KR20060135815A - Substituted pyrazoline compounds to reduce blood triglycerides - Google Patents

Abstract

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

Description

Substituted pyrazoline compounds for reducing triglycerides in blood}

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

Triglycerides are chemical forms in which most fat is present in the body as well as in food. Triglycerides are present in plasma and, in conjunction with cholesterol, form plasma lipids. Triglycerides in plasma are derived directly from spent fat or are synthesized, for example, from carbohydrates. Excess food intake is converted into triglycerides and transferred to fat cells for storage. Elevated triglycerides can also be the result of disease states, such as untreated diabetes. Excess triglycerides (hypertriglyceridemia) in plasma are associated with the development of coronary artery disease and possibly other diseases.

Thus, in particular, compounds that are effective against triglycerides in plasma are useful for the prevention and / or treatment of related diseases.

It was therefore an object of the present invention to provide novel compounds for use as active substances in medicaments, which are suitable for modulating, in particular, for reducing triglyceride levels in plasma.

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

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

Thus, in one of its aspects the present invention optionally comprises stereoisomers, preferably enantiomers or diastereomers, stereoisomers in the form or in a mixed ratio of one of the racemates, preferably enantiomers and / or diastereomers. To a substituted pyrazoline compound of the general formula, in the form of a mixture of at least two or more isomers, or in the form of a corresponding N-oxide, or a corresponding salt thereof, or a corresponding solvate thereof,

here

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R ⁸ , SH, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , NH ₂ , NHR ⁸ , NR ⁸ R ⁹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ^8, or - (C = O) -NR ⁸ R ⁹ represents a, where each substituent R ⁸ and R ⁹ are independently straight or branched chain C _{1 -6} - represents alkyl,

R ⁵ And R ⁶ is independently from each other straight or branched chain C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R ¹⁰ , SH, SR ¹⁰ , SOR ¹⁰ , NH ₂ , NHR ¹⁰ , NR ¹⁰ R ¹¹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ¹⁰ And - (C = O) represents a -NR ¹⁰ R ^11, wherein each substituent group R ¹⁰ and R ¹¹ optionally are independently straight or branched chain C _{1 -6} - represents alkyl,

R ⁷ is hydrogen, linear or branched C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO _2, - (C = O) -R ¹⁰ , SH, SR ¹⁰ , SOR ¹⁰ , NH ₂ , NHR ¹⁰ , NR ¹⁰ R ¹¹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ¹⁰ And - (C = O) represents a -NR ¹⁰ R ^11, where R ¹⁰ and R ¹¹ optionally are independently straight or branched chain C _{1 -6} substituents on each - represents an alkyl.

It is highly desirable if the following conditions apply to these compounds according to formula I:

R ¹ And R ⁷ is H and R ⁵ And R ⁶ Both represent Cl at the 3- and 4-positions of the phenyl ring, R ² , R ³ And R ⁴ If two of them represent H, then R ² , R ³ And R ⁴ Neither can represent F at the 4-position of the phenyl ring.

These compounds have had a surprising effect on blood levels of dietary related substances such as, for example, triglycerides.

Straight or branched, saturated or unsaturated aliphatic groups which may be substituted by one or more substituents are preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethynyl, propenyl, propynyl, butenyl and butynyl.

In the context of the present invention, alkyl and cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be mono- or polysubstituted. In these radicals, C _{1 -2} - alkyl represents C1- or C2- alkyl, C _{1 -3} - alkyl represents C1-, C2- or C3- alkyl, C _{1 -4} - alkyl is C1-, C2 - represents a C3- or C4- alkyl, C _{1 -5-alkyl} represents C1-, C2-, C3-, C4-, or C5- alkyl, C _{1 -6-alkyl} C1-, C2-, C3 -, C4-, C5- or C6- represents alkyl, C _{1 -7} - alkyl is C1-, C2-, C3-, C4-, C5-, C6- or represents C7- alkyl, C _{1 -8} - alkyl is C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8- represents alkyl, C _{1 -9} - alkyl is C1-, C2-, C3-, C4-, C5- , C6-, C7-, represents a C8-, C9- alkyl, C _{1 -10} - alkyl is C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, represents a C10- alkyl, C _{1 -18} - alkyl is C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13 -, C14-, C15-, C16-, C17- and C18-alkyl. Furthermore, C _{3 -4} - cycloalkyl represents C3- or C4- cycloalkyl, C _{3 -5} - cycloalkyl represents C3-, C4- or C5- cycloalkyl, C _{3 -6} - cycloalkyl is C3 -, C4-, C5- or C6- cycloalkyl represents, C _{3 -7} - cycloalkyl represents C3-, C4-, C5-, C6- C7- or cycloalkyl, C _{3 -8} - cycloalkyl C3-, C4-, C5-, C6-, C7- or C8- cycloalkyl represents, C _{4 -8} - cycloalkyl represents C4- or C5- cycloalkyl, C _{4 -6} - cycloalkyl C4- , C5- or C6- cycloalkyl represents, C _{4 -7} - cycloalkyl represents C4-, C5-, C6- C7- or cycloalkyl, C _{5 -6} - cycloalkyl C5- or C6- cycloalkyl It represents a C _{5 -7} - cycloalkyl represents a C5-, C6- C7- or cycloalkyl. With respect to cycloalkyl, the term also encompasses saturated cycloalkyl in which one or two carbon atoms are replaced by heteroatoms, S, N or O. However, cycloalkyl which is mono- or polyunsaturated, preferably monounsaturated, without heteroatoms in the ring, is also in the class of the term cycloalkyl, especially unless the cycloalkyl is an aromatic system. Alkyl and cycloalkyl radicals are preferably pyrazolinone, oxopyrazolinone, [1,4] -dioxane or dioxolane as well as 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 (also CHF if substituted) ₂ , CF ₃ or CH ₂ OH).

Here, with respect to alkyl and cycloalkyl-unless specifically defined otherwise-the term substituted in the context of the present invention refers to one by F, Cl, Br, I, NH ₂ , SH or OH. As understood to mean replacement of the above hydrogen radicals, “polysubstituted” radicals are as in CF ₃ , for example, three times for the same C atom, or —CH (OH) —CH═CH—CHCl As in the case of ₂ , it is understood that it is affected several times by the same or different substituents at different positions, for both different and identical atoms. Particularly preferred substituents here are F, Cl and OH. With respect to cycloalkyl, the hydrogen radical can also OC _1-3 - alkyl, C _{1 -3-alkyl} (in each case single-or multi-substituted or unsubstituted), in particular methyl, ethyl, n- propyl, i- propyl , CF ₃ , methoxy or ethoxy.

The term (CH ₂ ) _3-6 is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -And -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH _2- , (CH ₂ ) _1-4 is -CH _2- , -CH ₂ -CH _2- , Is understood as meaning -CH ₂ -CH ₂ -CH _2- , and -CH ₂ -CH ₂ -CH ₂ -CH _2- , and (CH ₂ ) _4-5 is -CH ₂ -CH ₂ -CH ₂ It is understood as meaning -CH ₂ -and -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH _2- , and the like.

Aryl radicals are understood as meaning ring systems that have one or more aromatic rings but even no heteroatoms in only one ring. Examples are phenyl, naphthyl, fluoroantenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted, monosubstituted or polysubstituted.

Heteroaryl radicals are understood to mean heterocyclic ring systems having one or more unsaturated rings and may contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and may also be mono- or polysubstituted. have. Examples that may be mentioned from the group of heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thia Diazoles, benzothiazoles, indole, benzotriazoles, benzodioxolane, benzodioxane, carbazole and quinazoline.

Here, in connection with aryl and heteroaryl, substituted Being R, OR, halogen, preferably are F and / or Cl, CF _3, CN, NO _2, NRR, C _{1 -6} - alkyl (saturated), C _1-6 - alkoxy, C _{3 -8-cycloalkoxy,} C _{3 -8-write} is to be understood to mean an aryl, or substituted heteroaryl by alkylene-cycloalkyl or a C _{2 -6.}

The term "salt" is understood to mean any form of active compound used in accordance with the present invention, where it is ionic or charged, coupled to a counter-ion (cation or anion) or in solution. This will also be understood as complexes of other molecules and ions with active compounds, in particular complexes which are complexed by ionic interactions.

The term "physiologically acceptable salt" means any salt which is physiologically acceptable when used properly in therapy in the context of the present invention, especially when used or applied to humans and / or mammals (mostly meaning toxic No-especially not caused by counter-ions).

These physiologically acceptable salts may be formed with cations or bases and in the context of the present invention anions with physiologically acceptable cations when used in one or more, preferably inorganic, especially humans and / or mammals By means of at least one salt of the compound used according to the invention, usually an acid (proton-free) acid. Salts of alkali metals and alkaline earth metals are particularly preferred, also those with NH 4, but especially those with (single)-or (di) sodium, (single)-or (di) potassium, magnesium or calcium salts.

These physiologically acceptable salts can also be formed with anions or acids in the context of this invention and are specifically -protonated as cations with one or more physiologically acceptable anions when used for humans and / or mammals. For example, with respect to nitrogen, is understood as meaning one or more salts of the compounds used according to the invention. In particular in the context of the present invention, salts formed by physiologically acceptable acids, ie salts of particularly active compounds with physiologically acceptable inorganic or organic acids, especially when used for humans and / or mammals, are hereby understood. Examples of physiologically acceptable salts of certain acids are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The term "solvent compound" according to the invention is understood to mean all forms of the active compounds according to the invention, wherein the compound is a non-covalently bound, in particular comprising hydrates and alcoholates, for example methanolate. It is attached to it by another molecule (most likely a polar solvent).

Unless otherwise specified, the compounds of the present invention are also meant to include different compounds only in the presence of one or more isotopically enriched atoms. For example, compounds having a current structure, except for the replacement of hydrogen by deuterium or tritium, or carbon by ¹³ C- or ¹⁴ C-enriched carbon or ¹⁵ N-enriched nitrogen, are described herein. Is in the area of.

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

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

R ^2, R ³ and R ⁴ are independently from each other hydrogen, linear or branched C _{1 -6} In a preferred embodiment of the invention for the compound according to formula Ⅰ example - represents an alkyl group, a halogen atom, or CF _3, preferably The following R ² , R ³ and R ⁴ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

R ⁵ and R ⁶ are independently linear or branched C _{1 -6} to each other in the preferred embodiment of the invention for the compound according to formula Ⅰ example - represents an alkyl group, a halogen atom, or CF _3, preferably to ⁵ and R is R ⁶ independently of one another represents methyl, ethyl, F, Cl, Br and CF ₃ .

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

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

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

In another very preferred aspect of the invention the compounds of general formula I are optionally stereoisomers, preferably in the form of one of the enantiomers or diastereomers, the racemates or in certain mixing ratios of the stereoisomers, preferably the enantiomers And / or a compound of Formula II, in the form of a mixture of at least two or more diastereomers, or in the form of its corresponding N-oxide, its corresponding salt, or its corresponding solvate:

In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ¹² And R ¹³ is independently a straight or branched chain with each other C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, 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 .

R ¹⁴ And R ¹⁵ is independently a straight or branched chain C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ , SH, NH ₂ , methyl, ethyl, F, Cl, Br and CF ₃ .

R ¹² in a preferred embodiment of the invention for the compound according to formula II And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

R ¹⁴ in a preferred embodiment of the invention for the compound according to formula II And R ¹⁵ is independently a straight or branched chain C _{1 -6} to each other - to the R ¹⁴ represents an alkyl group, a halogen atom, or CF _3, preferably And R ¹⁵ independently of each other represent methyl, ethyl, F, Cl, Br and CF ₃ .

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

R ¹⁴ in a preferred embodiment of the invention for the compound according to formula II And R ¹⁵ each represent Cl.

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

In another preferred embodiment the compound according to formula I or II is selected from the group consisting of: optionally in the form of corresponding N-oxides, corresponding salts or corresponding solvates:

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

Another preferred embodiment of the invention also includes certain prodrugs comprising them and any prodrugs thereof, as well as certain prodrugs of the compounds of the invention described above, in particular comprising their esters and ethers. Examples of well known methods for producing prodrugs of a given functional 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).

Another aspect of the invention is optionally at least a stereoisomer, preferably in the form of one of the enantiomers or diastereomers, the racemates, or in any mixing ratio of the stereoisomers, preferably the enantiomers and / or diastereomers. At least one substituted pyrazoline compound of formula I, in the form of a mixture of two or more, or in the form of a corresponding N-oxide thereof, a corresponding salt thereof, or a corresponding solvate thereof:

(In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R ⁸ , SH, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , NH ₂ , NHR ⁸ , NR ⁸ R ⁹ ,-(C = 0) -NH ₂ ,-(C ═O) —NHR ⁸ or — (C═O) —NR ⁸ R ⁹ , wherein at each substituent R ⁸ and R ⁹ independently represent a straight or branched chain C _1-6 -alkyl,

R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R ¹⁰ , SH, SR ¹⁰ , SOR ¹⁰ , NH ₂ , NHR ¹⁰ , NR ¹⁰ R ¹¹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ¹⁰ And - (C = O) represents a -NR ¹⁰ R ^11, where R ¹⁰ and R ¹¹ are independently straight or branched chain C _{1 -6} substituents on each - represents an alkyl)

Optionally in the form of one of stereoisomers, preferably enantiomers or diastereomers, racemates or mixtures of stereoisomers, preferably in the form of two or more mixtures of enantiomers and / or diastereomers, or a mixture thereof Is a combination of compounds comprising at least one substituted pyrazoline compound of formula X, in the form of a corresponding N-oxide, or a corresponding salt thereof, or a corresponding solvate thereof:

(In the formula

R ¹⁶ optionally represents at least a mono-substituted phenyl group,

R ¹⁷ optionally represents at least a mono-substituted phenyl group,

R ¹⁸ is a cycloaliphatic group which contains a saturated or unsaturated, optionally at least mono-substituted, optionally one or more heteroatoms as ring members, which may optionally be condensed into at least a mono-substituted mono- or polycyclic ring system Or optionally an at least mono-substituted aryl or heteroaryl group, or an NR ¹⁹ R ²⁰ -moiety, which may optionally be condensed into a mono-substituted mono- or polycyclic ring system,

R ¹⁹ and R ²⁰ are the same or different and are hydrogen atom, unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, saturated or unsaturated, optionally at least mono-substituted, optionally one or more hetero Cycloaliphatic groups containing atoms as ring members (which may optionally be condensed into at least mono-substituted mono- or polycyclic ring systems), or optionally at least mono-substituted mono- or polycyclic ring systems And / or optionally at least a single substituted aryl or heteroaryl group, -SO ₂ -R ²¹ -moiety, or R ¹⁹ and R ²⁰ , which may be bonded by a straight or branched chain alkylene group, Provided that it is not represented, the NR ²² R ²³ -moiety is represented,

R ²¹ is a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a cycloaliphatic group containing as saturated or unsaturated, optionally at least mono-substituted, optionally one or more heteroatoms as ring members ( Which may be condensed into a single or polycyclic ring system), or optionally at least a single substituted aryl or heteroaryl, which may be condensed into a mono- or polycyclic ring system and / or bonded by a straight or branched chain alkylene group Represents a group,

R ²² and R ²³ are the same or different and are hydrogen atom, unbranched or branched chain, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, saturated or unsaturated, optionally at least mono-substituted, optionally one or more hetero Cycloaliphatic groups containing atoms as ring members (which may optionally be condensed into at least mono-substituted single or polycyclic ring systems), or optionally at least mono-substituted mono- or polycyclic ring systems, and And / or optionally at least a single substituted aryl or heteroaryl group, which may be joined by a straight or branched chain alkylene group.

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

In a preferred embodiment of the combination of the compounds according to the invention for the compounds according to formula I, R ⁵ , R ⁶ Or R ⁷ One or more of represent hydrogen, while R ⁵ , R ⁶ Or R ⁷ At least one of is different from hydrogen.

In a preferred embodiment of the combination of the compounds according to the invention for the compound according to formula Ⅰ R ^2, R ³ and R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other alkyl group, a halogen atom, or CF ₃ , preferably R ² , R ³ and R ⁴ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

In a preferred embodiment of the combination of the compounds according to the invention for the compound according to formula Ⅰ example R ^5, R ⁶ and R ⁷ are independently hydrogen, linear or branched C _{1 -6} each other alkyl group, a halogen atom, or CF ₃ , preferably R ⁵ , R ⁶ and R ⁷ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

In a preferred embodiment of the combination of the compounds according to the invention for the compounds according to formula I, R ² represents a chlorine atom in the 4-position of the phenyl ring, while R ³ and R ⁴ represent hydrogen.

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

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

In a preferred embodiment of the combination of compounds according to the invention the compounds of general formula I are optionally stereoisomers, preferably enantiomers or diastereomers, racemates in the form of one of the racemates or in certain mixture ratios of stereoisomers, preferably Is represented by a compound of formula II, in the form of a mixture of two or more of the enantiomers and / or diastereomers, or in the form of the corresponding N-oxides, the corresponding salts thereof, or the corresponding solvates thereof. under:

In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ¹² , R ¹³ , R ¹⁴ Or R ¹⁵ is independently a straight or branched chain C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, 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 .

R ¹² in a preferred embodiment of the combination of the compounds according to the invention for the compounds according to formula II And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

In a preferred embodiment of the combination of the compounds according to the invention for the compound according to formula Ⅱ example R ^14, and R ¹⁵ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, a halogen atom, or CF ₃ And preferably R ¹⁴ And R ¹⁵ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

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

R ¹⁴ in a preferred embodiment of the combination of the compounds according to the invention for the compounds according to formula II And R ¹⁵ each represent Cl.

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

In a preferred embodiment of the combination of the compounds according to the invention the compounds according to formula I or II are selected from the group consisting of the following, optionally in the form of corresponding N-oxides, corresponding salts or corresponding solvates:

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

In a preferred embodiment of the combination of the compounds according to the invention for the compound according to the formula X R ¹⁶ is straight or branched chain C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF ₂ , CF ₃ , CN, OH, NO ₂ ,-(C = O) -R ', SH, SR', SOR ', SO ₂ R', NH ₂ , NHR ', NR'R'' Phenyl group optionally substituted by one or more substituents independently selected from the group consisting of-(C = 0) -NH ₂ ,-(C = 0) -NHR 'and-(C = 0) -NR'R''. represents, where R 'and R''are independently straight or branched chain C _{1 -6} substituents on each - represents an alkyl, preferably R ¹⁶ is from the methyl, ethyl, F, Cl, Br and the group consisting of CF ₃ Phenyl group optionally substituted by one or more substituents selected, more preferably R ¹⁶ represents a mono-substituted phenyl group having a chlorine atom in the 4-position.

In a preferred embodiment of the combination of the compounds according to the invention for the compound according to the formula X R ¹⁷ is straight or branched chain C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF ₂ , CF ₃ , CN, OH, NO ₂ ,-(C = O) -R ', SH, SR', SOR ', SO ₂ R', NH ₂ , NHR ', NR'R'' Phenyl group optionally substituted by one or more substituents independently selected from the group consisting of-(C = 0) -NH ₂ ,-(C = 0) -NHR 'and-(C = 0) -NR'R''. shows, in which each substituent R 'and optionally R''are independently straight or branched chain C _{1 -6} - represents an alkyl, preferably R ¹⁷ is the group consisting of methyl, ethyl, F, Cl, Br, and CF ₃ Phenyl group optionally substituted by one or more substituents independently selected from, more preferably R ¹⁷ represents a 2-substituted phenyl group having two chlorine atoms in the 2- and 4- positions.

Expression In a preferred embodiment the combination of the compounds according to the invention for the compound according to Example X R ¹⁸ is a saturated or unsaturated, optionally at least one - C _{3 -8,} which contain one or more heteroatoms substituted, optionally as a ring member Cycloaliphatic groups (which may optionally be condensed into at least a single substituted mono- or polycyclic ring system), or optionally at least mono-substituted, which may optionally be condensed into a mono- or polycyclic ring system Or a 6-membered aryl or heteroaryl group, or an -NR ¹⁹ R ²⁰ -moiety Indicates, preferably to the R ¹⁸ is a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring members, which contains a C _{3 -8} cyclic aliphatic group (which is optionally at least mono-substituted single-or multi-cyclic Condensed into a ring system), or an -NR ¹⁹ R ²⁰ -moiety Represents, more preferably to the R ¹⁸ is a pyrrolidinyl group, a piperidinyl group or a piperazinyl represents a piperazinyl, wherein each of these groups has one or more C _{1 -6} - alkyl group, or -NR ¹⁸ R ¹⁹ - moiety It may be substituted by.

R ¹⁹ in a preferred embodiment of the combination of the compounds according to the invention for the compound according to formula X And R ²⁰ is the same or different and is a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C _{1-6 -aliphatic} radical, saturated or unsaturated, optionally at least mono-substituted, optionally one C _{3 -8} cyclic aliphatic group that contains at least one heteroatom as a ring member substituted - (this is optionally at least mono-substituted with a single may be fused to step or multi-cyclic ring), or an optionally at least a single or multiple cyclic rings Optionally at least a mono-substituted 5- or 6-membered aryl or heteroaryl group which may be condensed into the system and / or may be bonded by a methylene (-CH _2- ) or ethylene (-CH ₂ -CH ₂ )-group , -SO ₂ -R ²¹ -moiety, or -NR ²² R ²³ -moiety And preferably these residues R ¹⁹ And R ²⁰ One represents a hydrogen atom and these residues R ¹⁹ And R ²⁰ Of the other is a saturated or unsaturated, optionally at least mono-substituted, optionally cyclic C _{3 -8,} which contains at least one heteroatom as a ring member an aliphatic group (which is optionally substituted with at least one single-or multi-cyclic rings fused to step , Or optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, -SO ₂ -R ^21- , which may optionally be condensed into at least a mono-substituted mono- or polycyclic ring system. Moiety, or -NR ²² R ²³ -moiety Or R ¹⁹ And R ²⁰ are the same or different and each is C _{1 -6} - to indicate an alkyl group, more preferably these residues R ¹⁹ And R ²⁰ One represents a hydrogen atom and these residues R ¹⁹ And R ²⁰ The other is optionally at least monosubstituted pyrrolidinyl group, optionally at least monosubstituted piperidinyl group, optionally at least monosubstituted piperazinyl group, optionally at least monosubstituted triazolyl group, -SO _2- R ²¹ -moiety, or -NR ²² R ²³ -moiety, or R ¹⁹ And R ²⁰ are the same or different and represent a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group or tert.-butyl group.

In a preferred embodiment of the combination of the compounds according to the invention for the compounds according to formula X, R ²¹ is a straight or branched chain, saturated or unsaturated, optionally at least mono-substituted C _1-6 aliphatic group, saturated or unsaturated, optionally at least mono-substituted, optionally C _{3 -8,} which contains at least one heteroatom as a ring member cyclic aliphatic group (which is a single-or multi-cyclic ring may be condensed to step), or a single-or multi-cyclic rings fused to step And optionally optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group which may be bonded and / or bonded by a methylene (-CH _2- ) or ethylene (-CH ₂ -CH ₂ )-group , Preferably R ²¹ is C _{1 -6-alkyl} group, a saturated, optionally at least mono-substituted aliphatic cyclic group (which is a single-or multi-cyclic ring-to step may be condensed), or one or more C _{1 -6} alkyl optionally substituted with Phenyl group.

R ²² in a preferred embodiment of the combination of the compounds according to the invention for the compound according to formula X And R ²³ is the same or different and is a hydrogen atom, unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C _{1-6 -aliphatic} radical, saturated or unsaturated, optionally at least mono-substituted, optionally one C _{3 -8} cyclic aliphatic group that contains at least one heteroatom as a ring member substituted - (this is optionally at least mono-substituted with a single may be fused to step or multi-cyclic ring), or an optionally at least a single or multiple cyclic rings Optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl, which may be condensed into the system and / or bonded by a methylene (-CH _2- ) or ethylene (-CH ₂ -CH ₂ )-group Gi Preferably, preferably R ²² And R ²³ are the same or different, each represents a hydrogen atom or a C _{1 -6} alkyl radical.

In a preferred embodiment of the combination of the compounds according to the invention optionally stereoisomers, preferably enantiomers or diastereomers, stereoisomers in the form of one of the racemates or in any mixing ratio, preferably enantiomers and / or moieties Compounds according to general formula X, in the form of a mixture of two or more stereoisomers, or in the form of their corresponding N-oxides, their corresponding salts, or their corresponding solvates,

R ¹⁶ represents a phenyl ring mono-substituted with a halogen atom in the 4-position, preferably a chlorine atom,

R ¹⁷ represents a phenyl ring 2-substituted with two halogen atoms in the 2- and 4- positions, preferably with a chlorine atom,

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

R ¹⁹ is a hydrogen atom or a straight or branched chain C _{1 -6} - represent alkyl,

R ²⁰ is straight or branched C _{1 -6-alkyl} group, -SO ₂ -R ²¹ - moiety, pyrrolidinyl group, piperidinyl group, possess blood group, homo Blow-piperazinyl group, morpholinyl group, represents a triazolyl, wherein each heterocyclic ring has one or more, same or different, C _{1 -6} - may be substituted with an alkyl,

R ²¹ can be the same or represented by the structure shown one or more C _{1 -6} alkyl group, optionally substituted phenyl group, which may be different.

In a preferred embodiment of the combination of compounds according to the invention the combination of compounds is at least one compound according to formula X, optionally in the form of a corresponding N-oxide, corresponding salt or corresponding solvate, selected from the group consisting of Includes:

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

5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid- [1,2,4] -triazole-4 -Yl-amide,

5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H-pyrazole-3-carboxylic acid- (4-methyl-piperazin-1-yl) -amides,

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

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

N- [5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazole-3-carbonyl] -4-methylphenylsulfonamide.

In a preferred embodiment of the combination of compounds according to the invention the combination of compounds comprises at least one compound according to formula X, each selected from the following, optionally in the form of a corresponding N-oxide, corresponding salt or corresponding solvate:

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

And

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

Another aspect of the invention also provides a process for the preparation of the substituted pyrazoline compounds of formula I or II, wherein R ¹ is hydrogen,

The process comprises one or more benzaldehyde compounds of formula III:

Where R ² and R ³ And R ⁴ has the meanings mentioned above)

By reaction with a pyruvate compound of formula (IV):

(Where G is OR group (wherein R a represents a branched or unbranched C _{1 -6} alkyl radical), or, G is OK group (where K is a cation, preferably is between Nord O (anorganic) cations, further Preferably an alkali metal cation, most preferably sodium).)

To yield the compound of formula (V):

And optionally separating and / or optionally purifying and reacting with an optionally substituted phenyl hydrazine of the general formula (VI) or its corresponding salt under an inert atmosphere:

Where R ⁵ and R ⁶ And R ⁷ has the meanings mentioned above)

To produce a compound of formula (VII):

Where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ has the meanings mentioned above)

Is an alkyl group, an optionally alkyl-optionally separating and / or refining and, and R ¹ is straight-chain or branched in the pyrazoline compound of general formula substituted Ⅰ or Ⅱ according to the invention C _{1 -4} by solidifying ester ester Is done.

The method of the present invention is also illustrated in Scheme I, given below:

Scheme I:

The reaction of the benzaldehyde compound of formula III with the pyruvate compound of formula IV is preferably, for example, in the presence of one or more bases, as described in Synthetic communications, 26 (11), 2229-33, (1996). , More preferably in the presence of alkali metal hydroxides such as sodium hydroxide or potassium hydroxide or alkali metal methoxides such as sodium methoxide. Each document is incorporated herein by reference and forms part of the disclosure. Preferably the reaction is C _{1 -4} - is carried out in a protic reaction medium such as an alkyl alcohol, or a mixture thereof.

In addition to the duration of the reaction, the reaction temperature can vary over a wide range. Preferred reaction temperatures range from -10 ° C to the boiling point of the reaction medium. Appropriate reaction times can vary from, for example, several minutes to several hours.

Also preferably, the reaction of the benzaldehyde compound of formula III with the pyruvate compound of formula IV is described under acidic catalyzed conditions, more preferably, for example, in Synlett, (1), 147-149, 2001. As is by refluxing the mixture in dichloromethane in the presence of copper (II) trifluoromethanesulfonate. Each description is hereby incorporated by reference and forms part of the disclosure.

Reaction of the formula (Ⅴ) compound represented by the general formula (Ⅵ) optionally substituted phenyl hydrazine of preferably to the C _{1 -4} - suitable reaction medium such as an alcohol or dioxane, or tetrahydrofuran, and ethers thereof, such as the above-mentioned It is carried out in a mixture of two or more. Also preferably, the reaction may be carried out in the presence of an acid, wherein the acid may be organic such as acetic acid and / or inorganic such as hydrochloric acid. In addition, the reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of two or more of these bases.

In addition to the duration of the reaction, the reaction temperature can vary over a wide range. Preferred reaction temperatures range from room temperature, ie, from approximately 25 ° C. up to the boiling point of the reaction medium. Appropriate reaction times can vary from, for example, several minutes to several hours.

The carboxyl groups of the compounds of formula (VII) may be activated for further reaction by the introduction of appropriate leaving groups according to conventional methods well known to those skilled in the art. Preferably the compounds of formula (Ⅶ) is an acid chloride, acid anhydride, mixed anhydride, C _{1 -4} - is moved to an activated ester such as an alkyl ester, p- nitrophenyl ester. Other well known methods for the activation of acids include N, N-dicyclohexylcarbodiimide or benzotriazole-N-oxotris (dimethylamino) phosphonium hexafluorophosphate (BOP).

If the active compound of formula (VIII) is an acid chloride, it is preferably prepared by reaction of the corresponding acid of formula (X) with thionyl chloride or oxaryl chloride, wherein the chloride is also used as a solvent. Used. Also preferably additional solvents may be used. 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. Two or more solvents from one kind or a mixture of two or more solvents from different kinds can be used. Preferred reaction temperatures range from 0 ° C. to the boiling point of the solvent, with reaction times ranging from several minutes to several hours.

If the active compound of formula (VIII) is a mixed anhydride, the anhydride is preferably ethyl chloro and the corresponding acid of formula (VIII) in the presence of a base such as, for example, triethylamine or pyridine in a suitable solvent. Formiate Can be prepared by reaction.

Following a straight or branched chain C _{1 -4} - alkyl, the active compound to result in a compound according to general formula Ⅰ or Ⅱ having an alkyl group R ¹ - can react with an alcohol.

Protection of sensitive groups or reagents may be necessary and / or desirable during the methods described above. Introduction of conventional protecting groups and their removal can be carried out by methods well-known to those skilled in the art.

If the substituted pyrazoline compounds of formula (I) or (II) per se are obtained in the form of stereoisomers, in particular enantiomers or diastereomers, the mixture is prepared by standard procedures known to those skilled in the art, for example by chromatography or chiral reagents. It can be separated by fractional crystallization. It is also possible to obtain pure stereoisomers via stereoselective synthesis.

In another aspect the invention also provides a process for preparing substituted pyrazoline compounds of formula I or II and salts of stereoisomers thereof, wherein at least one compound of formula I or II having at least one base group is preferred. The following is reacted with one or more inorganic and / or organic acids in the presence of a suitable reaction medium. Suitable reaction media include, for example, any of those given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and suitable organic acids are for example citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid.

In another aspect the present invention also provides a process for preparing a substituted pyrazoline compound of formula I or II or a salt of a stereoisomer thereof, wherein at least one compound of formula I or II having at least one acidic group is preferred The following is reacted with one or more suitable bases in the presence of a suitable reaction medium. Suitable bases are, for example, hydroxides, carbonates or alkoxides comprising suitable cations derived from, for example, alkaline metals, alkaline earth metals or organic cations such as, for example, [NH _n R _{4 -n} ] ⁺ , where n is 0, 1, 2, 3 or 4 and R is a branched or unbranched C _{1 -4} - represents a radical -alkyl. Suitable reaction media are any of those given above, for example.

Solvates, preferably hydrates of the corresponding stereoisomers, of the corresponding N-oxides, or of the corresponding salts thereof, of the substituted pyrazoline compounds of Formula I or II may also be obtained by standard procedures known to those skilled in the art. have.

Substituted pyrazoline compounds of formula I or II, including nitrogen-atoms containing saturated, unsaturated or aromatic rings, may also be obtained in the form of N-oxides by methods well known to those skilled in the art.

Purification and separation of the corresponding stereoisomers, or salts, or solvates or any intermediates thereof of the substituted pyrazoline compounds of the invention of general formula (I) or (II) are, if necessary, conventional methods known to those skilled in the art, for example, chromatography. It may be carried out by a graphic method or by recrystallization.

Substituted pyrazoline compounds of the general formulas I and II, their stereoisomers, the corresponding N-oxides, the corresponding salts thereof and the corresponding solvates given below are toxicologically acceptable and therefore for the preparation of a medicament Suitable as pharmaceutically active substance.

Substituted pyrazoline compounds of the general formulas (I) and (II) given below, their stereoisomers, their N-oxides, the corresponding salts and the corresponding solvates are characterized in that they modulate triglyceride levels in plasma. It was found that

Of the compounds comprising the substituted pyrazoline compounds of the general formulas (I) and (II) given below, their stereoisomers, the corresponding N-oxides, the corresponding salts thereof and the corresponding solvates and given below Combinations of substituted pyrazoline compounds of formula (X), their stereoisomers, the corresponding N-oxides, the corresponding salts thereof and the corresponding solvates are toxicologically acceptable and therefore pharmaceutically active for the preparation of a medicament It is suitable as a substance.

Substituted pyrazoline compounds of formula X, their stereoisomers, their N-oxides, the corresponding salts and the corresponding solvates given below have a high affinity for cannabinoid receptors, in particular cannabinoid 1 (CB ₁ ) -receptors It turned out. That is, they act as antagonists to these receptors. In particular, these pyrazoline compounds show little or no development of resistance, especially during treatments involving food intake. After termination of treatment with the pyrazoline compound, reduced weight gain is found compared to the pre-treatment level.

Thus, another aspect of the present invention relates to a medicament comprising at least one substituted pyrazoline compound of formula I or II and at least one pharmaceutically acceptable excipient according to the invention.

Thus, another aspect of the present invention is the stereoisomer, preferably in the form of one of the stereoisomers, preferably enantiomers or diastereomers, racemates or in any mixing ratio, preferably enantiomers and / or diastereomers. One or more substituted pyrazoline compounds of Formula I and optionally one or more agents in the form of a mixture of two or more isomers, or in the form of their corresponding N-oxides, their corresponding salts, or their corresponding solvates Regarding medicaments comprising academically acceptable excipients:

In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ^2, R ³ and R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF ₃ , CN, OH, NO ₂ ,-(C = O) -R 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 wherein R ⁸ at each substituent And R ⁹ denotes a straight-chain or branched-chain C _{1 -6} alkyl,

R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R 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 , wherein R ¹⁰ at each substituent And optionally R ¹¹ independently represent a straight chain or branched C _{1 -6} alkyl.

R ² , R ³ in an embodiment of the medicament according to the invention for a compound according to formula I Or at least one of R ⁴ represents hydrogen, while R ² , R ³ Or R ⁴ At least one of is different from hydrogen.

R ⁵ , R ⁶ in an embodiment of the medicament according to the invention for a compound according to formula I Or at least one of R ⁷ represents hydrogen, while R ⁵ , R ⁶ Or R ⁷ At least one of is different from hydrogen.

R ² , R ³ in an embodiment of the medicament according to the invention for a compound according to formula I And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other is R ^2, R ³ to represent an alkyl group, a halogen atom, or CF _3, preferably And R ⁴ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

R ⁵ , R ⁶ in an embodiment of the medicament according to the invention for a compound according to formula I And R ⁷ is independently hydrogen, linear or branched C _{1 -6} to each other - is R ^5, R ⁶ to represent an alkyl group, a halogen atom, or CF _3, preferably And R ⁷ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

In an embodiment of the medicament according to the invention for the compound according to formula I, R ² represents a chlorine atom in the 4-position of the phenyl ring, whereas R ³ And R ⁴ represents hydrogen.

R ⁵ in an embodiment of the medicament according to the invention for a compound according to formula I And R ⁶ represents a chlorine atom in the 2- and 4-positions of the phenyl ring, while R ⁷ represents hydrogen.

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

In an embodiment of the medicament according to the invention the compounds according to formula I are optionally stereoisomers, preferably enantiomers or diastereomers, stereoisomers in the form of one of racemates or in certain mixing ratios, preferably enantiomers And / or by a compound of formula (II), in the form of a mixture of two or more diastereomers, or in the form of its corresponding N-oxide, its corresponding salt, or its corresponding solvate :

In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ¹² , R ¹³ , R ¹⁴ Or R ¹⁵ is independently a straight or branched chain C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, 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 .

R ¹² in an embodiment of the medicament according to the invention for a compound according to formula II And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

R ¹⁴ in an embodiment of the medicament according to the invention for a compound according to formula II And R ¹⁵ is independently hydrogen, linear or branched C _{1 -6} to each other - to the R ¹⁴ represents an alkyl group, a halogen atom, or CF _3, preferably And R ¹⁵ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

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

R ¹⁴ in an embodiment of the medicament according to the invention for a compound according to formula II And R ¹⁵ each represent Cl.

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

In an embodiment of the medicament according to the invention the compound according to formula I or II is selected from the group consisting of the following in the form of the corresponding N-oxides, the corresponding salts or the corresponding solvates:

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

Another aspect of the invention is a medicament comprising one or more combinations of a compound according to the invention and optionally one or more pharmaceutically acceptable excipients.

In an embodiment of the medicament according to the invention the medicament is for the adjustment of triglyceride levels in the plasma and central nervous system diseases, in particular stroke, cardiovascular diseases and food intake diseases, preferably binge eating, cachexia, obesity, type 2 Diabetes (non-insulin dependent diabetes mellitus), preferably for the prevention and / or treatment of obesity and diabetes.

In an embodiment of a medicament comprising a compound according to formula I or II according to the invention the medicament is used for the prevention and / or prevention of central nervous system diseases, immune system diseases, cardiovascular diseases, endocrine diseases, respiratory diseases, gastrointestinal diseases or reproductive diseases It is for treatment.

In an embodiment of a medicament comprising a combination according to the invention the medicament is for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CB ₁ ) receptors, central nervous system diseases, immune system diseases, cardiovascular diseases, endocrine diseases, For the prevention and / or treatment of diseases of the respiratory system, diseases of the gastrointestinal tract or of reproductive diseases.

In an embodiment of the medicament according to the invention the medicament is for the prevention and / or treatment of food intake diseases, preferably binge eating, anorexia, cachexia, obesity, type 2 diabetes (non-insulin dependent diabetes mellitus), preferably obesity It is for.

In an embodiment of the medicament according to the invention the medicament is for the prevention and / or treatment of psychosis.

In an embodiment of the medicament according to the invention the medicament is used for alcohol abuse and / or poisoning, nicotine abuse and / or poisoning, drug abuse and / or poisoning and / or drug abuse and / or drug poisoning, preferably drug abuse and / or For prevention and / or treatment of addiction and / or nicotine abuse and / or addiction. .

In an embodiment of the medicament according to the invention the medicament is schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinal cerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, Migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremor disorder, obsessive compulsive disorder, senile dementia, thymic disorder, dyskinesia, bipolar disorder; Bone diseases including osteoporosis or Paget's disease of the bone; For the prevention and / or treatment of one or more diseases selected from the group consisting of cancer, preferably brain cancer, bone cancer, lips cancer, oral cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer For the prevention and / or treatment of one or more types of cancer selected from the group consisting of skin cancer, colon cancer, bowel cancer and prostate cancer; More preferably at least one type of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer; Prevention and / or treatment of drug-derived motor disorders, dystonia, endotoxin shock, bleeding shock, hypotension, insomnia, immunological disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, itching, pain To synergize the analgesic effect of narcotic and non-narcotic analgesics, or to influence intestinal fulfillment.

The medicament also comprises one or more substituted pyrazoline compounds of formula I, their stereoisomers, their corresponding N-oxides, their physiologically acceptable salts or their physiologically acceptable solvates given above. It can include any combination of.

Particularly preferably the medicament is suitable for the prevention and / or treatment of alcohol abuse, drug abuse and / or drug abuse, preferably drug abuse and treatment of obesity.

Agents and / or drugs that are frequently misused include opioids, barbiturates, hemp, cocaine, amphetamines, penciclidine, hallucinogens and benzodiazepines.

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

The medicaments of the invention may be administered parenterally in combination with conventional injectable liquid carriers such as, for example, water or suitable alcohols. Conventional pharmaceutical excipients such as stabilizers, solubilizers, and buffers can be included in such injectable compositions. These agents can be injected, for example, intramuscularly, intraperitoneally, or intravenously.

Solid oral compositions (preferably liquid compositions) can be prepared by conventional methods of mixing, filling or tableting. Repeated mixing operations can be used to dispense the active agent throughout the compositions using a large amount of filler. Such manipulations are common in the art. Tablets may be prepared, for example, by wet or dry granulation and may optionally be coated, in particular with an enteric coating, according to methods well known in general pharmaceutical practice.

The formulations mentioned will be prepared using standard methods such as those described or referenced in Spanish and US Pharmacopoeia and similar reference texts.

The medicaments according to the invention can also be formulated in orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binders, fillers, lubricants, and acceptable wetting agents. The compositions may be in any convenient form, such as tablets, pellets, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powder forms suitable for reconstitution with water or other suitable liquid medium prior to use for immediate or delayed release. Can be taken.

Liquid oral forms for administration may also contain certain additives such as sweeteners, flavorings, preservatives and emulsifiers. Non-aqueous liquid compositions for oral administration, containing edible oils may also be formulated. Such liquid compositions may conveniently be encapsulated in gelatin capsules, for example in unit dosages.

Compositions of the invention can also be administered topically or by suppository.

Dosages for humans and animals can vary depending on factors that have their basis in each species or other factors such as age, sex, weight or degree of illness, and the like. The dosage for humans may range from 1 to 2000, preferably from 1 to 1500, more preferably from 1 to 1000 milligrams of the active substance, preferably to be administered during one or several intakes per day.

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula I or II or compounds according to the invention (and optionally for the preparation of a medicament for the prevention and / or treatment of obesity and diabetes) One or more combinations of one or more pharmaceutically acceptable excipients.

Another preferred aspect of the present invention is directed to the present invention for the manufacture of a medicament for the prevention and / or treatment of central nervous system diseases, immune system diseases, cardiovascular diseases, endocrine diseases, respiratory diseases, gastrointestinal diseases or reproductive diseases. The use of one or more substituted pyrazoline compounds (and optionally one or more pharmaceutically acceptable excipients) according to formula I or II.

Another preferred aspect of the invention is a cannabinoid-receptor for the manufacture of a medicament for the prevention and / or treatment of central nervous system disease, immune system disease, cardiovascular disease, endocrine disease, respiratory disease, gastrointestinal disease or reproductive disease Preferably, it is the use of one or more combinations of the compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients) for the preparation of a medicament for the modulation of cannabinoid 1 (CB ₁ ) receptors.

Another preferred aspect of the invention is a medicament for the prevention and / or treatment of food intake diseases, preferably binge eating, anorexia, cachexia, obesity, type 2 diabetes (non-insulin dependent diabetes mellitus), preferably obesity For the preparation of one or more substituted pyrazoline compounds of formula I or II according to the invention or of one or more combinations of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients).

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

Another preferred aspect of the invention is alcohol abuse and / or addiction, nicotine abuse and / or addiction, drug abuse and / or addiction and / or drug abuse and / or addiction, preferably drug abuse and / or addiction or nicotine Of at least one substituted pyrazoline compound of formula I or II according to the invention or of a compound according to the invention (and optionally at least one pharmaceutically for the preparation of a medicament for the prevention and / or treatment of abuse and / or poisoning) Acceptable excipients).

Another preferred aspect of the invention is schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinal cerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremor disorder, obsessive compulsive disorder, senile dementia, thymic disorder, dyskinesia, bipolar disorder; Bone diseases including osteoporosis or Paget's disease of the bone; For the prevention and / or treatment of one or more diseases selected from the group consisting of cancer, preferably brain cancer, bone cancer, lips cancer, oral cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, At least one type of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer, more preferably for the prevention and / or treatment of one or more types of cancer selected from the group consisting of skin cancer, colon cancer, bowel cancer and prostate cancer; Prevention and / or treatment of drug-derived motor disorders, dystonia, endotoxin shock, bleeding shock, hypotension, insomnia, immunological disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, itching, pain One or more substituted pyrazolines of formula I or II according to the invention for the preparation of a medicament for or in synergy of the analgesic effects of narcotic and non-narcotic analgesics or for influencing intestinal fulfillment The use of one or more combinations of a compound or of a compound according to the invention (and optionally one or more pharmaceutically acceptable excipients).

Another preferred aspect of the present invention is directed to the regulation of triglyceride levels in plasma and to central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, preferably binge eating, anorexia, cachexia, obesity, type 2 diabetes ( Non-insulin dependent diabetes mellitus), preferably in the form or schedule of one of stereoisomers, preferably enantiomers or diastereomers, racemates, for the preparation of a medicament for the prevention and / or treatment of obesity and diabetes In the form of a mixture of two or more mixtures of stereoisomers, preferably enantiomers and / or diastereomers, or their corresponding N-oxides, their corresponding salts, or their corresponding solvates, One or more substituted pyrazoline compounds of Formula I and optionally one or more pharmaceutically acceptable excipients The purpose is:

In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R 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 wherein R ⁸ at each substituent And R ⁹ denotes a straight-chain or branched C _{1 -6} alkyl,

R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R 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 wherein R ¹⁰ at each substituent And optionally R ¹¹ represents a straight-chain or branched C _{1 -6} alkyl.

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula I, wherein R ² , R ³ , for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes Or R ⁴ One or more of represents hydrogen, while R ² , R ³ Or R ⁴ At least one of which is different from hydrogen).

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- One or more substituted pyrazoline compounds of formula I, wherein R ⁵ , R ⁶ , for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes, preferably Or R ⁷ One or more of represents hydrogen, while R ⁵ , R ⁶ Or R ⁷ At least one of which is different from hydrogen).

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula I, wherein R ² , R ³ , for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other is R ^2, R ³ to represent an alkyl group, a halogen atom, or CF _3, preferably And R ⁴ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ ).

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula I, wherein R is for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes⁵, R⁶ And R⁷Are independently of each other hydrogen, straight chain or branched chain C_{One -6}Alkyl groups, halogen atoms, or CF₃, Preferably R⁵, R⁶ And R⁷Are independently of each other hydrogen, methyl, ethyl, F, Cl, Br and CF₃It is used for).

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin-dependent diabetes), preferably one or more substituted pyrazoline compounds of formula I, wherein R ² represents a chlorine atom at the 4-position of the phenyl ring for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes R ³ on the other hand And R ⁴ represents hydrogen.

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula I, wherein R ⁵ for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes And R ⁶ represents a chlorine atom in the 2- and 4-positions of the phenyl ring, while R ⁷ represents hydrogen.

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of Formula I, wherein R ¹ is hydrogen, methyl or ethyl, preferably for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes Hydrogen).

Another preferred aspect of the invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes mellitus), preferably in the form of a stereoisomer, preferably an enantiomer or diastereomer, a racemate or in a mixed ratio, for the preparation of a medicament for the prevention and / or treatment of obesity and diabetes Of stereoisomers, preferably in the form of a mixture of two or more of the enantiomers and / or diastereomers, or in the form of their corresponding N-oxides, their corresponding salts, or their corresponding solvates The use of at least one pyrazoline compound, wherein the compound of general formula (I) is represented by a compound of general formula (II) They are:

In the formula

R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl,

R ¹² , R ¹³ , R ¹⁴ Or R ¹⁵ is independently a linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, 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 .

Another embodiment of the invention is directed to the regulation of triglyceride levels in plasma and to central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula II, wherein R ¹² for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

Another embodiment of the invention is directed to the regulation of triglyceride levels in plasma and to central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin-dependent diabetes), preferably one or more substituted pyrazoline compounds of formula II, wherein R ¹⁴ , and R ¹⁵ are independently of each other hydrogen, straight chain, for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes or branched-chain C _{1 -6} - to preferably represents an alkyl group, a halogen atom, or CF ₃ is R ¹⁴ And R ¹⁵ independently of one another represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ .

Another embodiment of the invention is directed to the regulation of triglyceride levels in plasma and to central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably one or more substituted pyrazoline compounds of formula II, wherein R ¹³ represents Cl and R ¹² represents hydrogen, for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes Is the use of.

Another preferred embodiment of the present invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non Insulin-dependent diabetes), preferably one or more substituted pyrazoline compounds of formula II, wherein R ¹⁴ and R ¹⁵ each represent Cl, for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes It is use.

Another preferred embodiment of the present invention is for the regulation of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non Insulin-dependent diabetes mellitus, preferably one or more substituted pyrazoline compounds of formula II, wherein R ¹ is hydrogen, methyl or ethyl, preferably for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes Hydrogen).

Another embodiment of the invention is directed to the regulation of triglyceride levels in plasma and to central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non- Insulin dependent diabetes), preferably for the preparation of a medicament for the prevention and / or treatment of obesity and diabetes, wherein the compound according to formula I or II is selected from the group consisting of The use of one or more substituted pyrazoline compounds of formula I or II in the form of salts or corresponding solvates:

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

The invention is described below with the aid of examples. These descriptions are given by way of example only and are not intended to limit the invention.

1 shows a clear decrease in triglyceride levels in plasma. The concentration (Group III) returns to the control level of Group I as compared to the apparently elevated levels found in Group II not treated with the compound according to Example 0.

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

Example  0:

(5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dehydro - Pyrazole -3- Carboxamide

a) 4- (4- Chlorophenyl ) -2-oxo-3- Butenoic Acid

In a three-necked flask, p-chlorobenzaldehyde (13.3 g, 95 mmoles) and ethyl pyruvate (10 g, 86 mmoles) were dissolved in 150 ml of absolute ethanol. The solution was cooled to 0 ° C. and an aqueous solution of NaOH (3.8 g in 45 mL water) was added dropwise and an orange precipitate formed by keeping the temperature below or equal to 10 ° C. The reaction mixture was stirred for 1 h at 0 ° C. and 1.5 h at room temperature (about 25 ° C.). The reaction mixture was then cooled to about 5 ° C. and the insoluble sodium salt of 4- (4-chlorophenyl) -2-oxo-3-butenoic acid was separated by filtration.

Leaving the filtrate overnight in the cooling device results in more precipitation, which is filtered, combined with the first fraction of salt and washed with diethyl ether. The sodium salt of 4- (4-chlorophenyl) -2-oxo-3-butenoic acid is then treated with a solution of 2N HCl, stirred for several minutes and solid 4- (4-chlorophenyl) -2-oxo- 3-butenoic acid was isolated via filtration and dried to obtain 12.7 g of the desired product (70% of theoretical yield).

a2 ) 5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dehydro - Pyrazole -3-carboxylic acid

Ethylpyruphate  Instead of using salts as alternative routes CH ₃ -C (O) -C (O) -O ^- Na ⁺ ( Sody Umpyruvate), In ethanol water  Dissolved.

b) 5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dehydro - Pyrazole -3-carboxylic acid

4- (4-Chlorophenyl) -2-oxo-3-butenoic acid (12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 mL) obtained according to step a) Was mixed under nitrogen environment, heated to reflux for 4 hours, cooled to room temperature (about 25 ° C.) and placed in ice water, thereby obtaining a sticky mass which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried over sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).

Examples 1-6 represent compounds according to formula X.

Example  One:

N- Piperidinyl -5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dehydro -1H- Pyrazole -3-carboxamide

(a) 5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dehydro - Pyrazole -3-carboxylic acid

Dissolve 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazole-3-carboxylic acid obtained according to Example 0 in a nitrogen environment in 4 mL of thionyl chloride. And heated to reflux for 2.5 hours. Excess thionyl chloride was removed from the reaction mixture under reduced pressure and the resulting crude residue (2.6 g) was used without any further purification.

(b) N- Piperidinyl -5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dihydropyrazole -3-carboxamide

N-aminopiperidine (0.6 mL, 5.6 mmoles) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL) under a nitrogen environment. The resulting mixture was cooled to 0 ° C. and 5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazole-3-carboxylic acid chloride obtained in step (c). Solution was added dropwise to methylene chloride (15 mL). The resulting reaction mixture is stirred overnight at room temperature (about 25 ° C.). The reaction mixture is then washed with water, followed by an aqueous solution of saturated sodium bicarbonate, then again with water, dried over sodium sulfate, filtered and evaporated to dry on a rotavapor. The resulting crude solid is crystallized from ethanol.

The crystallized solid is removed through filtration and the mother liquor is concentrated to produce a second fraction of the crystallized product. The second fraction combines 1.7 g (57% of theoretical yield) of N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) with a melting point of 183-186 ° C. The total amount of -4,5-dihydropyrazole-3-carboxamide was obtained.

The compounds according to Examples 2-6 below are prepared analogously to the methods described in Example 1 in conjunction with Example 0.

Example  2:

5- (4- Chloro - Phenyl ) -1- (2,4- Dichloro - Phenyl ) -4,5- Dehydro -1H- Pyrazole -3-carboxylic acid- [1,2,4] Triazole -4-yl amide

Melting Point: 134-138 ℃

Example  3:

5- (4- Chloro - Phenyl ) -1- (2,4- Dichloro - Phenyl ) -4,5- Dehydro -1H- Pyrazole -3-carboxylic acid- (4- methyl -Piperazin-1-yl) -amide Hydrochloride

Melting Point: 150-155 ℃

Example  4:

5- (4- Chloro - Phenyl ) -1- (2,4- Dichloro - Phenyl ) -4,5- Dehydro -1H- Pyrazole -3-carboxylic acid Diethylamide

This compound is obtained in the form of an oil.

Example  5:

[5- (4- Chloro - Phenyl ) -1- (2,4- Dichloro - Phenyl ) -4,5- Dehydro -1H- Pyrazole -3-yl] -piperidin-1-yl- Metanon

Melting Point: 105-110 ℃

Example  6:

N- [5- (4- Chloro - Phenyl ) -1- (2,4- Dichloro - Phenyl ) -4,5- Dehydro -1H- Pyrazole -3-carbonyl] -4- methyl - Phenylsulfonamide

This compound is obtained in the form of an amorphous solid.

Example  7:

N- Piperidinyl -5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4,5- Dihydropyrazole N-oxide of -3-carboxamide

N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazole-3-carboxamide (0.15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. The resulting solution was ice cooled to 0 ° C. and m-chloroperbenzoic acid (0.204 g, 0.83 mmoles) was added in several portions. After stirring for 15 minutes the control showed thin layer chromatography indicating no starting material remained. The saturated solution of sodium bicarbonate is then slowly added, the organic phase is separated off, washed with water, dried over sodium sulphate and filtered. The filtered solution was evaporated to dryness and the crude product was purified via column chromatography to yield 78 mg (50% of theoretical yield) of N-piperidinyl-5- in the form of a white solid with a melting point of 115-120 ° C. The N-oxide of (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazole-3-carboxamide was produced.

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

Pharmaceutical Data / Test:

The compound according to example 0 is an inhibitor of high blood levels of triglycerides. This effect was demonstrated in fat mice fed a high fat diet. It is described in the following paragraph lapping and the method and results were obtained in this study.

I. In plasma Triglyceride  In Vivo Testing for Adjustment

The study was conducted using 6 week old male mouse B6 Lep ob / ob obtained from Charles River (France). Mice were divided into three groups: I (control), II (vehicle), III (Example 0).

County Ⅰ:

Animals in Group I received a standard diet (D-12450B, Research Diets, NJ, USA).

Group II:

Animals in group II received a high fat diet (D-12493, Research Diets, NJ, USA) for 7 weeks in both cases.

Group III:

Animals in group III received a high fat diet (D-12492, Research Diets, NJ, USA) for 7 weeks in both cases.

At the end of the 7 week feeding period, the treatment period (14 days) commenced: Group II mice received vehicle (5% W / V, 10 ml / kg / day of aqueous solution of acacia gum, po). Group III is a compound of the invention 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazole-3-carboxylic acid according to Example 0 po, 30 mg / administered at kg / day. Group I received no treatment. Three groups of mice had the same diet than in the previous period.

At the end of the 14-day treatment period, blood levels of triglycerides in the animals were measured.

Analysis of whole blood samples was performed using the test strip “lipid panel” and photometric analyzer Cardio-Check Test System, from PA instruments Polymer Technology Systems Indianapolis, IN-46268, USA (supplied by Novalab Iberica SAL in Madrid, Madrid, Spain). It was done using.

The results obtained are as follows:

(*): p <0.05, compared to group I, Anova followed Bonferroni t-test.

NS: Compared with group I, this is not a significant difference.

The results showed that group II mice receiving a high fat diet had significantly higher triglyceride blood levels than control group I. However, administration of the compound according to Example 0 (Group III) improved triglyceride blood levels, which was no different from the level of Group I receiving a standard diet.

Thus, it was found that high blood levels of the compound 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazole-3-carboxylic acid of the present invention according to Example 0 The inhibitory effect on triglycerides was demonstrated.

Reference

II. In Vivo Testing for Modulation of Triglycerides in Plasma

In a second set of experiments performed similar to the test shown above, blood TG (triglyceride) levels in diet-derived fat mice were measured. Mice receiving a high fat diet were fed -6 days post-p.o. Treatment with vehicle (0.5% HPMC) or compound according to Example 0 (30 mg / kg / day p.o.).

Blood TG levels were measured 28 days after the start of treatment.

TG (triglyceride) level was 1.28 ± 25 mmoles / l in the group treated with vehicle and according to Example 0 compound 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5 Only 0.80 ± 0.07 mmoles / l in the group treated with dihydro-pyrazole-3-carboxylic acid. The results were ANOVA factorial, p <0.005 vs. Vehicle's Fisher's post-hoc test was statistically significant.

Thus, the inhibitory effect of the compound 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazole-3-carboxylic acid of the present invention according to Example 0 was again proved It became.

Claims (86)

Optionally in the form of one of stereoisomers, preferably enantiomers or diastereomers, racemates or mixtures of stereoisomers, preferably in the form of at least two or more mixtures of enantiomers and / or diastereomers Substituted pyrazoline compounds of the general formula I in the form of the corresponding N-oxides, or their corresponding salts, or their corresponding solvates:

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _{2, 3} CF, 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 = 0) -NH ₂ ,-(C ═O) —NHR ⁸ or — (C═O) —NR ⁸ R ⁹ , wherein at each substituent R ⁸ and R ⁹ independently represent a straight or branched chain C _1-6 -alkyl, R ⁵ And R ⁶ is independently from each other straight or branched chain C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R ¹⁰ , SH, SR ¹⁰ , SOR ¹⁰ , NH ₂ , NHR ¹⁰ , NR ¹⁰ R ¹¹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ¹⁰ And - (C = O) represents a -NR ¹⁰ R ^11, wherein each substituent group R ¹⁰ and R ¹¹ optionally are independently straight or branched chain C _{1 -6} - represents alkyl, R ⁷ is hydrogen, linear or branched C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO _2, - (C = O) -R ¹⁰ , SH, SR ¹⁰ , SOR ¹⁰ , NH ₂ , NHR ¹⁰ , NR ¹⁰ R ¹¹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ¹⁰ And - (C = O) represents a -NR ¹⁰ R ^11, wherein each substituent group R ¹⁰ and R ¹¹ optionally are independently straight or branched chain C _{1 -6} - represents alkyl, R ¹ And R ⁷ is H and R ⁵ And R ⁶ Both represent Cl at the 3- and 4-positions of the phenyl ring, R ² , R ³ And R ⁴ If two represent H, then R ² , R ³ And R ⁴ Neither can represent F at the 4-position of the phenyl ring. The method of claim 1 wherein, R ^2, R ³ or R ⁴ represents one or more of the hydrogen, while R ^2, R ³ or R ⁴ At least one of which is different from hydrogen. A compound according to claim 1 or 2, wherein R ⁷ represents hydrogen. The method according to any one of claims 1 to 3, R ^2, R ³ and R ⁴ are independently from each other hydrogen, linear or branched C _{1 -6} - represents an alkyl group, a halogen atom, or CF _3, preferably The following are compounds wherein R ² , R ³ and R ⁴ independently represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . The method according to any one of claims 1 to 4, R ⁵ and R ⁶ are independently linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, is preferred to R ⁵ and R ⁶ independently of each other represents methyl, ethyl, F, Cl, Br and CF ₃ . 6. The compound of claim 1, wherein R ² represents a chlorine atom at the 4-position of the phenyl ring, while R ³ and R ⁴ represent hydrogen. 7. 7. A compound according to any one of claims 1 to 6, wherein R ⁵ and R ⁶ each represent a chlorine atom in the 2- and 4-positions of the phenyl ring, while R ⁷ represents hydrogen. 8. A compound according to any one of the preceding claims, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. The stereoisomer according to any one of claims 1 to 8, optionally in the form of one of stereoisomers, preferably enantiomers or diastereomers, racemates or in any mixing ratio, preferably enantiomers and / or Or a compound of formula II in the form of a mixture of two or more diastereomers, or in the form of its corresponding N-oxide, its corresponding salt, or its corresponding solvate:

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ¹² Or R ¹³ is independently a straight or branched chain with each other C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, 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 , R ¹⁴ And R ¹⁵ is independently a straight or branched chain C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ , SH, NH ₂ , methyl, ethyl, F, Cl, Br and CF ₃ . 10. The compound of claim 9, wherein R ¹² And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . The compound of claim 9 or 10, wherein R ¹⁴ And R ¹⁵ is independently a straight or branched chain C _{1 -6} to each other - to the R ¹⁴ represents an alkyl group, a halogen atom, or CF _3, preferably And R ¹⁵ independently of each other represents methyl, ethyl, F, Cl, Br and CF ₃ . 12. A compound according to any one of claims 9-11, wherein R ¹³ represents Cl and R ¹² represents hydrogen. The compound of claim 9, wherein R ^14. And R ¹⁵ each represent Cl. 14. A compound according to any one of claims 9 to 13, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. The compound according to any one of claims 1 to 14, optionally selected from the group consisting of: in the form of a corresponding N-oxide, corresponding salt or corresponding solvate: 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H-pyrazole-3-carboxylic acid. Optionally in the form of one of stereoisomers, preferably enantiomers or diastereomers, racemates or mixtures of stereoisomers, preferably in the form of at least two or more mixtures of enantiomers and / or diastereomers Compounds comprising one or more substituted pyrazoline compounds of Formula I and optionally stereoisomers, preferably enantiomers, in the form of the corresponding N-oxides, their corresponding salts, or their corresponding solvates thereof In the form of one of the diastereomers, racemates, or in a mixed ratio of stereoisomers, preferably in the form of a mixture of two or more of the enantiomers and / or diastereomers, or their corresponding N-oxides, or their corresponding One of general formula X in the form of a salt, or a corresponding solvate thereof Combinations of the above substituted pyrazoline compounds:

(In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R ⁸ , SH, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , NH ₂ , NHR ⁸ , NR ⁸ R ⁹ ,-(C = 0) -NH ₂ ,-(C ═O) —NHR ⁸ or — (C═O) —NR ⁸ R ⁹ , wherein at each substituent R ⁸ and R ⁹ independently represent a straight or branched chain C _1-6 -alkyl, R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O)-R ¹⁰ , SH, SR ¹⁰ , SOR ¹⁰ , NH ₂ , NHR ¹⁰ , NR ¹⁰ R ¹¹ ,-(C = 0) -NH ₂ ,-(C = O) -NHR ¹⁰ And -(C = O) -NR ¹⁰ R ¹¹ , wherein at each substituent R ¹⁰ and R ¹¹ independently represent a straight or branched chain C _1-6 -alkyl)

(In the formula R ¹⁶ optionally represents at least a mono-substituted phenyl group, R ¹⁷ optionally represents at least a mono-substituted phenyl group, R ¹⁸ is a cycloaliphatic group which contains a saturated or unsaturated, optionally at least mono-substituted, optionally one or more heteroatoms as ring members, which may optionally be condensed into at least a mono-substituted mono- or polycyclic ring system Or optionally an at least mono-substituted aryl or heteroaryl group, or an NR ¹⁹ R ²⁰ -moiety, which may optionally be condensed into a mono-substituted mono- or polycyclic ring system, R ¹⁹ and R ²⁰ are the same or different and are hydrogen atom, unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, saturated or unsaturated, optionally at least mono-substituted, optionally one or more Cycloaliphatic groups containing heteroatoms as ring members (which may optionally be condensed into at least mono-substituted mono- or polycyclic ring systems), or optionally at least mono-substituted mono- or polycyclic ring systems Optionally and at least a single substituted aryl or heteroaryl group, an —SO ₂ —R ²¹ —moiety, or R ¹⁹ and R ²⁰ , which may be bonded by a straight or branched chain alkylene group, or Provided that it does not represent NR ²² R ²³ -moiety, R ²¹ is a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a cycloaliphatic group containing as saturated or unsaturated, optionally at least mono-substituted, optionally one or more heteroatoms as ring members ( Which may be condensed into a single or polycyclic ring system), or optionally at least a single substituted aryl or heteroaryl, which may be condensed into a mono- or polycyclic ring system and / or bonded by a straight or branched chain alkylene group Represents a group, R ²² and R ²³ are the same or different and are hydrogen atom, unbranched or branched chain, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, saturated or unsaturated, optionally at least mono-substituted, optionally one or more hetero Cycloaliphatic groups containing atoms as ring members (which may optionally be condensed into at least mono-substituted single or polycyclic ring systems), or optionally at least mono-substituted mono- or polycyclic ring systems, and And / or optionally at least a single substituted aryl or heteroaryl group, which may be joined by a straight or branched chain alkylene group. The compound of claim 16, wherein R ² , R ³ or R ⁴ Wherein at least one of is hydrogen, while at least one of R ² , R ³ or R ⁴ is different from hydrogen. The method according to claim 16 or 17, wherein R ⁵ , R ⁶ Or R ⁷ One or more of represent hydrogen, while R ⁵ , R ⁶ Or R ⁷ Combination of compounds characterized in that at least one of is different from hydrogen. _{19. The compound} of any one of claims 16 to 18, wherein R ² , R ³ and R ⁴ independently of each other represent a hydrogen, a straight or branched C _1-6 -alkyl group, a halogen atom, or CF ₃ , The following is a combination of compounds in which R ² , R ³ and R ⁴ independently represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . The method according to any one of claims 16 to 19, wherein, R ^5, R ⁶ and R ⁷ independently represent hydrogen, linear or branched C _{1 -6} - represents an alkyl group, a halogen atom, or CF _3, preferably The following is a combination of compounds in which R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 21. A combination according to any one of claims 16 to 20, wherein R ² represents a chlorine atom in the 4-position of the phenyl ring, while R ³ and R ⁴ represent hydrogen. 22. A compound according to any of claims 16 to 21, wherein R ⁵ and R ⁶ each represent a chlorine atom in the 2- and 4-positions of the phenyl ring, while R ⁷ represents hydrogen. Combination. 23. A combination of compounds according to any one of claims 16 to 22, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. 24. The stereoisomer according to any one of claims 16 to 23, wherein the compound of formula I is optionally stereoisomer, preferably enantiomer or diastereomer, stereoisomers in the form or in a mixed ratio of one of the racemates, Preferably in the form of a mixture of two or more of the enantiomers and / or diastereomers, or in the form of their corresponding N-oxides, their corresponding salts, or their corresponding solvates, Combination of compounds characterized in that:

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ¹² , R ¹³ , R ¹⁴ Or R ¹⁵ is independently a linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, 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 . The compound of claim 24, wherein R ¹² And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 25. The method of claim 24 or claim 25 wherein, R ^14, and R ¹⁵ are independently hydrogen, linear or branched C _{1 -6} to each other - to the R ¹⁴ represents an alkyl group, a halogen atom, or CF _3, preferably And R ¹⁵ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . The combination of compounds of any one of claims 24 to 26, wherein R ¹³ represents Cl and R ¹² represents hydrogen. 28. The compound of any of claims 24-27, wherein R ¹⁴ And R ¹⁵ each represent Cl. 29. The combination of compounds of any one of claims 24 to 28, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. 30. The compound according to any one of claims 16 to 29, optionally in the form of a corresponding N-oxide, corresponding salt or corresponding solvate, is selected from the group consisting of Combination of compounds characterized by: 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H-pyrazole-3-carboxylic acid. 17. The method of claim 16 according to any one of claim 30 wherein, R ¹⁶ is straight or branched chain C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF ₂ , CF ₃ , CN, OH, NO ₂ ,-(C = O) -R ', SH, SR', SOR ', SO ₂ R', NH ₂ , NHR ', NR'R'',-(C = 0) -NH ₂ ,-(C = O) -NHR 'and-(C = O) -NR'R''represents a phenyl group optionally substituted by one or more substituents independently selected from the group consisting of: each substituent a represents an alkyl, preferably R ¹⁶ is methyl, ethyl, F, Cl, Br, and one or more substituents selected from the group consisting of CF ₃ - in which R 'and R''are independently straight or branched chain C _{1 -6} A phenyl group optionally substituted by R ³ , more preferably R ¹⁶ represents a mono-substituted phenyl group having a chlorine atom in the 4-position. 17. The method of claim 16 according to any one of claim 31 wherein, R ¹⁷ is straight or branched chain C _{1 -6} - alkyl group, linear or branched C _{1 -6} - alkoxy group, a halogen atom, CH ₂ F, CHF ₂ , CF ₃ , CN, OH, NO ₂ ,-(C = O) -R ', SH, SR', SOR ', SO ₂ R', NH ₂ , NHR ', NR'R'',-(C = 0) -NH ₂ ,-(C = O) -NHR 'and-(C = O) -NR'R''represents a phenyl group optionally substituted by one or more substituents independently selected from the group consisting of: each substituent in R 'and optionally R''are independently straight or branched chain C _{1 -6} - represents an alkyl, preferably R ¹⁷ is methyl, ethyl, F, Cl, independently selected from the group consisting of Br, and CF ₃ A phenyl group optionally substituted by the above substituents, more preferably R ¹⁷ represents a 2-substituted phenyl group having two chlorine atoms in the 2- and 4- positions. Of claim 16 to claim 32 according to any one of items, R ¹⁸ denotes a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom to C _{3 -8} cyclic, which contains as a ring member an aliphatic group (this Optionally condensed into at least a single substituted mono- or polycyclic ring system), or optionally at least mono-substituted, 5- or 6-membered, which may optionally be condensed into a mono- or polycyclic ring system Aryl or heteroaryl groups, or -NR ¹⁹ R ²⁰ -moiety Indicates, preferably to the R ¹⁸ is a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring members, which contains a C _{3 -8} cyclic aliphatic group (which is optionally at least mono-substituted single-or multi-cyclic Condensed into a ring system), or an -NR ¹⁹ R ²⁰ -moiety Represents, more preferably to the R ¹⁸ is a pyrrolidinyl group, a piperidinyl group or a piperazinyl represents a piperazinyl, wherein each of these groups has one or more C _{1 -6} - alkyl group, or -NR ¹⁸ R ¹⁹ - moiety Combination of compounds characterized in that can be substituted by. 34. The compound of any of claims 16 to 33, wherein R ^19. And R ²⁰ is the same or different and is a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C _{1-6 -aliphatic} radical, saturated or unsaturated, optionally at least mono-substituted, optionally one C _{3 -8} cyclic aliphatic group that contains at least one heteroatom as a ring member substituted - (this is optionally at least mono-substituted with a single may be fused to step or multi-cyclic ring), or an optionally at least a single or multiple cyclic rings Optionally at least a mono-substituted 5- or 6-membered aryl or heteroaryl group which may be condensed into the system and / or may be bonded by a methylene (-CH _2- ) or ethylene (-CH ₂ -CH ₂ )-group , -SO ₂ -R ²¹ -moiety, or -NR ²² R ²³ -moiety And preferably these residues R ¹⁹ And R ²⁰ One represents a hydrogen atom and these residues R ¹⁹ And R ²⁰ Of the other is a saturated or unsaturated, optionally at least mono-substituted, optionally cyclic C _{3 -8,} which contains at least one heteroatom as a ring member an aliphatic group (which is optionally substituted with at least one single-or multi-cyclic rings fused to step , Or optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, -SO ₂ -R ^21- , which may optionally be condensed into at least a mono-substituted mono- or polycyclic ring system. Moiety, or -NR ²² R ²³ -moiety Or R ¹⁹ And R ²⁰ are the same or different and each is C _{1 -6} - to indicate an alkyl group, more preferably these residues R ¹⁹ And R ²⁰ One represents a hydrogen atom and these residues R ¹⁹ And R ²⁰ The other is optionally at least monosubstituted pyrrolidinyl group, optionally at least monosubstituted piperidinyl group, optionally at least monosubstituted piperazinyl group, optionally at least monosubstituted triazolyl group, -SO _2- R ²¹ -moiety, or -NR ²² R ²³ -moiety, or R ¹⁹ And R ²⁰ is the same or different and represents a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group or tert.-butyl group. Claim 16 A method according to any one of claims 34, wherein, R ²¹ is linear or branched, saturated or unsaturated, optionally at least mono-substituted C _{1 -6} aliphatic group, saturated or unsaturated, optionally at least mono-substituted an, optionally C _{3 -8} cyclic, containing at least one heteroatom as a ring member an aliphatic group (which is single-or multi-cyclic ring can be condensed to step), or a single-can be condensed to step or multiple cyclic rings and / or Or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be bonded by methylene (-CH _2- ) or ethylene (-CH ₂ -CH ₂ ) -group, preferably R ²¹ is C _{1 -6-alkyl} group, a saturated, optionally at least mono-substituted aliphatic cyclic group (which is a single-or multi-cyclic ring-to step may be condensed), or one or more C _{1 -6} alkyl optionally substituted with A combination of compounds characterized in that it represents a phenyl group. The compound of any one of claims 16-35, wherein R ^22. And R ²³ is the same or different and is a hydrogen atom, unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C _{1-6 -aliphatic} radical, saturated or unsaturated, optionally at least mono-substituted, optionally one C _{3 -8} cyclic aliphatic group that contains at least one heteroatom as a ring member substituted - (this is optionally at least mono-substituted with a single may be fused to step or multi-cyclic ring), or an optionally at least a single or multiple cyclic rings Optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl, which may be condensed into the system and / or bonded by a methylene (-CH _2- ) or ethylene (-CH ₂ -CH ₂ )-group Gi Preferably, preferably R ²² And R ²³ are the same or different, each representing a combination of compounds wherein represents a hydrogen atom or a C _{1 -6} alkyl radical. 37. The stereoisomer according to any one of claims 16 to 36, optionally in the form of one of stereoisomers, preferably enantiomers or diastereomers, racemates or in any mixing ratio, preferably enantiomers and / or Or a compound according to formula X, in the form of a mixture of two or more of the diastereomers, or in the form of its corresponding N-oxide, its corresponding salt, or its corresponding solvate: R ¹⁶ represents a phenyl ring mono-substituted with a halogen atom in the 4-position, preferably a chlorine atom, R ¹⁷ represents a phenyl ring 2-substituted with two halogen atoms in the 2- and 4- positions, preferably with a chlorine atom, R ¹⁸ represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or a -NR ¹⁹ R ²⁰ -moiety, R ¹⁹ is a hydrogen atom or a straight or branched chain C _{1 -6} - represent alkyl, R ²⁰ is straight or branched C _{1 -6-alkyl} group, -SO ₂ -R ²¹ - moiety, pyrrolidinyl group, piperidinyl group, possess blood group, homo Blow-piperazinyl group, morpholinyl group, represents a triazolyl, wherein each heterocyclic ring has one or more, same or different, C _{1 -6} - may be substituted with an alkyl, R ²¹ is a combination of a compound, characterized in that the same group, or one or more C _{1 -6} alkyl, which may be different are represented by the structure represents an optionally substituted phenyl. 38. The combination according to any one of claims 16 to 37, wherein the combination of compounds is in the form of a corresponding N-oxide, corresponding salt or corresponding solvate, optionally selected from the group consisting of: Combination of compounds characterized in that it comprises a compound of: N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazole-3-carboxamide, 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid- [1,2,4] -triazole-4 -Yl-amide, 5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1 H-pyrazole-3-carboxylic acid- (4-methyl-piperazin-1-yl) -amides, 5- (4-chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid diethylamide, [5- (4-Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazol-3-yl] -piperidin-1-yl-methanone , N- [5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazole-3-carbonyl] -4-methylphenylsulfonamide. 39. The process according to any one of claims 16 to 38, wherein at least each optionally in the form of a corresponding N-oxide, corresponding salt or corresponding solvate, 5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid, And N-piperidinyl-5- (4-chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazole-3-carboxamide Combination of compounds. A process for the preparation of substituted pyrazoline compounds of formula I or II, wherein R ¹ is hydrogen, wherein the process comprises one or more benzaldehyde compounds of formula III

Where R ² and R ³ And R ⁴ has the meaning according to any one of claims 1 to 8). By reaction with a pyruvate compound of formula (IV):

(Wherein G represents an OR group (wherein R is a branched or unbranched C _{1 -6} alkyl radical), or G represents an OK group (where K is a cation)) To yield the compound of formula (V):

And optionally separated and / or optionally purified, and reacted with an optionally substituted phenyl hydrazine of the general formula (VI) or a corresponding salt thereof under an inert atmosphere

Where R ⁵ and R ⁶ And R ⁷ has the meaning according to any one of claims 1 to 8). To produce a compound of formula (VII):

Where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ has the meanings mentioned above) Optionally separating and / or purifying and in the substituted pyrazoline compound of formula I according to any one of claims 1 to 15 if R ¹ is a straight or branched C _1-4 -alkyl group, optionally A process consisting of esterifying with alkyl esters. A medicament comprising at least one substituted pyrazoline compound of formula I or II according to any one of claims 1 to 15 and at least one pharmaceutically acceptable excipient. Optionally in the form of one of stereoisomers, preferably enantiomers or diastereomers, racemates or in a mixture at a certain ratio of stereoisomers, preferably in the form of a mixture of two or more of the enantiomers and / or diastereomers A medicament comprising at least one substituted pyrazoline compound of formula I and optionally at least one pharmaceutically acceptable excipient, in the form of a corresponding N-oxide, a corresponding salt thereof, or a corresponding solvate thereof:

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ^2, R ³ and R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF ₃ , CN, OH, NO ₂ ,-(C = O) -R 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 wherein R ⁸ at each substituent And R ⁹ is other out or a straight or branched chain C _{1 -6} alkyl, R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R 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 , wherein R ¹⁰ at each substituent And optionally R ¹¹ independently represent a straight chain or branched C _{1 -6} alkyl. 43. The compound of claim 42 wherein R ² , R ³ Or R ⁴ One or more of represents hydrogen, while R ² , R ³ Or R ⁴ At least one of which is different from hydrogen. 44. The compound of claim 42 or 43 wherein R ⁵ , R ⁶ Or R ⁷ One or more of represents hydrogen, while R ⁵ , R ⁶ Or R ⁷ At least one of which is different from hydrogen. The compound of any one of claims 42-44, wherein R ² , R ^3. And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other is R ^2, R ³ desirable to represent an alkyl group, a halogen atom, or CF _3, bar And R ⁴ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . The compound of any one of claims 42-45, wherein R ⁵ , R ^6. And R ⁷ is independently hydrogen, linear or branched C _{1 -6} to each other - is R ^5, R ⁶ to represent an alkyl group, a halogen atom, or CF _3, preferably And R ⁷ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 47. The compound of any of claims 42-46, wherein R ² represents a chlorine atom in the 4-position of the phenyl ring, while R ³ And R ⁴ represents hydrogen. 48. The compound of any of claims 42-47, wherein R ⁵ And R ⁶ represents a chlorine atom in the 2- and 4-positions of the phenyl ring, while R ⁷ represents hydrogen. 49. A medicament according to any one of claims 42 to 48, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. The stereoisomer according to any one of claims 42 to 49, wherein the compound of general formula (I) is optionally a stereoisomer, preferably in one of enantiomers or diastereomers, racemates, or in a mixed ratio of stereoisomers. For example, preferably in the form of a mixture of two or more of the enantiomers and / or diastereomers, or in the form of their corresponding N-oxides, their corresponding salts, or their corresponding solvates. A medicament characterized by the compound of

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ¹² , R ¹³ , R ¹⁴ Or R ¹⁵ is independently a linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, 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 . The compound of claim 50, wherein R ¹² And R ¹³ is independently hydrogen, linear or branched C _{1 -6} to each other - is R ¹² to preferably represents an alkyl group, a halogen atom, or CF ₃ And R ¹³ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 52. The compound of claim 50 or 51 wherein R ¹⁴ And R ¹⁵ is independently hydrogen, linear or branched C _{1 -6} to each other - to the R ¹⁴ represents an alkyl group, a halogen atom, or CF _3, preferably And R ¹⁵ independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 53. The agent of any one of claims 50-52, wherein R ¹³ represents Cl and R ¹² represents hydrogen. The compound of any one of claims 50-53, wherein R ^14. And R ¹⁵ each represent Cl. 55. The agent according to any one of claims 50 to 54, wherein R ¹ represents hydrogen, methyl, ethyl, preferably hydrogen. The compound according to any one of claims 42 to 55, wherein the compound according to formula I or II in the form of a corresponding N-oxide, corresponding salt or corresponding solvate is selected from the group consisting of: Pharmaceutical Made: 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H-pyrazole-3-carboxylic acid. 40. A medicament comprising a compound according to any one of claims 16 to 39 and optionally one or more combinations of one or more pharmaceutically acceptable excipients. 58. The method according to any one of claims 42 to 57, for the adjustment of triglyceride levels in plasma and for central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, preferably binge eating, anorexia, cachexia, obesity , Medicament for the prevention and / or treatment of type 2 diabetes (non-insulin dependent diabetes mellitus), preferably obesity and diabetes. 59. The medicament according to any one of claims 42 to 58 for the prevention and / or treatment of central nervous system disease, immune system disease, cardiovascular disease, endocrine system disease, respiratory system disease, gastrointestinal disease or reproductive disease. 58. The method of claim 57, wherein the central nervous system disease, immune system disease, cardiovascular disease, endocrine system disease, respiratory disease, gastrointestinal disease or reproductive disease, for the modulation of cannabinoid-receptor, preferably cannabinoid 1 (CB ₁ ) receptor Medicaments for prophylaxis and / or treatment. 58. The method according to any one of claims 42 to 57, for the prevention of food intake diseases, preferably binge eating, anorexia, cachexia, obesity, type 2 diabetes (non-insulin dependent diabetes), preferably obesity and Or pharmaceuticals for therapy. 58. A medicament according to any one of claims 42 to 57 for the prevention and / or treatment of psychosis. 58. The method of any of claims 42-57, wherein alcohol abuse and / or addiction, nicotine abuse and / or addiction, drug abuse and / or addiction and / or drug abuse and / or drug addiction, preferably drugs A medicament for abuse and / or addiction and / or nicotine abuse and / or prevention and / or treatment of addiction. 58. The method of any one of claims 42-57, wherein schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinal cerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathy Glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremor disorder, obsessive compulsive disorder, senile dementia, thymic disorder, dyskinesia, bipolar disorder; Bone diseases including osteoporosis or Paget's disease of the bone; For the prevention and / or treatment of one or more diseases selected from the group consisting of cancer, preferably brain cancer, bone cancer, lips cancer, oral cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, At least one type of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer, more preferably for the prevention and / or treatment of one or more types of cancer selected from the group consisting of skin cancer, colon cancer, bowel cancer and prostate cancer; Prevention and / or treatment of drug-derived motor disorders, dystonia, endotoxin shock, bleeding shock, hypotension, insomnia, immunological disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, itching, pain A medicament for, or for synergistic, analgesic effects of narcotic and non-narcotic analgesics, or to influence intestinal fulfillment. For the adjustment of triglyceride levels in plasma and for central nervous system diseases, especially stroke, cardiovascular and food intake diseases, especially binge eating, anorexia, cachexia, obesity, type 2 diabetes (non-insulin dependent diabetes), preferably 40. The at least one substituted pyrazoline compound according to any one of claims 1 to 15 or any one of claims 16 to 39 for the manufacture of a medicament for the prevention and / or treatment of obesity and diabetes. Use of one or more combinations of a compound according to and optionally one or more pharmaceutically acceptable excipients. The method according to any one of claims 1 to 15, for the manufacture of a medicament for the prevention and / or treatment of diseases of the central nervous system, immune system, cardiovascular, endocrine, respiratory, gastrointestinal or reproductive diseases. The use of at least one substituted pyrazoline compound and optionally at least one pharmaceutically acceptable excipient. Modulation of the cannabinoid-receptor, preferably cannabinoid 1 (CB ₁ ) receptor, for the prevention and / or treatment of diseases of the central nervous system, immune system, cardiovascular, endocrine, respiratory, gastrointestinal or reproductive diseases Use of one or more combinations of a compound according to any one of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament. 1. For the preparation of a medicament for the prevention and / or treatment of food intake disorders, preferably binge eating, anorexia, cachexia, obesity, type 2 diabetes (non-insulin dependent diabetes mellitus), preferably obesity Use of at least one substituted pyrazoline compound according to any one of claims 15 to 15 or a combination of a compound according to any one of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients. . 40. A method for the preparation of a medicament for the prophylaxis and / or treatment of psychosis, comprising at least one substituted pyrazoline compound according to any one of claims 1 to 15 or according to any one of claims 16 to 39. Use of one or more combinations of a compound and optionally one or more pharmaceutically acceptable excipients. Prevention of alcohol abuse and / or addiction, nicotine abuse and / or addiction, drug abuse and / or addiction and / or drug abuse and / or addiction, preferably drug abuse and / or addiction or nicotine abuse and / or addiction 40. or one or more substituted pyrazoline compounds according to any one of claims 1 to 15 or a compound according to any one of claims 16 to 39 and optionally one or more for the manufacture of a medicament for treatment. Use of one or more combinations of pharmaceutically acceptable excipients. Schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinal cerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremor disorder, obsessive compulsive disorder, senile dementia, thymic disorder, dyskinesia, bipolar disorder; Bone diseases including osteoporosis or Paget's disease of the bone; For the prevention and / or treatment of one or more diseases selected from the group consisting of cancer, preferably brain cancer, bone cancer, lips cancer, oral cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, At least one type of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer, more preferably for the prevention and / or treatment of one or more types of cancer selected from the group consisting of skin cancer, colon cancer, bowel cancer and prostate cancer; Prevention and / or treatment of drug-derived motor disorders, dystonia, endotoxin shock, bleeding shock, hypotension, insomnia, immunological disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, itching, pain At least one according to any one of claims 1 to 15 for the manufacture of a medicament for or in synergy of the analgesic effects of narcotic and non-narcotic analgesics, or to influence intestinal fulfillment. Use of one or more combinations of a substituted pyrazoline compound or a compound according to any one of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients. For the adjustment of triglyceride levels in plasma and for central nervous system diseases, in particular stroke, cardiovascular and food intake diseases, preferably binge eating, anorexia, cachexia, obesity, type 2 diabetes (non-insulin dependent diabetes), preferably Is a stereoisomer, preferably an enantiomer or diastereomer, one of racemates or stereoisomers of a certain mixed ratio, preferably for the preparation of a medicament for the prevention and / or treatment of obesity and diabetes. Is one or more substituted of Formula I, in the form of a mixture of two or more of the enantiomers and / or diastereomers, or in the form of the corresponding N-oxides, the corresponding salts thereof, or the corresponding solvates thereof. Use of the pyrazoline compound and optionally one or more pharmaceutically acceptable excipients:

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R 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 wherein R ⁸ at each substituent And R ⁹ is other out or a straight or branched chain C _{1 -6} alkyl, R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, a halogen atom, CH ₂ F, CHF _2, CF _3, CN, OH, NO ₂ ,-(C = O) -R 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 wherein R ¹⁰ at each substituent And optionally R ¹¹ represents a straight-chain or branched C _{1 -6} alkyl. The method of claim 72, wherein R ² , R ³ Or R ⁴ One or more of represents hydrogen, while R ² , R ³ Or R ⁴ At least one of which is different from hydrogen. The method of claim 72 or 73, wherein R ⁵ , R ⁶ Or R ⁷ One or more of represents hydrogen, while R ⁵ , R ⁶ Or R ⁷ At least one of which is different from hydrogen. 75. The compound of any of claims 72-74, wherein R ² , R ³ And R ⁴ are independently hydrogen, linear or branched C _{1 -6} each other is R ^2, R ³ desirable to represent an alkyl group, a halogen atom, or CF _3, bar And R ⁴ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 76. The compound of any of claims 72 to 75, wherein R ⁵ , R ⁶ And R ⁷ is independently hydrogen, linear or branched C _{1 -6} to each other - is R ^5, R ⁶ to represent an alkyl group, a halogen atom, or CF _3, preferably And R ⁷ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 77. The compound of any of claims 72-76, wherein R ² represents a chlorine atom at the 4-position of the phenyl ring, while R ³ And R ⁴ represents hydrogen. 78. The compound of any of claims 72 to 77, wherein R ⁵ And R ⁶ represents a chlorine atom in the 2- and 4-positions of the phenyl ring, while R ⁷ represents hydrogen. 79. The use of any of claims 72 to 78, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. 79. The stereoisomer according to any one of claims 72 to 79, wherein the compound of general formula (I) is optionally a stereoisomer, preferably in one of enantiomers or diastereomers, racemates, or in any mixture ratio For example, preferably in the form of a mixture of two or more of the enantiomers and / or diastereomers, or in the form of their corresponding N-oxides, their corresponding salts, or their corresponding solvates. Use characterized by the compound represented by:

In the formula R ¹ is hydrogen or straight or branched chain C _{1 -4} - represent alkyl, R ¹² , R ¹³ , R ¹⁴ Or R ¹⁵ is independently a straight or branched chain C _{1 -6} each other an alkyl group, linear or branched C _{1 -6-alkoxy} group, 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 . 81. The compound of claim 80, wherein R ¹² And R ¹³ is independently hydrogen, linear or branched C _{1 -6} each other represents an alkyl group, a halogen atom, or CF _3, R ¹² is preferable to And R ¹³ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . The method of claim 80 or claim 81 wherein, R ^14, and R ¹⁵ are independently hydrogen, linear or branched C _{1 -6} to each other - is R ¹⁴ to preferably represents an alkyl group, a halogen atom, or CF ₃ And R ¹⁵ independently of one another represents hydrogen, methyl, ethyl, F, Cl, Br and CF ₃ . 83. The use of any one of claims 80-82, wherein R ¹³ represents Cl and R ¹² represents hydrogen. 84. The use of any one of claims 80-83, wherein R ¹⁴ and R ¹⁵ each represent Cl. 85. The use of any one of claims 80-84, wherein R ¹ represents hydrogen, methyl or ethyl, preferably hydrogen. 86. The compound according to any one of claims 72 to 85, wherein the compound according to formula I or II, optionally in the form of a corresponding N-oxide, corresponding salt or corresponding solvate, is selected from the group consisting of: Uses as: 5- (4-Chloro-phenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H-pyrazole-3-carboxylic acid.

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