

Another preferred aspect of the invention is a method for the treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, peripheral neuropathy, glaucoma , migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremors, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, bone disorders including osteoporosis or Paget's disease; cancer, preferably for the prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, Bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, intestinal cancer and prostate cancer, more preferably for prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of colon cancer, intestinal cancer and prostate cancer; medication-induced movement disorders, dystonia, endotoxémic shock, hemorrhagic shock, hypotension, insomnia, immunological disorders, sclera plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiating the analgesic effect of narcotic analgesics and non-narcotic, or to influence intestinal transit, which comprises administering to a subject, preferably a human being, a therapeutically effective amount of one or more of the substituted pyrazoline compounds or mixtures such as those described herein.
document.

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Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of the general formula I

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14

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at that

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

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, 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 represent, independently for each substituent, alkyl C 1-6 linear or branched,

R 5, R 6 and R 7, independently each other, they 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 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 represent, independently for each substituent, linear C 1-6 alkyl or branched;

optionally in the form of an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof;

and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the regulation of triglyceride levels in plasma blood and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes.

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Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of the general formula I

fifteen

at that

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

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 represent, independently for each substituent, alkyl C 1-6 linear or branched,

R 5, R 6 and R 7, independently each other, they 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 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 represent, independently for each substituent, linear C 1-6 alkyl or branched;

optionally in the form of an N-oxide corresponding thereof, or a corresponding salt of the themselves, or a corresponding solvate thereof;

and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the regulation of triglyceride levels in plasma blood and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes.

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

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

Another preferred aspect of the invention is the use for the manufacture of a medicament of at least one compound of substituted pyrazoline of formula I for which at least one of R 2, R 3 or R 4 represents hydrogen, while at minus one of R2, R3 or R4 is different from hydrogen for the manufacture of a medicine for the regulation of triglyceride levels in blood plasma and for prophylaxis and / or the treatment of disorders of the central nervous system, in particular strokes, system disorders cardiovascular and eating disorders, in particular bulimia, anorexia, cachexia, obesity, diabetes mellitus type II (non-insulin dependent diabetes mellitus), preferably obesity and diabetes

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which at least one of R 5, R 6 or R 7 represents hydrogen, while at least one R 5, R 6 or R 7 is different from hydrogen for the manufacture of a medicine for regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, particularly strokes, of disorders of the cardiovascular system and eating disorders of food, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R2, R3 and R4 independently of each other represent hydrogen, a C 1-6 alkyl group linear or branched, a halogen atom, or CF3, preferably R2, R3 and R4 independently between they do represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 for the manufacture of a drug for the regulation of levels of triglycerides in blood plasma and for prophylaxis and / or treatment of central nervous system disorders, in particular strokes, system disorders cardiovascular and eating disorders, in particular bulimia, anorexia, cachexia, obesity, diabetes mellitus type II (non-insulin dependent diabetes mellitus), preferably obesity and diabetes

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 5, R 6 and R 7, independently of each other, represent hydrogen, a C 1-6 alkyl group linear or branched, a halogen atom, or CF3, preferably R 5, R 6 and R 7, independently between yes, they represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 for the manufacture of a drug for the regulation of levels of triglycerides in blood plasma and for prophylaxis and / or treatment of central nervous system disorders, in particular strokes, system disorders cardiovascular and eating disorders, in particular bulimia, anorexia, cachexia, obesity, diabetes mellitus type II (non-insulin dependent diabetes mellitus), preferably obesity and diabetes

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 2 represents a chlorine atom at position 4 of the phenyl ring, while R 3 and R 4 represents hydrogen for the manufacture of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular strokes, of system disorders cardiovascular and eating disorders, in particular bulimia, anorexia, cache-
xia, obesity, type II diabetes mellitus (non-insulin dependent diabetes mellitus), preferably obesity and diabetes.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 5 and R 6 each represent a chlorine atom in positions 2 and 4 of the phenyl ring, while R 7 represents hydrogen for the manufacture of a medicine for the regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, particularly strokes, of disorders of the cardiovascular system and eating disorders of food, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 1 represents hydrogen, methyl or ethyl, preferably hydrogen for the manufacture of a medicament for regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, particularly strokes, of disorders of the cardiovascular system and eating disorders of food, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula in the that the compound of general formula (I) is represented by a compound of general formula (II)

16

at that

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

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 the form of an N-oxide corresponding thereof, or a corresponding salt of the same, or a corresponding solvate thereof

for the manufacture of a medicine for regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, particularly strokes, of disorders of the cardiovascular system and eating disorders of food, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

Another embodiment of the invention is the use of al minus a substituted pyrazoline compound of formula II for the which R 12 and R 13, independently of each other, represent hydrogen, a linear C 1-6 alkyl group or branched, a halogen atom, or CF 3, preferably R 12 and R 13, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 for manufacturing of a medicine for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes.

Another embodiment of the invention is the use of al minus a substituted pyrazoline compound of formula II for the which R 14, and R 15, independently of each other, represent hydrogen, a linear C 1-6 alkyl group or branched, a halogen atom, or CF 3, preferably R 14 and R 15, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 for manufacturing of a medicine for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes.

Another embodiment of the invention is the use of al minus a substituted pyrazoline compound of formula II for the which R 13 represents Cl and R 12 represents hydrogen for the manufacture of a drug for the regulation of the levels of triglycerides in blood plasma and for prophylaxis and / or treatment of central nervous system disorders, in particular strokes, system disorders cardiovascular and eating disorders, in particular bulimia, anorexia, cachexia, obesity, diabetes mellitus type II (non-insulin dependent diabetes mellitus), preferably obesity and diabetes

Another preferred embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 14 and R 15 each represent Cl for the manufacture of a drug for the regulation of the levels of triglycerides in blood plasma and for prophylaxis and / or treatment of central nervous system disorders, in particular strokes, system disorders cardiovascular and eating disorders, in particular bulimia, anorexia, cachexia, obesity, diabetes mellitus type II (non-insulin dependent diabetes mellitus), preferably obesity and diabetes

Another preferred embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 1 represents hydrogen, methyl or ethyl, preferably hydrogen for the manufacture of a medicament for regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, particularly strokes, of disorders of the cardiovascular system and eating disorders of food, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

Another embodiment of the invention is the use of al minus a substituted pyrazoline compound of formula I or II for which the compound according to formulas I or II is selected from group consisting of:

acid (R) -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;

for the manufacture of a medicine for regulation of triglyceride levels in blood plasma and for the prophylaxis and / or treatment of system disorders central nervous, particularly strokes, of disorders of the cardiovascular system and eating disorders of food, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity and diabetes.

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The use of al is also particularly preferred. minus one of the pyrazoline compounds as described in this document and optionally one or more pharmaceutically excipients acceptable, for the preparation of a medicine for Metabolic syndrome treatment.

The metabolic syndrome and its definitions are described in detail by Eckel et al ., Lancet, Vol. 365 (2005), 1415-1428, included as a reference herein. One of the respective definitions was established by WHO in 1998 (as described in Alberti et al ., Diabet. Med. 1998, 15, pages 539-53, the respective description of the same is incorporated by reference to this document and form part of this description). The other, more widespread definition of metabolic syndrome was established by the Adult Treatment Panel (ATP III) of the US National Cholesterol Education Program (NCEP) in 2001 , as described in JAMA 2001; 285; 2486-97, the respective description thereof is incorporated by reference to this document and forms part of this description.

The metabolic syndrome is characterized by a interaction of several physiological parameters such as triglycerides, lipids, blood pressure, blood sugar levels and insulin.

Even when obesity can play a role critical in the development of metabolic syndrome, many of its aspects are independent of weight, especially some lipid parameters. Especially, the positive influence on the independent aspects of the weight of the metabolic syndrome (see, for example, Pagotto and Pasquali, The Lancet, Vol. 365 (2005), 1363, 1364, included as reference in this document) as some blood parameters, especially lipid parameters, It is one of the main and surprising advantages of the compounds of substituted pyrazoline used according to the invention.

Another aspect of the invention is the use of one or more pyrazoline compounds, as defined herein document, for the manufacture of a medicine for the improvement of cardiovascular and / or metabolic risk factors, such as one or more of the following factors:

High triglycerides, in which elevated triglyceride levels are preferably understood to be>
150 mg / dl

Low HDL cholesterol, in which the low cholesterol levels of HDL is preferably understood which are <40 mg / dl in men and <50 mg / dl in women,

Hypertension, in which hypertension is understood preferably that is> 130/85 mmHg,

Fasting impaired glucose, in which the alteration of fasting blood glucose is preferably understood that is> 110 mg / dl,

Insulin resistance

Dyslipidemia

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Another aspect of the invention is the use of one or more pyrazoline compounds, as defined herein document, for the manufacture of a drug for treatment of the independent aspects of the weight of the metabolic syndrome.

Another aspect of the invention is a method for improve cardiovascular and / or metabolic risk factors, such as one or more of the following factors:

High triglycerides, in which elevated triglyceride levels are preferably understood to be>
150 mg / dl,

Low HDL cholesterol, in which the low cholesterol levels of HDL is preferably understood which are <40 mg / dl in men and <50 mg / dl in women,

Hypertension, in which hypertension is understood preferably that is> 130/85 mmHg,

Fasting impaired glucose, in which the alteration of fasting blood glucose is preferably understood that is> 110 mg / dl,

Insulin resistance

Dyslipidemia,

in a subject, preferably a human being.

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Another aspect of the invention is a method for treat independent aspects of the weight of the syndrome metabolic.

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

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Examples

Example 0 represents a compound according to formula I or II.

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

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17

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

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

IR (KBr, cm -1): 3500-2500, 1719, 3, 1686, 5, 1603, 4, 1587.8, 1081.9.

1 H-NMR (CDCl 3, δ): 7.4 (d, J = 8.4 Hz, 2H), 7.5 (d, J = 16.1 Hz, 1H), 7.6 (d, J = 8.4 Hz, 2H), 8, l (d, J = 16.1 Hz, 1H).

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

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

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

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18

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

IR (KBr, cm -1): 3200-2200, 1668, 4, 1458, 1251, 4, 1104.8.

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

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c) Resolution of the acid enantiomers 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

The resolution of the acid enantiomers 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic was carried out by reaction with the following bases chiral:

Brucina

Quinine

• (-) - cinconidine

? (+) - cinconine

? R - (+) - 1-phenylethylamine

? (1R, 2S) - (-) - ephedrine hydrochloride

? (1S, 2R) - (+) - ephedrine hydrochloride.

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The reactions were carried out, in each case, with 0.5 and 1 base equivalents with respect to 1 equivalent of acid compound and using the following solvents

Ethanol

Acetone

Acetonitrile

Dioxane

ethyl acetate

Chloroform.

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The results are summarized in the tables following. It can be understood that the crystallization experiments previously mentioned that are not reflected in the tables following did not give crystals of their respective salts in the given conditions.

However, those skilled in the art can determine suitable conditions for the crystallization of these salts through routine experiments.

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In the following tables

Acid represents acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic racemic

R-acid represents the respective derivative of acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

S-acid represents the respective derivative of acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

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Crystallization Procedures

Procedure A: A solution of the chiral base on top of a solution of racemic acid a room temperature.

Procedure C: A solution of the racemic acid on top of a chiral base solution. Be heated the mixture to reflux and solvent was added until Complete the dissolution. The solution was allowed to crystallize at room temperature.

Procedure D: The chiral base was added directly on top of a solution of racemic acid to room temperature.

Procedure E: The chiral base was added directly on top of a solution of racemic acid to reflux temperature.

Procedure F: Evaporated to dryness salt dissolution. The residue was dissolved in a minimum amount of the solvent by refluxing. It allowed to crystallize the dissolution at room temperature.

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Resolution with brucina

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19

Resolution with Quinine

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twenty

Resolution with (-) - Cinconidine

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twenty-one

Resolution with (+) - Cinconina

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22

Resolution with R - (+) - 1-phenylethylamine

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2. 3

Detailed description Acid Resolution 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic with (+) - cinconina

35 g (294.68 mmol) of the acid were added 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic racemic in 630 m of acetonitrile to a suspension of 16.39 g (47, 34 mmol) of (+) - cinconine in 920 mL of acetonitrile with vigorous agitation. The resulting suspension was heated to reflux and acetonitrile (1300 mL) was added until complete dissolution. The resulting solution was allowed to crystallize at room temperature over the weekend, so obtained a crystalline solid. The crystalline solid was filtered, washed with 50 mL of cold acetonitrile and dried to give 25.26 g of a white solid (ee \ approx 91-92%). It could not obtain a second fraction of crystals from the mother liquors, nor cooling them in the fridge or concentrating them. So, the recrystallization of diastereomeric salt was carried out in Different solvents to improve enantiomeric excess:

24

Therefore, the product was recrystallized from starting from acetonitrile to give 22.6 g of crystals (yield 72 mol-% in relation to the chiral base). The reason of enantiomers determined by capillary electrophoresis was:

99.7% acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic (+) - Cinconina

0.3% acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic (+) - cinconina

ee = 99.4%.

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Acid preparation (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic from the acid addition compound (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic- (+) - cinconina

22.59 g (34 mmol) of the salt was suspended diastereomeric that was recrystallized from acetonitrile, in 200 mL of 6N HCl and stirred at room temperature for 15 minutes. After 200 mL of toluene was added until dissolution was complete. Be The mixture was stirred for 30 minutes and the phases were separated. Be extracted the aqueous phase with toluene, the organic phases were washed combined with water, dried over sodium sulfate, filtered and evaporated to dryness, whereby 11.9 g were obtained (95%) of a white crystalline microsolid (melting point 129-133).

Enantiomeric excess determined by capillary electrophoresis, ee = 99.2%

Chemical purity determined by HPLC: 99.3%

[α] D (c = 1.23 ° C, MeOH) = -429

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Acid enantiomer isolation (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic of the mother liquor obtained from the crystallization of acid enantiomer (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic with Brucina

The residue obtained from the evaporation of the mother liquor obtained from the crystallization of the acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic with Brucina it was treated with 6N HCl as described above to Get the free acid. After evaporation of the organic phase, they obtained 21.86 g of a mixture with a theoretical composition of 20 mmol of acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic and 39.9 mmol of the acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic. A suspension of 13.82 g (39.9 mmol) of (+) - cinconine in 1000 mL of acetonitrile and Heated the mixture to reflux. More acetonitrile was added until complete the solution (total volume of acetonitrile 4000 mL). Then the mixture was cooled slowly to room temperature To get the crystals. After a few hours a white solid, which was filtered and dried to give 22.42 (yield 84.5% in relation to the acid salt (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic acid).

The enantiomeric excess as determined by capillary electrophoresis it was ee = 92%.

The purity of the isolated salt was comparable to the of the salt obtained directly from the resolution of the racemate Therefore, the same procedure could be applied of purification as described above.

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Acid Resolution 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic racemic with Brucina Preparation of diastereomeric salt with Brucina

15.74 g were dissolved at room temperature (39.9 mmol) of Brucina in 475 mL of acetone with vigorous stirring. A solution of 29.5 g (79.8 mmol) of the acid was added 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4, 5-dihydro-pyrazol-3-carboxylic racemic in 85 mL of acetone. The resulting mixture was left crystallize for a couple of days, after which a crystalline solid The crystalline solid was filtered, washed with cold acetone and dried to give 13.66 g (45 mol% in relation to base) of a beige solid.

The reason of the enantiomers as it is determined by capillary electrophoresis was:

99% acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic Brucina

1% acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic Brucina

Enantiomeric excess ee = 98%

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The filtered mother liquors were left in the refrigerator and they gave a second fraction of crystals, which were filtered and dried to give another 1.56 g (5.1 molar% relative to base).

The analysis of the 2nd fraction through capillary electrophoresis gave

99.3% acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic Brucina

0.7% acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic Brucina

Enantiomeric excess ee = 98.6%

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Total yield:

15.22 g (50.1 mol% based on) of the salt with ee = 98%.

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Determination of the chirality of Brucina salt by means of x-ray crystallography

The chirality of the enantiomer that crystallized with Brucina (ee 98%) was determined by X-ray crystallography and this corresponds to the S enantiomer. Therefore, the other enantiomer that crystallized with
(+) - Cinconine is the corresponding R enantiomer.

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Acid preparation (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic from the acid addition compound (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic Brucina

15.17 g (19.85 mmol) of the acid were suspended (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl1) -4,5-dihydro-pyrazol-3-carboxylic Brucina in 150 mL of 6N HCl and the suspension was stirred for 10 minutes, followed by the addition of 150 mL of toluene, after which He observed the complete dissolution. The resulting mixture was stirred. for an additional 30 minutes under control with chromatography of column (silica gel, Cl2CH2: MeOH 95: 5). Later the phases were separated, the aqueous phase was extracted with toluene and the combined phases of toluene were washed three times with water, dried over sodium sulfate, filtered and evaporated until dryness. 7 g (95.5%) of an oil that solidified were obtained with the addition of a small amount of diethyl ether to give a white amorphous solid that showed a crystalline transformation with melting at 130-133 ° C.

TLC (Cl 2 CH 2: MeOH 95: 5): R f = 0.3

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The analysis of the enantiomers by means of capillary electrophoresis gave

99.1% of the acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

0.9% acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic

Enantiomeric excess ee = 98.2%

[α] D (c = 1.23 ° C, MeOH) = -480, 5.

Chemical purity determined by HPLC: 99.1%

1 H-NMR (CDCl 3) δ ppm: 3.2 (dd, J = 6, 4 and 18.2 Hz, 1H), 3.7 (dd, J = 12, 7 and 18.2 Hz, 1H), 5.85 (dd, J = 6.4 and 12.6 Hz, 1H), 7.0-7.2 (m, 7H).

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Acid enantiomer isolation (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic of the mother liquor obtained from the crystallization of the other acid enantiomer (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic with (+) - cinconina

The residue obtained from the evaporation of the mother liquor obtained from the crystallization of the acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic with (+) - cinconine was treated with 6N HCl as described above to obtain the free acid. Behind the evaporation of the organic phase 23.63 g of a mixture were obtained with a theoretical composition of 13.34 mmol of the acid (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic and 47, 34 mmol of the acid (S) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic. Said mixture, dissolved in 118 mL of acetone, was added on top of a solution of 18.7 g (47.4 mmol) of Brucina in 650 mL of acetone, is stirred for a couple of minutes and allowed to crystallize overnight at room temperature. A cream colored solid was obtained which was filtered and dried to give 28 g (77.5% relative to salt (S)).

The enantiomeric excess as determined by capillary electrophoresis was ee = 98.2%

The purity of the isolated salt was comparable to the of the salt obtained directly from the resolution of the racemate Therefore, the same procedure could be applied of purification as described above.

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

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

25

It dissolved under an atmosphere of acid nitrogen 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic (2.5 g, 6.8 mmol) obtained according to example 0 in 4 mL of thionyl and heated to reflux for 2.5 hours. The excess thionyl chloride from the reaction mixture under reduced pressure and the resulting crude residue (2.6 g) is used without additional purification

IR (KBr, cm -1): 1732, 3, 1700, 1533, 3, 1478, 1, 1212, 9, 826.6.

From this compound can be prepared compounds according to general formulas I and II in which R1 is a linear or branched C 1-4 alkyl group, by reacting this compound with the alkyl alcohol suitable.

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

26

They dissolved under nitrogen atmosphere N-aminopiperidine (0.6 mL, 5.6 mmol) and triethylamine (4 mL) in methylene chloride (25 mL). The resulting mixture is cooled on ice to 0 ° C and a solution was added dropwise of acid chloride 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic obtained in step (a) in methylene chloride (15 mL). He stirred the resulting reaction mixture at room temperature (approximately 25 ° C) overnight. Then he washed the reaction mixture with water, followed by an aqueous solution saturated with sodium bicarbonate, and then again with water, it dried over sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. The resulting crude solid was crystallized from ethanol. The crystallized solid was removed by filtration and concentrated the mother liquor to give a second fraction of crystallized product The two fractions were combined to give a 1.7 g total amount (57% 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 18.3 Hz, 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).

Compounds were prepared according to following examples 2-6 according to the procedure described in example 1, in combination with example 0.

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Example 2 [1,2,4] triazol-4-yl amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-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 17.9 Hz, 1H), 3.7 (dd, J = 12, 3 and 17, 9 Hz, 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 3 Hydrochloride (4-methyl-piperazin-1-yl) -amide of the acid 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -pyrazol-3-carboxylic acid

Melting point: 150-155 ° C.

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

1 H-NMR (CDCl 3, δ): 2.7 (d, J = 4.2 Hz, 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 = 8.4 Hz, 2H), 7.25 (2d, J = 8.4 and 8.7 Hz, 3H), 7.4 (d, J = 2.2 Hz, 1H), 7.5 (d, J = 8.7 Hz, 1H), 9.8 (s, 1H), 11.2 (sa).

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

This compound was obtained as 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 5 [5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -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 17.9 Hz, 1H), 3.7 (m, 3H), 3.9 (m, 2H), 5.6 (dd, J = 6, 1 and 11.9 Hz, 1H), 7-7.25 (m, 7H).

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Example 6 N- [5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H -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 18.3 Hz, 1H), 3.6 (dd, J = 12.8 and 18.3 Hz, 1H), 5.8 (dd, J = 6, 6 and 12.8 Hz, 1H), 7 (d, J = 8.2 Hz, 2H), 7.2 (s, 1H), 7.3-7.4 (m, 6H), 8 (d, J = 8.1 Hz, 2H), 9 (s, 1H).

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

It dissolves, under nitrogen gas as inert atmosphere, (R) -N-Piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide (0.15 g, 332 mmol) (according to example 0) in 7 mL of dichloromethane. The resulting solution is cooled on ice to 0 ° C and the m-chloroperbenzoic acid (0.204 g, 0.83 mmol) in Several servings After stirring for 15 minutes, a control by thin layer chromatography shows that there is no material left departure. Then a saturated solution of slowly added sodium bicarbonate, the organic phase is separated, washed with water, It is dried over sodium sulfate and filtered. Filtered solution evaporate to dryness and the crude product is purified by column chromatography, giving 78 mg (50% theoretical yield) N-oxide (R) -N-Piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide in the form of a white solid.

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Pharmacological data / Tests

The compound according to example 0 is an inhibitor of high blood levels of triglycerides. This effect is tested in obese mice fed a high-fat diet. The study method is described in the paragraphs.
following.

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

The study is performed using male mice of six weeks old B6 Lep ob / ob, obtained from Charles River (France). Mice are divided into 3 groups: I (control), II (vehicle), III (example 0).

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Group I

Group I animals receive the diet usual (D-12450B, Research Diets, NJ, USA).

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Group II

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

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Group III

Group III animals were fed with a high-fat diet (D-12492, Research Diets, NJ, USA), in both cases for 7 weeks (references 1 and 2).

At the end of the feeding period of 7 weeks begins the treatment period (14 days): the mice Group II receive the vehicle (10 mL / kg / day, v.o., of the solution aqueous acacia gum, 5% P / V). Group III is given 30 mg / kg / day, v. o., of the compound of the acid invention (R) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic according to example 0. Group I receives no treatment. The three groups of mice have the same diet as in the period previous.

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

Analysis of whole blood samples It is done using "Lipid panel" test strips and the analyzer PA Cardio-Check Test System photometric Instruments Polimer Technology Systems Indianapolis, EN-46268, USA (Distributed in Spain by Novalab Ibérica S.A.L, Madrid, Spain).

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Bibliography

1.- Lambert PD et al ., "Ciloiary neurotrophic factor activates leptin-like pathways and reduces body fat" PNAS 2001 , 28 (8): 4652-4657

2.- Fat MM et al "Oleoyl-Estrone lowers the body weight of both ob / ob and db / db mice". Sickle Metab Res 2000 , 32 : 246-250.

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

In a second set of experiments similar to The tests described above determine TG levels (triglycerides) in blood in mice with obesity induced by diet.

Mice receiving a high fat diet are treated, after a feeding period of 6 days, or vehicle v.o. (0.5% HPMC) or with the compound according to example 0 (30 mg / kg / day v.o.).

Blood TG levels are determined on the day 28 after the start of treatment.

Claims (60)

1. Substituted pyrazoline compound of general formula I, 27 at that

quad

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

quad

R 2, R 3 and R 4 independently between they do represent hydrogen, a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 represent, independently for each substituent, alkyl C 1-6 linear or branched,

quad

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 represent, independently for each substituent, linear C 1-6 alkyl or branched;

quad

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

         \ vskip1.000000 \ baselineskip
      

with the condition of

quad

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

quad

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

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2. Compounds according to claim 1, characterized in that at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R 4 is different from hydrogen. 3. Compounds according to any one of claims 1 or 2, characterized in that R7 represents hydrogen. 4. Compounds according to any one of claims 1 to 3, characterized in that R 2, R 3 and R 4 independently of each other represent hydrogen, a linear or branched C 1-6 alkyl group , a halogen atom, or CF 3, preferably R 2, R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 . 5. Compounds according to any one of claims 1 to 4, characterized in that R 5 and R 6, independently of one another, represent a linear or branched C 1-6 alkyl group, a halogen atom, or CF 3, preferably R 5 and R 6, independently of each other, represent methyl, ethyl, F, Cl, Br and CF 3. 6. Compounds according to any one of claims 1 to 5, characterized in that R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen. 7. Compounds according to any one of claims 1 to 6, characterized in that R 5 and R 6 each represent a chlorine atom at positions 2 and 4 of the phenyl ring, while R 7 } represents hydrogen. 8. Compounds according to any one of claims 1 to 7, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 9. Compounds of general formula II according to a or more of claims 1 to 8 28 in the that

quad

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

quad

R 12 or R 13, 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,

quad

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,

quad

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

         \ vskip1.000000 \ baselineskip
      

10. Compounds according to claim 9 characterized in that R 12 and R 13, independently of one another, represent hydrogen, a linear or branched C 1-6 alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3. 11. Compounds according to any one of claims 9 or 10, characterized in that R 14, and R 15, independently of one another, represent a linear or branched C 1-6 alkyl group, a halogen atom , or CF 3, preferably R 14 and R 15, independently of each other, represent methyl, ethyl, F, Cl, Br and CF 3. 12. Compounds according to any one of claims 9 to 11, characterized in that R 13 represents Cl and R 12 represents hydrogen. 13. Compounds according to any one of claims 9 to 12, characterized in that R 14 and R 15 each represent Cl. 14. Compounds according to any one of claims 9 to 13, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 15. Compounds according to one or more of the claims 1 to 14 selected from the group consisting of:

quad

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

quad

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

16. Process for the manufacture of substituted pyrazoline compound of general formula I or II, wherein R1 is hydrogen, according to one or more of claims 1 to 15, characterized in that at least one benzaldehyde compound of formula general III 29

quad

wherein R 2, R 3 and R 4 have the meaning according to one or more of the claims 1-8, are reacted with a compound of general formula pyruvate (IV)

30

quad

in which G represents a group O with R being a C 1-6 alkyl radical branched or unbranched or G represents a 0-K group with K being a cation, to give a compound of general formula (V)

31

quad

that optionally it is isolated and / or purified, and that reacts with an optionally substituted phenylhydrazine of general formula (VI)

32

quad

or a corresponding salt thereof, in which R 5, R 6 and R 7 have the meaning according to one or more of claims 1-8, under an inert atmosphere, to give a compound of general formula (VII)

33

quad

wherein R 2, R 3, R 4, R 5, R 6 and R 7 have the meaning given above, which is optionally isolated and / or purified, and optionally esterified to an alkyl ester if in the pyrazoline compound substituted of general formula I according to one or more of the claims 1 to 15 R1 is an alkyl group C 1-4 linear or branched, substituted or not substituted, saturated or unsaturated, achieving a compound of formula VIIa

3. 4

quad

followed by reacting the resulting compound of general formula VII or VIIa with a chiral base suitable for produce a compound of general formula I or II.

         \ vskip1.000000 \ baselineskip
      

17. Method according to claim 16, characterized in that the suitable chiral base is selected from
(+) - cinconine or R - (+) - 1-phenylethylamine. 18. Medication comprising at least one substituted pyrazoline compound of general formula I or II according to one or more of claims 1 to 15, and optionally one or more excipients pharmaceutically acceptable.

         \ vskip1.000000 \ baselineskip
      

19. Medication comprising at least one substituted pyrazoline compound of general formula I 35 at that

quad

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

quad

R 2, R 3 and R 4 independently between they do represent hydrogen, a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 represent, independently for each substituent, alkyl C 1-6 linear or branched,

quad

R 5, R 6 and R 7, independently between yes, they 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 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 represent, independently for each substituent, linear C 1-6 alkyl or branched;

quad

optionally in the form of a corresponding N-oxide thereof, or a corresponding salt thereof, or a solvate corresponding thereof;

and optionally one or more excipients pharmaceutically acceptable.

         \ vskip1.000000 \ baselineskip
      

20. A medicament according to claim 19, characterized in that at least one of R 2, R 3 or R 4 represents hydrogen, while at least one of R 2, R 3 or R 4 is different from hydrogen. 21. A medicament according to any one of claims 19 or 20, characterized in that at least one of R 5, R 6 or R 7 represents hydrogen, while at least one R 5, R 6 or R 7 is different from hydrogen. 22. A medicament according to any one of claims 19 to 21, characterized in that R 2, R 3 and R 4 independently of each other represent hydrogen, a linear or branched C 1-6 alkyl group , a halogen atom, or CF 3, preferably R 2, R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 . 23. A medicament according to any one of claims 19 to 22, characterized in that R 5, R 6 and R 7, independently of each other, represent hydrogen, a linear C 1-6 alkyl group or branched, a halogen atom, or CF 3, preferably R 5, R 6 and R 7, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF_ {3}. 24. A medicament according to any one of claims 19 to 23, characterized in that R2 represents a chlorine atom at position 4 of the phenyl ring, while R3 and R4 represent hydrogen. 25. A medicament according to any one of claims 19 to 24, characterized in that R 5 and R 6 each represent a chlorine atom at positions 2 and 4 of the phenyl ring, while R 7 } represents hydrogen. 26. A medicament according to any one of claims 19 to 25, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 27. A medicament according to one or more of claims 19 to 26, characterized in that the compound of general formula (I) is represented by a compound of general formula (II) 36 at that

quad

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

quad

R 12, 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,

quad

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

28. A medicament according to claim 27 characterized in that R 12 and R 13, independently of one another, represent hydrogen, a linear or branched C 1-5 alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3. 29. A medicament according to any one of claims 27 or 28, characterized in that R 14, and R 15, independently of one another, represent hydrogen, a linear or branched C 1-6 alkyl group, an atom halogen, or CF 3, preferably R 14 and R 15, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3. 30. A medicament according to any one of claims 27 to 29, characterized in that R 13 represents Cl and R 12 represents hydrogen. 31. A medicament according to any one of claims 27 to 30, characterized in that R 14 and R 15 each represent Cl. 32. A medicament according to any one of claims 27 to 31, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 33. Medication according to one or more of claims 19 to 32 characterized in that the compound according to formulas I or II is selected from the group consisting of:

quad

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

quad

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

         \ vskip1.000000 \ baselineskip
      

34. Medication according to claim 19 a 33 for the regulation of triglyceride levels in plasma blood and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes. 35. Medication according to one or more of the claims 19 to 33 for the prophylaxis and / or treatment of central nervous system disorders, system disorders immune, cardiovascular system disorders, disorders of the endocrine system, respiratory system disorders, disorders of the gastrointestinal tract or reproductive disorders. 36. Medication according to one or more of the claims 19 to 33 for the prophylaxis and / or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity. 37. Medication according to one or more of the claims 19 to 33 for the prophylaxis and / or treatment of the psychosis. 38. Medication according to one or more of the claims 19 to 33 for the prophylaxis and / or treatment of alcoholism and / or alcohol addiction, nicotine abuse and / or smoking, drug abuse and / or drug addiction and / or drug abuse and / or drug dependence, preferably drug abuse and / or drug addiction and / or abuse of nicotine and / or smoking. 39. Medication according to one or more of the claims 19 to 33 for the prophylaxis and / or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, disorders neurodegenerative, cerebellar disorders, disorders spinocerebellar, cognitive disorders, head trauma, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud, tremors, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of cancer brain, bone cancer, lip cancer, mouth cancer, cancer esophagus, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, cancer lung, breast cancer, skin cancer, colon cancer, cancer intestinal and prostate cancer, more preferably for prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of colon cancer, cancer intestinal and prostate cancer; induced movement disorders for 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. 40. Use of at least one pyrazoline compound substituted according to one or more of the claims 1-15 and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the regulation of triglyceride levels in plasma blood and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes. 41. Use of at least one pyrazoline compound substituted according to one or more of the claims 1-15 and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of system disorders central nervous, immune system disorders, disorders of the cardiovascular system, endocrine system disorders, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders

         \ newpage
      

42. Use of at least one pyrazoline compound substituted according to one or more of the claims 1-15 and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of ingestion disorders of food, preferably bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes mellitus no insulin dependent), preferably obesity. 43. Use of at least one pyrazoline compound substituted according to one or more of the claims 1-15 and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of psychosis. 44. Use of at least one pyrazoline compound substituted according to one or more of the claims 1-15 and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of alcoholism and / or the alcohol addiction, nicotine abuse and / or smoking, abuse of drugs and / or drug addiction and / or drug abuse and / or Drug dependence, preferably drug abuse and / or drug addiction and / or nicotine abuse and / or smoking. 45. Use of at least one pyrazoline compound substituted according to one or more of the claims 1-15 and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, disorders cerebellar, spinocerebellar disorders, cognitive disorders, head trauma, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's, Raynaud's disease, tremors, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, disorders bipolar, bone disorders including osteoporosis or disease Paget's bone; cancer, preferably for prophylaxis and / or treatment of one or more types of cancer selected from the group that It consists of brain cancer, bone cancer, lip cancer, cancer mouth, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cancer cervical, lung cancer, breast cancer, skin cancer, cancer of colon, bowel cancer and prostate cancer, more preferably for the prophylaxis and / or treatment of one or more types of cancer selected from the group consisting of cancer colon, bowel cancer and prostate cancer; disorders of medication-induced movement, dystonia, shock Endotoxémico, hemorrhagic shock, hypotension, insomnia, disorders immunological, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for the potentiation of analgesic effect of narcotic and non-narcotic analgesics, or for influence intestinal transit. 46. Use of at least one pyrazoline compound substituted of general formula I 37 at that

quad

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

quad

R 2, R 3 and R 4 independently between they do represent hydrogen, a C 1-6 alkyl group linear or branched, a C 1-6 alkoxy group linear or branched, a halogen atom, CH2F, CHF2, CF 3, CN, OH, NO 2, - (C = O) -R 8, SH, SR 8, SOR 8, NH 2, NHR 8, NR 8 R 9, - (C = O) -NH 2, - (C = O) -NHR 8 or - (C = O) -NR 8 R 9 in which R 8 and R 9 represent, independently for each substituent, alkyl C 1-6 linear or branched,

quad

R 5, R 6 and R 7, independently between yes, they 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 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 represent, independently for each substituent, linear C 1-6 alkyl or branched;

quad

optionally in the form of a corresponding N-oxide thereof, or a corresponding salt thereof, or a solvate corresponding thereof; and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the regulation of triglyceride levels in plasma blood and for the prophylaxis and / or treatment of disorders of the central nervous system, in particular accidents cerebrovascular, cardiovascular system disorders and food intake disorders, in particular bulimia, anorexia, cachexia, obesity, type II diabetes mellitus (diabetes non-insulin dependent mellitus), preferably obesity and diabetes.

         \ vskip1.000000 \ baselineskip
      

47. Use according to claim 46, characterized in that at least one of R 2, R 3 or R 4 represents hydrogen, while at least one of R 2, R 3 or R 4 is different from hydrogen. 48. Use according to any one of claims 46 or 47, characterized in that at least one of R 5, R 6 or R 7 represents hydrogen, while at least one R 5, R 6 or R 7 is different from hydrogen. 49. Use according to any one of claims 46 to 48, characterized in that R 2, R 3 and R 4 independently of each other represent hydrogen, a linear or branched C 1-6 alkyl group , a halogen atom, or CF 3, preferably R 2, R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 . 50. Use according to any one of claims 46 to 49, characterized in that R 5, R 6 and R 7, independently of each other, represent hydrogen, a linear C 1-6 alkyl group or branched, a halogen atom, or CF 3, preferably R 5, R 6 and R 7, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF_ {3}. 51. Use according to any one of claims 46 to 50, characterized in that R2 represents a chlorine atom at position 4 of the phenyl ring, while R3 and R4 represent hydrogen. 52. Use according to any one of claims 46 to 50, characterized in that R 5 and R 6 each represent a chlorine atom in positions 2 and 4 of the phenyl ring, while R 7 } represents hydrogen. 53. Use according to any one of claims 46 to 52, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 54. Use according to one or more of claims 46 to 53 characterized in that the compound of general formula (I) is represented by a compound of general formula (II) 38 at that

quad

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

quad

R 12, 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,

quad

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

         \ vskip1.000000 \ baselineskip
      

55. Use according to claim 54, characterized in that R 12 and R 13, independently of one another, represent hydrogen, a linear or branched C 1-6 alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3. 56. Use according to any one of claims 54 or 55, characterized in that R 14, and R 15, independently of one another, represent hydrogen, a linear or branched C 1-6 alkyl group, an atom halogen, or CF 3, preferably R 14 and R 15, independently of each other, represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3. 57. Use according to any one of claims 54 to 56, characterized in that R 13 represents Cl and R 12 represents hydrogen. 58. Use according to any one of claims 54 to 57, characterized in that R 14 and R 15 each represent Cl. 59. Use according to any one of claims 54 to 58, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen. 60. Use according to one or more of claims 46 to 59 characterized in that the compound according to formulas I or II is selected from the group consisting of:

quad

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

quad

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