ES2245226B1 - COMBINATION OF ACTIVE SUBSTANCES. - Google Patents

Abstract

Combination of active substances. The present invention relates to a combination of active substances comprising at least one substituted carbinol compound and at least one opioid, to a medicament comprising said combination of active substances, to a pharmaceutical formulation comprising said combination of active substances and to the use of said combination of active substances for the manufacture of a medicament.

Description

Combination of active substances.

The present invention relates to a combination of active substances comprising at least one carbinol compound substituted and at least one opioid, at a medicament comprising said combination of active substances, to a pharmaceutical formulation comprising said combination of active substances and the use of said combination of substances active for the manufacture of a medicine.

Opioids such as morphine, which they belong to the central acting analgesic class, they are key compounds for the treatment of moderate to very severe pain intense. However, in addition to its analgesic properties desired, these opioid analgesics show a spectrum multifaceted unwanted side effects when administered to the patient in need of treatment, which vary from unpleasant effects such as emesis, inhibition of gastrointestinal function, sedation or vertigo to severe effects, to often life threatening, such as depression respiratory Other problems associated with the administration of opioids are the development of tolerance, the risk of addiction as well as the illicit use of such substances.

Therefore, an object of the present invention was to provide a medication with analgesic properties suitable for the treatment of moderate to very severe pain, which preferably will not show unwanted side effects of opioids, or at least present these effects with less frequency and / or to a lesser extent.

It has now been discovered that, surprisingly, the pharmacological efficacy of opioids is improved by means of their administration in combination with one or more carbinol compounds Substitutes of general formula I provided below. By consequently, the dose of the opioid analgesic can be reduced producing less side effects, less pronounced or without that there are no side effects.

In this way, in one of its aspects, the The present invention relates to a combination of substances active comprising

(A) at least one carbinol compound substituted of general formula I, where

one

where

R 1 represents a hydrogen atom, a linear or branched alkyl radical, a linear alkenyl radical or branched, a cycloaliphatic radical optionally at least mono-substituted, which may contain at least one nitrogen atom as a member of the ring, or a radical phenyl,

R2 represents a hydrogen atom, a cycloaliphatic radical that optionally contains at least one atom of nitrogen as a member of the ring, which can be at least mono-substituted with a linear alkyl radical or branched and / or which may be linked through an alkylene group linear or branched, a NR 3 R 4 moiety, which is attached to through a linear or branched alkylene group, or a moiety NR 5 R 6, which is linked through an alkylene group linear or branched,

R3 and R4, identical or different, represent a linear or branched alkyl radical or a radical unsubstituted benzyl,

R 5 and R 6 together with the atom of binding nitrogen represent a saturated heterocyclic radical, not substituted, optionally containing at least one heteroatom additional as a member of the ring,

X represents a phenyl radical optionally at less mono-substituted or a thienyl radical optionally at least mono-substituted, where in In each case, the substituents are selected from the group composed of a linear or branched alkyl radical, a group linear or branched alkoxy, a linear or branched alkyl radical which is at least partially halogenated or an atom of halogen,

Y represents a heteroaryl radical containing one or more nitrogen atoms as ring members and not is substituted or at least mono-substituted with one or more substituents selected, independently each other, from the group consisting of a halogen atom, a radical linear or branched alkyl, an unsubstituted benzyl radical, a clan group linked through an alkylene group with 1 to 4 atoms of linear or branched carbon, a carboxy group linked through a alkylene group with 1 to 4 linear or branched carbon atoms, a methoxy carbonyl group linked through an alkylene group with 1 to 4 linear or branched carbon atoms, a hydroxy group attached to through an alkylene group with 1 to 4 linear carbon atoms or branched, an amino group linked through an alkylene group with 1 to 4 linear or branched carbon atoms, a dialkylamino group (with 1 to 4 carbon atoms) linked through an alkylene group with 1 to 4 linear or branched carbon atoms and a radical cycloaliphatic that contains one or more nitrogen atoms as ring member and that is attached through an alkylene group with 1 to 4 linear or branched carbon atoms, or Y represents a unsubstituted heteroaryl radical containing two atoms of nitrogen as ring members and that is condensed with (ringed a) a saturated, methyl substituted nitrogen atom,  as a cycloaliphatic group containing ring member,

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

(B) at least one opioid.

Preferably, the combination of substances active according to the present invention comprises one or more substituted carbinol compounds of general formula I provided above, where R 1 represents an atom of hydrogen, an alkyl radical with 1 to 4 linear carbon atoms or branched, an alkenyl radical with 2 to 4 linear carbon atoms or branched, a cycloaliphatic radical of 5 or 6 members, which may contain at least one nitrogen atom as a member of the ring and / or which may be at least mono-substituted with an alkyl radical with 1 to 4 linear carbon atoms or branched, or a phenyl radical, preferably an atom of hydrogen, an alkyl radical with 1 to 4 linear carbon atoms or branched, a vinyl group, a cyclohexyl radical, a radical N-methyl-piperidyl or a radical phenyl, and the other substituents R 2 -R 6, X and Y have the meaning given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate or in the form of a mixture of at least two its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a salt corresponding thereof, or a corresponding solvate.

It is also preferred that the combination of active substances according to the present invention comprise one or more substituted carbinol compounds of the general formula I provided above, where R2 represents an atom of hydrogen, a 5 or 6 membered cycloaliphatic radical that contains optionally at least one nitrogen atom as a member of the ring, which can be at least mono-substituted with an alkyl radical with 1 to 4 linear carbon atoms or branched and / or which may be linked through an alkyl radical with 1 to 4 linear or branched carbon atoms, a residue NR 3 R 4, which is linked through an alkylene group with 1 at 4 linear or branched carbon atoms, or a residue NR 5 R 6, which is linked through an alkylene group with 1 at 4 linear or branched carbon atoms, preferably one atom of hydrogen, a 5 or 6 membered cycloaliphatic radical that optionally contains at least one nitrogen atom as a member of the ring, which can be at least mono-substituted with an alkyl radical with 1 to 4 linear or branched carbon atoms and / or which may be attached to through an alkyl radical with 1 to 4 linear carbon atoms or branched, a NR 3 R 4 moiety, which is linked through a alkylene group with 1 to 4 linear or branched carbon atoms, or an NR 5 R 6 moiety that is linked through a group alkylene with 1 to 4 linear or branched carbon atoms, and the other substituents R 1, R 3 -R 6, X and Y they have the meanings given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a salt corresponding thereof, or a corresponding solvate.

In another preferred embodiment of the present invention, the combination of active substances of the invention comprises one or more substituted carbinol compounds of the general formula 1 provided above, where R 3 and R 4, identical or different, independently of each other, they represent an alkyl radical with 1 to 4 linear carbon atoms or branched or an unsubstituted benzyl radical, preferably a alkyl radical with 1 to 4 linear or branched carbon atoms, and the other substituents R 1, R 2, R 5, R 6, X and Y they have the meanings given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a salt corresponding thereof, or a corresponding solvate.

It is also preferred that the combination of active substances according to the present invention comprise one or more substituted carbinol compounds of the general formula I provided above, where R 5 and R 6 together with the binding nitrogen atom represent a heterocyclic radical of 5 or 6 members saturated, unsubstituted, optionally containing at least one oxygen atom as a member of the ring, and the others R 1 -R 4, X and Y substituents have the meanings given above, optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, your racemate or in the form of a mixture of at least two of your stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding salt of the themselves, or a corresponding solvate.

It is also preferred that the combination of active substances according to the present invention comprise one or more substituted carbinol compounds of the general formula I provided above, where X represents a phenyl radical optionally at least mono-substituted or a radical optionally at least mono-substituted thienyl, where in each case the substituents are selected independently between the group consisting of an alkyl radical with 1 to 4 linear or branched carbon atoms, an alkoxy radical with 1 to 4 linear or branched carbon atoms, an alkyl radical with 1 to 4 linear or branched carbon atoms that is at least partially fluorinated, a fluorine atom, a chlorine atom and a bromine atom, preferably a phenyl radical optionally at less mono-substituted or a thienyl radical optionally at least mono-substituted, where in each case the substituents are independently selected between the group consisting of a methyl radical, a methoxy radical, a trifluoromethyl radical, a fluorine atom, a chlorine atom and a bromine atom, and the other substituents R 1 -R 6 and Y have the meanings provided above, optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding salt of the themselves, or a corresponding solvate.

It is also preferred that the combination of active substances according to the present invention comprise one or more substituted carbinol compounds of general formula I, where Y represents an azol radical selected from the group composed by

a) a pyrazole of the general formula (a):

2

in which R 7 represents a alkyl radical with 1 to 12 linear or branched carbon atoms, a benzyl radical or a radical of kind:

3

where n = 1 or 2, Y

R 8 represents a hydrogen atom, a methyl radical or a halogen atom, preferably an atom of hydrogen, a methyl radical, a bromine atom or an atom of chlorine,

b) an imidazole of the general formula

4

in which R 9 represents a hydrogen atom, an alkyl radical with 1 to 12 carbon atoms, a benzyl radical or a radical of the general formula (b1):

(b1) R 10 - (CH 2) n -

in which n is 2, 3 or 4 and R 10 represents a piperidinyl radical, a phenyl radical, a group cyano, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group or a methyl group ester,

Y

an imidazole of the following formula:

       \ vskip1.000000 \ baselineskip
    

5

and the rest of substituents R 1 R 6 and X have the meanings provided above, optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a solvate correspondent.

In a particularly preferred embodiment of the present invention, the combination of active substances of the invention comprises one or more substituted carbinol compounds of general formula I

6

where

R 1 represents a hydrogen atom, a methyl radical, an ethyl radical, a radical n-propyl, an iso-propyl radical, a sec-butyl radical, a radical tert-butyl, an n-butyl radical, a vinyl radical, a cyclohexyl radical, a group N-methyl-piperidinyl or a group phenyl,

R2 represents a hydrogen atom, a dimethylaminoethyl group, a pyrrolidinylethyl group, a group piperidinylethyl, a group methyl benzyl aminoethyl, a group morpholinyl ethyl, a diisopropylaminoethyl group, a group dimethylaminopropyl, a piperidinylpropyl group, a group pyrrolidinylpropyl, a morpholinylpropyl group, a group N-methyl-2-piperidyl, a group N-ethyl-2-piperidyl, a group N-propyl-2-piperidyl, a group N-methyl-2-pyrrolidinyl, a group N-ethyl-2-pyrrolidinyl, a group N-propyl-2-pyrrolidinyl, or a group 2-dimethylaminoethyl-1-methyl,

X represents a phenyl radical, a radical 2-methyl-phenyl, a radical 3-methyl-phenyl, a radical 4-methyl phenyl, a radical 2-chloro-phenyl, a radical 3-chloro-phenyl, a radical 4-chloro-phenyl, a radical 2-fluoro-phenyl, a radical 3-fluoro-phenyl, a radical 4-fluoro-phenyl, a radical 2-trifluoromethyl-phenyl, a radical 3-trifluoromethyl-phenyl, a radical 4-trifluoromethyl-phenyl, a radical 2-methoxy-phenyl, a radical 3-methoxy-phenyl, a radical 4-methoxy-phenyl, a radical 3,4,5-tris-methoxy-phenyl, a 3,4-dichloro phenyl radical, a radical 2,4-dichloro-phenyl, a radical tien-2-yl, a radical tien-3-yl, a radical 3-methyl-thien-2-yl, a radical 5-methyl-thien-2-yl, a radical 5-bromo-tien-2-yl or a radical 4-bromo-tien-2-yl,

And represents an azol radical selected from the group consisting of

a) a pyrazole of the general formula (a):

       \ vskip1.000000 \ baselineskip
    

7

in the that

R 7 represents a methyl radical, a radical ethyl, an n-propyl radical, a radical iso-propyl, an n-butyl radical, a sec-butyl radical or a radical tert-butyl,

R 8 represents a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,

b) an imidazole of the general formula

8

in which R 9 represents a hydrogen atom, a methyl radical, an ethyl radical, a radical n-propyl, an iso-butyl radical, a n-butyl radical, a radical sec-butyl, a tert-butyl radical, an n-pentyl radical, a radical n-hexyl, an n-heptyl radical, a n-octyl radical, a radical n-nonyl, an n-decyl radical, a n-undecyl radical, a radical n-dodecyl, a benzyl radical or a radical of the General Formula (b1):

(b1) R 10 - (CH 2) n -

in which n is 2, 3 or 4 and R 10 represents a piperidinyl radical, a phenyl radical, a group cyano, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group or a methyl group ester,

Y

(c) an imidazole of the following formula:

9

In a more particularly preferred embodiment of the present invention, the combination of active substances of the invention comprises one or more substituted carbinol compounds selected from the group consisting of:

[1] 2 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole,

[2] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[3] 2- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole,

[4] 2- {3-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole,

[5] 2- {4-chloro-? - [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[6] 2- {4-fluoro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[7] 2 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole,

[8] 2- {3-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[9] 2- {3-chloro- ?- [2- (dimethylamino) ethoxy] -? -Propylbenzyl} -1-methyl-1 H -imidazole,

[10] 1-Butyl-2- {4-chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1 H -imidazole,

[11] 2 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-4-methoxybenzyl} -1-methyl-1 H -imidazole,

[12] 2- {3-Chloro-? -Methyl- ?- [2- (N-pyrrolidinyl) ethoxy] benzyl} -1-methyl-1 H -imidazole,

[13] 2 - {α- [2- (dimethylamino) ethoxy] -? -Propyl-3,4,5-trimethoxybenzyl} -1-dodecyl-1 H -imidazole,

[14] 1-Butyl-2 - {α- [2- (dimethylamino) ethoxy] -4- (trifluoromethyl) benzyl} -1 H -imidazole,

[15] 1-methyl-2 - {? -Methyl- ?- [2- (N-piperidyl) ethoxy] -3- (trifluoromethyl) benzyl} -1 H -imidazole,

[16] 2 - {? -Cyclohexyl-3,4-dichloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole,

[17] 2- {3,4-dichloro- ?- [2- (dimethylamino) ethoxy] -? -Propylbenzyl} -1-methyl-1 H -imidazole,

[18] 2- {3,4-dichloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[19] 2- {3,4-dichloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole,

[20] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1- [2- (N-piperidyl) ethyl] -1 H -imidazole,

[21] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1- [2- (N-piperidyl) propyl] -1 H -imidazole,

[22] 1- (3-Cyanopropyl) -2- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1 H -imidazole,

[23] 2- {4-chloro-? - [2- (dimethylamino) ethoxy] -? - (N-methyl-4-piperidyl) benzyl} -1-methyl-1 H -imidazole,

[24] 1-Benzyl-2 - {α- [2- (N-benzyl-N-methylamino) ethoxy] -4-chlorobenzyl} -1 H -imidazole,

[25] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -7-methyl-6,7,8,9-tetrahydro-1 H -imidazol [1,5 -a] [1,4] diazepine,

[26] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -7-methyl-6,7,8,9-tetrahydro-1 H -imidazol [1,5-a] [ 1,4] diazepine,

[27] 1-Butyl-5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1 H -pyrazol,

[28] 5 - {α- (4-chlorophenyl) - α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[29] 1-Butyl-5 - {α- [2- (dimethylamino) ethoxy] -3,4,5-trimethoxybenzyl} -1 H -pyrazol,

[30] 1-Butyl-5- {4-chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1 H -pyrazol,

[31] 5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[32] 5 - {α- [2- (dimethylamino} ethoxy} -? -Methylbenzyl} -1-methyl-1 H -pyrazol,

[33] 5 - {α- [2- (dimethylamino) ethoxy] -3,4,5-trimethoxybenzyl} -1-methyl-1 H -pyrazol,

[34] 1-methyl-5 - {α- [2- (N-pyrrolidinyl) ethoxy] benzyl} -1 H -pyrazol,

[35] 1-methyl-5 - {α- [2- (N-morpholinyl) ethoxy] benzyl} -1 H -pyrazol,

[36] 5 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-3,4,5-trimethoxybenzyl} -1-methyl-1 H -pyrazol,

[37] 4-Bromo-5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[38] 1,3-dimethyl-5 - {α- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1 H -pyrazol,

[39] 1,3-dimethyl-5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1 H -pyrazol,

[40] 5 - {α- [2- (dimethylamino) ethoxy] -2-methylbenzyl} -1-methyl-1 H -pyrazol,

[41] 4-chloro-5- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[42] 5- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[43] 5- {3-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[44] 5 - {α- [2- (dimethylamino) ethoxy] -4-methylbenzyl} -1-methyl-1 H -pyrazol,

[45] 5- {2-Chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[46] 1-methyl-5 - {α- [2- (N-piperidyl) ethoxy] benzyl} -1 H -pyrazol,

[47] 1-methyl-5 - {α- [2- (N-propyl-2-piperidyl) ethoxy] benzyl} -1 H -pyrazol,

[48] 5 - {α- [2- (N-ethyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[49] 1-methyl-5 - {α- [2- (N-methyl-2-pyrrolidinyl) ethoxy] benzyl} -1 H -pyrazol,

[50] 5 - {α- [2- (diisopropylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[51] 1-methyl-5 - {α- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1 H -pyrazol,

[52] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[53] 2- {3-Chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[54] 2- {4-chloro-? - [3- (dimethylamino) propoxy] -? -Ethylbenzyl} -1-methyl-1 H -imidazole,

[55] 2 - {α-butyl-3-chloro-α- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole.

[56] 2 - {? -Cyclohexyl-4-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[57] 2 - {α- [3- (dimethylamino) propoxy] -4-fluoro-? -Methylbenzyl} -1-methyl-1 H -imidazole,

[58] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole,

[59] 2- {2-Chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[60] 2- {3-Chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[61] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-3,4,5-trimethoxybenzyl} -1-methyl-1 H -imidazole,

[62] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-4-methoxybenzyl} -1-methyl-1 H -imidazole,

[63] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[64] 2 - {α- [3- (dimethylamino) propoxy] -3,4,5-trimethoxybenzyl} -1-methyl-1 H -imidazole,

[65] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-4- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole,

[66] 2 - {α- [3- (dimethylamino) propoxy] -3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole,

[67] 2 - {α- [3- (dimethylamino) propoxy] -4- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole,

[68] 2 - {α- [3- (dimethylamino) propoxy] -4-methoxybenzyl} -1-methyl-1 H -imidazole,

[69] 2 - {α-butyl- ?- [3- (dimethylamino) propoxy] -3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole,

[70] 1-Butyl-2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1 H -imidazole,

[71] 1-Butyl-2 - {? -Butyl- ?- [3- (dimethylamino) propoxy] -3,4,5-trimethoxybenzyl} -1 H -imidazole,

[72] 1-Butyl-2 - {α-butyl-2-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1 H -imidazole,

[73] 1-Butyl-2 - {? -Butyl-2,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1 H -imidazole,

[74] 1-Butyl-2 - {α- [3- (dimethylamino) propoxy] -4- (trifluoromethyl) benzyl} -1 H -imidazole,

[75] 2- {4-chloro- ?- [3- (N-piperidyl) propoxy] benzyl} -1-methyl-1 H -imidazole,

[76] 1-methyl-2 - {α-methyl- ?- [3- (N-piperidyl) propoxy] -4- (trifluoromethyl) benzyl} -1 H -imidazole,

[77] 2 - {α-butyl-2-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[78] 2 - {α-butyl-3,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[79] 2- {3,4-dichloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole,

[80] 2- {3,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[81] 2 - {? -Cyclohexyl-3,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole,

[82] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -? - [2- (N-piperidyl) ethyl] -1 H -imidazole,

[83] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1- [2- (N-piperidyl) propyl] -1 H -imidazole,

[84] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? (N-methyl-4-piperidyl) benzyl} -1-methyl-1 H -imidazole,

[85] 1-Butyl-5 - {α- [3- (dimethylamino) propoxy] benzyl} -1 H -pyrazol,

[86] 1-Butyl-5- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1 H -pyrazol,

[87] 5 - {α- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -pyrazol,

[88] 5 - {α- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -pyrazol,

[89] 1,3-dimethyl-5 - {α- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1 H -pyrazol,

[90] 1,3-dimethyl-5 - {α- [3- (dimethylamino) propoxy] benzyl} -1 H -pyrazol,

[91] 5 - {α- [3- (dimethylamino) propoxy] -2-methylbenzyl} -1-methyl-1 H -pyrazol,

[92] 5-Chloro-5- {4-chloro-? - [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -pyrazol,

[93] 1-methyl-5 - {α- [3- (N-piperidyl) propoxy] benzyl} -1 H -pyrazol,

[94] 1-methyl-5 - {α- [3- (N-pyrrolidinyl) propoxy] benzyl} -1 H -pyrazol,

[95] 4- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[96] 4- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -pyrazol,

[97] 4- {4-chloro- ?- [2- (N-propyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[98] 4- {4-chloro- ?- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[99] 4- {4-chloro- ?- [2- (N-ethyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[100] 4- {4-chloro- ?- [2- (diisopropylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[101] 4- {4-chloro- ?- [2- (N-methyl-2-pyrrolidinyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[102] 4 - {α- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -pyrazol,

[103] 4- {4-chloro- ?- [3- (N-morpholinyl) propoxy] benzyl} -1-methyl-1 H -pyrazol,

[104] 4- {4-chloro- ?- [3- (N-pyrrolidinyl) propoxy] benzyl} -1-methyl-1 H -pyrazol,

[105] 2 - (? -Hydroxybenzyl) -1 H -imidazole,

[106] 2- (4-Chloro-? -Hydroxybenzyl) -1 H -imidazole,

[107] 2- (4-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[108] 2- (3-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[109] 2- (4-Fluoro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[110] 2 - [α-hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole,

[111] 2 - [α-hydroxy-4- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole,

[112] 2 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1-methyl-1 H -imidazole,

[113] 2- (3,4-Dichloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[114] 1-Butyl-2 - [α-hydroxy-4- (trifluoromethyl) benzyl] -1 H -imidazole,

[115] 1-Butyl-2- (3,4-dichloro-? -Hydroxybenzyl) -1 H -imidazole,

[116] 1-Butyl-2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole,

[117] 1-Butyl-2 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole,

[118] 1-dodecyl-2 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole,

[119] 2 - (? -Butyl-3-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[120] 2- (3-Chloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole,

[121] 2- (4-Chloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole,

[122] 2- [4-Chloro-? -Hydroxy- ?- (N-methyl-4-piperidyl) benzyl] -1-methyl-1 H -imidazole,

[123] 2- (4-Chloro-? -Ethyl-? -Hydroxybenzyl) -1-methyl-1- H -imidazole,

[124] 2 - (? -Butyl-4-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[125] 2 - (? -Cyclohexyl-4-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[126] 2- (2-Chloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole,

[127] 2 - (? -Butyl-2-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[128] 2 - [α-hydroxy-α-methyl-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole,

[129] 2 - [α-butyl-? -Hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole,

[130] 2 - [α-cyclohexyl-α-hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole,

[131] 2 - [α-hydroxy-α-methyl-4- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole,

[132] 2- (4-Fluoro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole,

[133] 2 - (? -Hydroxy-? -Methyl-4-methoxybenzyl) -1-methyl-1 H -imidazole,

[134] 2- (3,4-Dichloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole,

[135] 2 - (? -Butyl-3,4-dichloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[136] 2 - (? -Cyclohexyl-3,4-dichloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole,

[137] 2 - (? -Hydroxy-? -Methyl-3,4,5-trimethoxybenzyl) -1-methyl-1 H -imidazole,

[138] 1-Butyl-2- (4-chloro-? -Hydroxy-? -Methylbenzyl) -1 H -imidazole,

[139] 1-Butyl-2 - (? -Butyl-4-chloro-? -Hydroxybenzyl] -1 H -imidazole,

[140] 1-Butyl-2- [4-chloro-? -Hydroxy-α- (N-methyl-4-piperidyl) benzyl] -1 H -imidazole,

[141] 1-Butyl-2 - (? -Butyl-? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole,

[142] 1-Butyl-2 - (? -Butyl-2-chloro-? -Hydroxybenzyl) -1 H -imidazole,

[143] 1-Butyl-2 - [α-ethyl-? -Hydroxy-3- (trifluoromethyl) benzyl] -1 H -imidazole,

[144] 1-Butyl-2 - (? -Butyl-2,4-dichloro-? -Hydroxybenzyl) -1 H -imidazole,

[145] 2- (4-Chloro-? -Hydroxy-? -Methylbenzyl) -1- [2- (N-piperidyl) ethyl] -1 H -imidazole,

[146] 2- (4-Chloro-? -Hydroxy-? -Methylbenzyl) -1- (3-dimethylaminopropyl) -1 H -imidazole,

[147] 2 - (? -Butyl-? -Hydroxy-3,4,5-trimethoxybenzyl) -1-dodecyl-1 H -imidazole,

[148] 1-Benzyl-2 - [α-butyl-? -Hydroxy-3- (trifluoromethyl) benzyl] -1 H -imidazole,

[149] 1-benzyl-2- (4-chloro-? -Hydroxy-? -Methylbenzyl) -1 H -imidazole,

[150] 1- (2-Cyanoethyl) -2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole,

[151] 1- (3-aminopropyl) -2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole,

[152] 3- [2- (3-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] propanoic acid,

[153] 2- (4-Chloro-? -Hydroxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole,

[154] 3- [2- (3-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] methyl propanoate,

[155] 2 - (? -Hydroxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole,

[156] 2 - (? -Hydroxy-4-methylbenzyl) -1- (3-hydroxypropyl) -1 H -imidazole,

[157] 2 - (? -Hydroxy-4-methoxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole,

[158] 2- (3,4-Dichloro-? -Hydroxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole,

[159] 3- {2 - (α-hydroxybenzyl) -1 H -imidazol-1-yl} methyl propanoate,

[160] 2- (4-Chloro-? -Hydroxybenzyl) -1- (4-hydroxybutyl) -1 H -imidazole,

[161] 1- (3-Cyanopropyl) -2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole,

[162] 4- [2- (4-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] butanoic acid,

[163] 4- [2- (4-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] methyl butanoate,

[164] 1-Butyl-5 - (? -Hydroxybenzyl) -1 H -pyrazol,

[165] 5- (4-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -pyrazol,

[166] 5 - (α-hydroxy-3,4,5-trimethoxybenzyl) -1-methyl-1 H -pyrazol,

[167] 1-Butyl-5 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -pyrazol,

[168] 4-Bromo-5 - (? -Hydroxybenzyl) -1-methyl-1 H -pyrazol,

[169] 5 - [α- (4-chlorophenyl) - α-hydroxybenzyl] -1-methyl-1 H -pyrazol,

[170] 1-Butyl-5- (4-chloro-? -Hydroxy-? -Methylbenzyl) -1 H -pyrazol,

[171] 5 - (? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -pyrazol,

[172] 5 - (? -Hydroxy-? -Methyl-3,4,5-trimethoxybenzyl) -1-methyl-1 H -pyrazol,

[173] 1,3-dimethyl-5 - (? -Hydroxy-? -Methylbenzyl) -1 H -pyrazol,

[174] 1-Butyl-5 - (α-hydroxy-α-vinylbenzyl) -1 H -pyrazol,

[175] 1-Butyl-5- (4-chloro-? -Hydroxy-α-vinylbenzyl) -1 H -pyrazol,

[176] 4-Chloro-5 - (α-hydroxybenzyl) -1-methyl-1 H -pyrazol,

[177] 5 - (α-hydroxy-2-methylbenzyl) -1-methyl-1 H -pyrazol,

[178] 5- (3-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -pyrazol,

[179] 5 - (? -Hydroxy-4-methylbenzyl) -1-methyl-1 H -pyrazol,

[180] 5- (2-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -pyrazol,

[181] 5 - (α-hydroxy-4-methoxybenzyl) -1-methyl-1 H -pyrazol,

[182] 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol,

[183] 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol citrate citrate,

[184] 5 - {α- [2- (dimethylamino) ethoxy] -3-thienylmethyl} -1-methyl-1 H -pyrazol,

[185] 2 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -imidazole,

[186] 5 - {α- [2- (dimethylamino) ethoxy] -3-methyl-2-thienylmethyl} -1-methyl-1 H -pyrazol,

[187] 5 - {α- [2- (dimethylamino) ethoxy] -5-methyl-2-thienylmethyl} -1-methyl-1 H -pyrazol,

[188] 5- {5-bromo- ?- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol,

[189] 5- {4-bromo- ?- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol,

[190] 5 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-2-thienylmethyl} -1-methyl-1 H -pyrazol,

[191] 5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol citrate,

[192] (±) -5 - {α- [2- (dimethylamino) -1- (methyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[193] (±) -5 - {α- [2- (dimethylamino) -1- (methyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol,

[194] (+) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol,

[195] (-) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol,

[196] Citrate of (+) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol,

[197] (-) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol citrate citrate,

[198] (+) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol D-ditholuoyltartrate,

[199] (-) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol L-ditholuoyltartrate,

[200] (+) - 5 - {α- [2-dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol citrate citrate,

[201] (-) - 5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol citrate citrate,

[202] 5 - (? -Hydroxy-2-thienylmethyl) -1-methyl-1 H -pyrazol,

[203] 5 - (? -Hydroxy-3-methyl-2-thienylmethyl) -1-methyl-1 H -pyrazol,

[204] 5 - (α-hydroxy-5-methyl-2-thienylmethyl) -1-methyl-1 H -pyrazol,

[205] 5- (5-Bromo-? -Hydroxy-2-thienylmethyl) -1-methyl-1 H -pyrazol,

[206] 5- (4-Bromo-? -Hydroxy-2-thienylmethyl) -1-methyl-1 H -pyrazol and

[207] 5 - (? -Hydroxy-? -Methyl-2-thienylmethyl) -1-methyl-1 H -pyrazol,

as a component (TO).

The preparation of carbinol compounds substituted of general formula I, its stereoisomers, its salts corresponding and their corresponding solvates can be performed by means of the reagents and methods described, for example, in the EP 0 0289380, W099152525 and W099 / 07684. In the documents W099 / 02500 and W097120817, for example, methods for the optical resolution of said compounds, that is, the preparation or separation of the respective stereoisomers. The parts Corresponding of these publications are incorporated herein document as a reference and are part of this description.

Pharmaceutically available salts can be obtained. acceptable of the substituted carbinol compounds of the formula general I previously provided by conventional methods known to those skilled in the art. Salts Preferred pharmaceutically acceptable of these compounds of substituted carbinol of the general formula I provided above are citrate salts or salts ditoluyltartrate

For the purposes of the present invention, the term "opioid" includes substances that have an affinity for one or more of the opioid receptors such as the opioid receptors, or the opioid receptors, and / or the opioid receptors. Opioids that act as agonists or partial agonists in these receptors are preferred.
beef.

Suitable opioids according to component (B) of the combination of pharmacologically active substances of the invention as well as methods for their preparation are well known to those skilled in the art, for example, by E. Friderichs, T. Christoph and H. Buschmann, "Analgesics and Antipyretics", Ullmann's Encyclopedia of Industry Chemistry, sixth edition, Wiley-VCH Verlag GmbH, Weinheim 2000, pages 27-45. Opioid 14-methoxymethopon is described, for example, in the publication of MA King et al ., Eur. J. of Pharmacology, 459 (2003), 203-209. The respective descriptions are incorporated herein by reference and form part of this description.

Preferably, the combination of substances of the invention comprises as component (B) at least one opioid with weak analgesic efficacy, which can preferably be selected from the group consisting of codeine, dextropropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, loperamide, meptazinol, nalbuphine, pethidine, tilidine, tramadol, viminol and corresponding physiologically acceptable salts of these compounds.

If the combination of active substances of the The present invention comprises as component (B) an opioid with weak analgesic efficacy, the molar relationship between component (B) and component (A) is preferably in the range of 1: 1 to 1:20, preferably from 1: 1 to 1:10 and more preferably from 1: 1 to 1: 5.

Also preferably, the combination of active substances of the invention comprises one or more analgesics opioids with a medium to strong analgesic efficacy, which preferably they can be selected from the group consisting of alfentanil, buprenorphine, butorphanol, dextromoramide, dezocine, diacetylmorphine (heroin), etorphine, fentanyl, hydrocodone, hydromorphone, ketobemidone, levometadone, levometadyl acetate, levorphanol, morphine, nalorphine, oxycodone, oxymorphone, pentazocine, piritramide, remifentanil, sufentanil and physiologically salts corresponding acceptable thereof.

If the combination of active substances of the The present invention comprises as component (B) an opioid with weak analgesic efficacy, the molar relationship between the component (B) and component (A) is in the range of 1: 1 to 1: 400, preferably from 1: 1 to 1: 200, more preferably from 1: 1 to 1:10 and even more preferably from 1: 1 to 1: 5.

Physiologically acceptable salts of opioid analgesics according to component (B) of the combination of active substances of the invention are also well known to those skilled in the art and preferably can be selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, tartrate, citrate and acetate.

The active substance according to the component (B) and / or the active substance according to the component (A) of the combination of active substances of the invention may also be present, each in the form of a mixture of two or more different salts.

If an active substance according to the component (A) is basic and an active substance according to the component (B) is acidic or vice versa, the two components can at least partially form a salt with each other. These salts can be prepared according to conventional methods well known for those skilled in the art, for example, by dissolution of two components in a suitable solvent and the subsequent evaporation of the solvent.

Thus, in another preferred embodiment of the present invention, component (A) and component (B) are present at least partially in the form of a salt formed between These two components.

The combination of active substances of the invention is suitable for administration to humans, including infants, children and adults, as well as for administration to animals

Preferably, the total amount of the active substance or substances according to component (A), calculated as the free compound or compounds, to be administered to the patient in a 24-hour period does not exceed
800 mg

The total amount of the substance or substances active according to component (B), calculated as the compound or free compounds, to be administered to the patient in a 24 hour period does not exceed 200 mg.

Preferably, the combination of substances of the invention comprises components (A) and (B) in the molar relationships defined above and within limits provided above for the maximum dose to be administered by day.

The pharmaceutically active substances, particularly opioids, they can be the object of abuse. By example, a certain dose of an active opioid substance It is usually more potent when administered parenterally, particularly intravenous, compared to the same dose when administered orally. Therefore, a common mode of abuse for an oral pharmaceutical formulation comprising a Opioid active substance includes the extraction of the opioid from the formulation with a subsequent intravenous injection.

Thus, in another preferred embodiment of the present invention, the combination of active substances it also comprises as component (C) one or more agents that are adequate to reduce and even prevent abuse of active substances of component (A) and / or component (B).

If such anti-abuse agents are present in the combination of active substances of the invention, are included in such a way that they are not released or in such a way that do not develop its anti-abuse effect if the combination of active substances is administered to the patient of according to your desired route of administration.

However, if the combination of substances of the invention or - after separation - one of its components are only administered through a different route than the desired route of administration, said agent anti-abuse will exert its effect and therefore It will reduce or even prevent abuse.

They are agents that are particularly suitable for the reduction or prevention of opioid abuse, for example, opioid antagonists, which have a small or no effect if they take by mouth, but they will block the effect of the opioid if administered parenterally with the opioid after extraction.

The right opioid antagonists preferably they can be selected from the group consisting of levalorfano, naloxone, naltrexone and physiologically salts corresponding acceptable thereof.

Other anti-abuse agents include aversive agents such as agents that provide a bitter taste, irritants, emetics and / or agents that cause nausea, as well as gelling agents.

Types and quantities agents anti-abuse used as component (C) in the combination of active substances of the invention, as well as their mode Formulation together with components (A) and / or (B), depend on the type of abuse that you want to reduce or prevent, for example, a bad parenteral, intranasal or oral use. Different modes can be used. of formulations and / or different anti-abuse agents from the same class or from different classes to reduce or eliminate more than one type of abuse, for example, the combination of substances active agents of the invention may comprise an agent suitable for the reduction or prevention of parenteral abuse and an appropriate agent for the reduction or prevention of nasal abuse.

Opioid antagonists suitable agree with component (C) of the substance combination of the invention as well as the methods for its preparation are well known to those skilled in the art, for example, by E. Friderichs, T. Christoph and H. Buschmann, "Analgesics and Antipyretics ", Ullmann's Encyclopedia of Industrial Chemistry, sixth edition, Wiley-VCH Verlag GmbH, Weinheim 2000, pages 45-47.

By EP 1 201 233, WO03 / 013476 and WO 99132120, those skilled in the art also know opioid antagonists as well as other agents adequate anti-abuse for reduction or prevention of different forms of abuse of active substances, quantities suitable and methods for incorporation into formulations Pharmaceuticals

The respective parts of the descriptions of the publications mentioned above are incorporated in this document as a reference and are part of this description.

In another aspect, the present invention is refers to a medicine that comprises a combination of active substances of the invention and optionally at least one other additional active substance and / or optionally at least one auxiliary substance

Preferably, the medicament of the invention It is suitable for the treatment of pain, particularly for the pain treatment selected from the group consisting of neuropathic pain, acute pain, chronic pain, postoperative pain, chronic low back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, pain resistant, visceral pain, surgical pain, injury pain bone, pain during childbirth, pain due to burns, pain due to sunburn, postpartum pain, migraine, pain angina, pain related to the genitourinary tract, pain of cystitis and nociceptive pain. Also preferably, the medicament of the invention is suitable for prophylaxis and / or Urinary incontinence treatment. In addition, the medicine of The invention is also suitable for prophylaxis and / or treatment. of neurogenic inflammation.

Those skilled in the art will understand that the components (A) and (B) of the combination of active substances according to the present invention can be administered simultaneously or sequentially with each other, and can be administered in each case the components (A) and (B) through them or different routes of administration, for example, orally or parenterally, preferably, the two components (A) and (B) are administered simultaneously in one and the same form of administration.

Another aspect of the present invention relates to to the use of a combination of pharmacologically active substances of the invention for the manufacture of a medicament for the pain treatment, preferably for pain treatment  selected from the group consisting of neuropathic pain, pain acute, chronic pain, postoperative pain, chronic low back pain, cluster headaches, herpes neuralgia, limb pain phantom, central pain, dental pain, resistant pain, pain visceral, surgical pain, bone injury pain, pain during childbirth, pain due to burns, pain due to burns solar, postpartum pain, migraine, angina pain, pain related to the genitourinary tract, cystitis pain and pain nociceptive Another aspect of the present invention is the use of a combination of active substances of the invention for the preparation of a medication for prophylaxis and / or treatment of urinary incontinence Another aspect of the present invention is the use of a combination of active substances of the invention for the preparation of a medication for prophylaxis and / or Neurogenic inflammation treatment.

Another aspect of the present invention relates to to pharmaceutical formulations in different pharmaceutical forms comprising a combination of active substances of the invention and optionally at least one other active substance and / or optionally at least one auxiliary substance.

Preferably, the pharmaceutical formulation of the invention is suitable for oral or parenteral administration, more preferably for intravenous oral administration, intraperitoneal, intramuscular, subcutaneous, intrathecal, rectal, transdermal, transmucosal or nasal.

The pharmaceutical formulation of the invention for oral administration is preferably selected from the group composed of tablets, dragees, capsules, drops, gels, juices, syrups, solutions and suspensions.

The pharmaceutical formulation of the present invention for oral administration may also be in the form of multiparticulates, preferably pellets or granules, optionally compressed in the form of a tablet, introduced into a capsule or suspended in a suitable liquid. Liquids Suitable are known to those skilled in the art.

The pharmaceutical formulations of the invention may also contain -depending on their route of administration-
tion- one or more auxiliary substances known to those skilled in the art. Pharmaceutical formulations according to the present invention can be produced according to conventional procedures known to those skilled in the art, for example, by the tables of contents of "Pharmaceutics: the Science of Dosage Forms", second edition, Aulton, ME ( Ed.) Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", second edition, Swarbrick, J. and Boylan JC (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", fourth edition, Banker, GS and Rhodes CT (Eds.) Marcel Dekker, Inc., New York 2002 and "The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. and Kanig J. ( Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are incorporated by reference and form part of this description.

In an embodiment of the present invention, the Pharmaceutical formulation comprises one or both components (A) and (B) at least partially in a sustained release form. Preferably, the pharmaceutical formulation of the invention comprises component (B) at least partially in a form of sustained release

Through the incorporation of one or these two components at least partially or completely in one form of sustained release, it is possible to prolong the duration of your effect, providing the beneficial effects of such form of sustained release, for example, the maintenance of uniform blood concentrations.

Suitable sustained-release forms as well as materials and methods for their preparation are known to those skilled in the art, for example, by the table of contents of "Modified-Release Drug Delivery Technology" Rathbone, MJ Hadgraft, J. and Roberts , MS (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology", Wise, DL (Ed.), Marcel Dekker, Inc. New York, (2000); "Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, SD (Ed.), CRC Press Inc., Boca Ratos (1983) and by Takada, K. and Yoshikawa, H., "Oral Drug delivery", Encyclopedia of ControHed Drug Delivery, Mathiowitz, E. (Ed.), John Wiley &
Sons, Inc., New York (1999), Vol., 2, 728-742, Fix, J., "Oral drug delivey, small intestine and colon", Encydopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.) , John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are incorporated by reference and are part of the description.

If the pharmaceutical formulation according to the The present invention comprises at least one of the components (A) and (B) and at least partially in a sustained release form, said sustained release can preferably be achieved applying at least one coating or providing a matrix that contain at least one sustained release material.

The sustained release material preferably it is based on a natural, semi-synthetic or synthetic, insoluble in water, optionally modified, or in a natural, semi-synthetic or synthetic wax, grease, fatty alcohol or fatty acid, or in a mixture of at least two of the components mentioned above.

The water insoluble polymers used to produce a sustained release material preferably it based on an acrylic resin, which is preferably selected between the group of poly (meth) acrylates, in a way particularly preferred among poly (meth) acrylates of alkyl (with 1 to 4 carbon atoms), dialkyl (meth) acrylates (with 1 to 4 carbon atoms) aminoalkyl (with 1 to 4 atoms of carbon) and / or copolymers or mixtures thereof, and in a manner more particularly preferred among acrylate copolymers of ethyl and methyl methacrylate with a molar ratio of monomers 2: 1 (Eudragit NE30ED®), ethyl acrylate copolymers, methyl methacrylate and ethyl methacrylate chloride trimethylammonium with a molar ratio of monomers of 1: 2: 0.1 (Eudragit RS®), copolymers of ethyl acrylate, methacrylate methyl and ethyl trimethylammonium methacrylate chloride with a 1: 2: 0.2 molar ratio of monomers (Eudragit RL®), or a mixture of at least two of the aforementioned copolymers. These coating materials are available in the market as 30% by weight aqueous latex dispersions, that is, as Eudragit RS30D®, Eudragit NE30D® or Eudragit RL 30D®, and also they can be used as is for coating purposes.

In another embodiment, the release material sustained is based on water insoluble cellulose derivatives, preferably alkyl celluloses, particularly preferred ethyl cellulose, or cellulose esters, for example acetate of cellulose. Aqueous dispersions of ethyl cellulose, for example, with the Aquacoat® trademarks or Surelease®.

As it is natural, semi-synthetic or Synthetic, fatty or fatty alcohols, the release material sustained can be based on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol dithripalmitoestearate, microcrystalline wax, alcohol cetyl, cetyl steary alcohol or a molt of at least two of these components.

The polymers mentioned above of sustained release material may also comprise a physiologically acceptable and conventional plasticizer in amounts known to those skilled in the art.

Examples of suitable plasticizers lipophilic diesters of an aliphatic or aromatic dicarboxylic acid with 6 to 40 carbon atoms and an aliphatic alcohol with 1 to 8 carbon atoms, for example, dibutyl phthalate, phthalate diethyl, dibutyl sebacate or diethyl sebacate, esters of hydrophilic or lipophilic citric acid, for example, citrate triennium, tributyl citrate, acetyltributyl citrate or citrate of acetyltrilethyl, polyethylene glycols, propylene glycol, esters of glycerol, for example triacetin, Myvacet® (mono- and diglycerides acetylated, C 23 H 44 O 5 to C 25 H 47 O 7), medium chain triglycerides (Miglyol®), oleic acid or mixtures of at least two of said plasticizers. The aqueous dispersions of Eudragit RS® and optionally Eudragit RL® preferably contain triethyl citrate. Sustained release material can comprise one or more plasticizers in amounts of, for example, 5 to 50% by weight with respect to the amount of polymer or Polymers used

The sustained release material also may contain other conventional auxiliary substances known to those skilled in the art, for example, lubricants, colored pigments or surfactants.

The pharmaceutical formulation of the present invention can also comprise at least one of the components (A) and (B) covered by an enteric coating form that is dissolves depending on the pH. Because of this coating, part or The entire pharmaceutical formulation can pass through the stomach without dissolving and components (A) and / or (B) are only released in the intestinal tract The enteric coating is preferably dissolves at a pH between 5 and 7.5.

The enteric coating may be based on any enteric material known to specialists in the technique, for example, in acid copolymers methacrylic / methyl methacrylate with a molar ratio of 1: 1 monomers (Eudragit L®), acid copolymers methacrylic / methyl methacrylate with a molar ratio of 1: 2 monomers (Eudragit S®), acid copolymers methacrylic / ethyl acrylate with a molar ratio of monomers of 1: 1 (Eudragit L30D-55®), acid copolymers methacrylic / methyl acrylate / methyl methacrylate with a molar ratio of 7: 3: 1 monomers (Eudragit FS®), shellac, hydroxypropyl methyl cellulose acetate succinates, cellulose acetate phthalates or a mixture of al at least two of these components, which can optionally also be used in combination with poly (meth) acrylates water insoluble mentioned above, preferably in combination with Eudragit NE30D® and / or Eudragit RL® and / or Eudragit RS®

The formulations coatings Pharmaceuticals of the present invention can be applied by conventional processes known to specialists in the technique, for example, by Johnson, J.L., "Pharmaceutical tablet coating ", Coating Technology Handbook (second edition), Satas, D. and Tracton, A.A. (Eds.), Marcel Dekker, Inc., New York (2001), 863-866, Carstensen, T., "Coating Tablets in Advanced Pharmaceutical Solids ", Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001), 455-468; Leopold, C.S., "Coated dosage forms for colon-specific drug delivery ", Pharmaceutical Science & Technology Today, 2 (5), 197-204 (1999), Rhodes, C.T. and Porter, S.C., Coatings, in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 1, 299-311. The descriptions respective are incorporated as a reference and are part of the description.

In another embodiment, the pharmaceutical formulation of the present invention contains one or both components (A) and (B) not only in a form of sustained release, but also in A non delayed form. By means of the combination with the form of immediate release, a high initial dose can be achieved to the rapid onset of the beneficial effect. Then the release slow from the sustained release form prevents it from decreasing the beneficial effect Such pharmaceutical formulation is particularly useful for the treatment of health problems acute

This can be achieved, for example, by of a pharmaceutical formulation that has at least one coating immediate release comprising at least one of the components (A) and (B) to provide the rapid onset of the effect beneficial after administration to the patient.

Surprisingly, it has been discovered that in the combination of active substances of the present invention, the Pharmacological efficacy of the opioid component is enhanced by its administration in combination with one or more carbinol compounds substituted of the general formula I provided above. As a result of this synergistic effect, the opioid dose may be reduced by producing fewer side effects, effects less pronounced side effects or no side effects and it reduces the risk of tolerance development, while at least analgesic efficacy is maintained.

In addition to this, withdrawal syndrome resulting from the administration of such an analgesic component opioid is reduced or completely suppressed, although the amount of Opioid analgesic administered is not reduced compared to administration of an opioid analgesic alone.

Pharmacological methods A. Hot plate assay in mice

The analgesic activity of the combination of Active substances of the invention are determined in Swiss mice male (weighing 20 to 25 g, Hartan Ibérica, S. Feliu de Codinas, Barcelona, Spain) as described in the publication of G.  Woolfe and A. D. MacDonald, J. Pharm. Exp. Ther. 1944, 80, pages 300-307. The respective description of this publication is incorporated as a reference and is part of the present description

According to this test, mice get in a plate that is heated to 55 ° C and the time is determined elapsed until the mice show signs of pain such as a vigorous and repeated licking of the legs, jumps or leg removal. The mice are kept on the hot plate for no more than 40 seconds to prevent the development of injuries cutaneous First, untreated mice undergo hot plate test to determine a baseline value for your pain-induced behavior After 10 minutes, it administer the vehicle, the active substances and the combination of active substances of the invention to be tested at different groups of mice. 0.5 hours, 1 hour and 2 hours after administration, the animals are put on the hot plate and the time is measured elapsed until they show signs of pain. Efficiency analgesic of the active substances or of the combination of active substances is calculated based on the values obtained for the comparison group of mice that only received the vehicle.

B. Determination of withdrawal syndrome

The effect of the combination of active substances of the invention on withdrawal syndrome after treatment with an opioid is determined in accordance with the publication of JK Saelens et al . Int. Pharmacodyn. 1971, 190, pages 213-218 in Swiss male albino mice (weighing 20-25 g, Hartan Ibérica, S. Feliu de Codinas, Barcelona, Spain).

Opioid dependence develops in mice by intraperitoneal administration of opioid at an appropriate dose known to specialists in the technique, for example 5 mg / kg / day for 4 consecutive days in the case of morphine. After the withdrawal syndrome is induced by means of intravenous administration of an antagonist of adequate opioids in a dose known to specialists in the technique, for example 2 mg / kg of naloxone in the case of morphine, 30 minutes after completing the administration of the final dose Opioid

In the 30-minute period after the naloxone administration, mice show a syndrome of typical abstinence, particularly jumps and jolts (of the type that they perform dogs when they are wet), which are counted and register.

The combination of active substances is also administered to mice for 4 consecutive days. After the administration of 2 mg / kg of naloxone 30 minutes after complete administration of the final dose of the combination of active substances, the mice are closely observed for detect any withdrawal symptoms, particularly jumps and shaking (of the type that dogs do when they are wet), which are then counted and recorded.

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

Examples A. Hot plate assay in mice

The analgesic efficacy of a combination of active substances of the invention comprising as a component (A) the citrate compound of (±) -5 - [α- [2- (dimethylamino) ethoxy] benzyl] -1-methyl-1H-pyrazole (hereinafter cizolirtine citrate) and as component (B) Morphine in mice has been determined as described previously and has been compared to vehicle management, Cizolirtine citrate and morphine alone.

The combination of active substances, as well as the comparison substances, their mode of administration and the respective amounts are provided in the following table A together with the determined activities.

TABLE A

10

1: time later of the administration 2: 5% gum arabic by weight in water for injection 3: fit of citrate salt s.c .: subcutaneous i.p .: intraperitoneal

As can be seen from table A, the combination of active substances of the invention shows an effect synergistic

B. Determination of withdrawal syndrome

The influence of the combination of substances active on withdrawal syndrome has been determined as described above The results are provided in the table B:

TABLE B

eleven

1: gum arabic 5% by weight in water for injection 2 in citrate salt form i.p .: intraperitoneal s.c .: subcutaneous

As can be seen from the values provided in table B, withdrawal syndrome normally associated with Opioid administration (in this case morphine) is reduced significantly through co-administration with a substituted carbinol compound -component (A) - citrate cizolirtine, although the administered amount of the opioid

Claims (38)

1. Combination of active substances that understands (A) at least one carbinol compound substituted of general formula I, 12 where R 1 represents a hydrogen atom, a linear or branched alkyl radical, a linear alkenyl radical or branched, a cycloaliphatic radical optionally at least mono-substituted, which may contain at least one nitrogen atom as a member of the ring, or a radical phenyl, R2 represents a hydrogen atom, a cycloaliphatic radical that optionally contains at least one atom of nitrogen as a member of the ring, which can be at least mono-substituted with a linear alkyl radical or branched and / or which may be linked through an alkylene group linear or branched, a NR 3 R 4 moiety, which is attached to through a linear or branched alkylene group, or a moiety NR 5 R 6, which is linked through an alkylene group linear or branched, R3 and R4, identical or different, represent a linear or branched alkyl radical or a radical unsubstituted benzyl, R 5 and R 6 together with the atom of binding nitrogen represent a saturated heterocyclic radical, not substituted, optionally containing at least one heteroatom additional as a member of the ring, X represents a phenyl radical optionally at less mono-substituted or a thienyl radical optionally at least mono-substituted, where in Each case, the substituents can be selected independently between the group consisting of an alkyl radical linear or branched, a linear or branched alkoxy group, a radical linear or branched alkyl that is at least partially halogenated, and a halogen atom, Y represents a heteroaryl radical containing one or more nitrogen atoms as ring members and not is substituted or at least mono-substituted with one or more substituents selected, independently each other, from the group consisting of a halogen atom, a radical linear or branched alkyl, a benzyl radical, a ciara group bonded through an alkylene group with 1 to 4 carbon atoms linear or branched, a carboxy group linked through a group alkylene with 1 to 4 linear or branched carbon atoms, a group methoxy carbonyl linked through an alkylene group with 1 to 4 linear or branched carbon atoms, a hydroxy group attached to through an alkylene group with 1 to 4 linear carbon atoms or branched, an amino group linked through an alkylene group with 1 to 4 linear or branched carbon atoms, a dialkylamino group (with 1 to 4 carbon atoms) linked through an alkylene group with 1 to 4 linear or branched carbon atoms, and a radical cycloaliphatic that contains at least one nitrogen atom as ring member and that is attached through an alkylene group with 1 to 4 linear or branched carbon atoms, or Y represents a unsubstituted heteroaryl radical containing two atoms of nitrogen as ring members and that is condensed with a Methyl substituted nitrogen atom, saturated, as a group cycloaliphatic containing ring member, optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate, or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding salt of the themselves, or a corresponding solvate, and (B) at least one opioid. 2. Combination of active substances according to claim 1, characterized in that R1 represents a hydrogen atom, an alkyl radical with 1 to 4 linear or branched carbon atoms, an alkenyl radical with 2 to 4 carbon atoms linear or branched, a cycloaliphatic radical of 5 or 6 members, which may contain at least one nitrogen atom as a member of the ring and / or which may be at least mono-substituted with an alkyl radical with 1 to 4 linear carbon atoms or branched, or a phenyl radical, preferably a hydrogen atom, an alkyl radical with 1 to 4 linear or branched carbon atoms, a vinyl group, a cyclohexyl radical, an N-methyl-piperidyl radical or a phenyl radical. 3. A combination of active substances according to claim 1 or 2, characterized in that R2 represents a hydrogen atom, a 5 or 6 membered cycloaliphatic radical optionally containing at least one nitrogen atom as a ring member, which may be at least mono-substituted with an alkyl radical with 1 to 4 linear or branched carbon atoms and / or which may be linked through an alkylene radical with 1 to 4 linear or branched carbon atoms, an NR ^ moiety 3 R 4, which is linked through an alkylene group with 1 to 4 linear or branched carbon atoms, or an NR 5 R 6 moiety, which is linked through a alkylene group with 1 to 4 linear or branched carbon atoms, preferably a hydrogen atom, a 5 or 6 membered cycloaliphatic radical optionally containing at least one nitrogen atom as a ring member, which may be at least mono-substituted with an alkyl radical with 1 to 4 c atoms linear or branched argon and / or which may be linked through an alkylene group with 1 to 4 linear or branched carbon atoms, an NR 3 R 4 moiety, which is linked through an alkylene group with 2 to 3 linear or branched carbon atoms, or an NR 5 R 6 moiety that is linked through an alkylene group with 2 to 3 linear or branched carbon atoms. 4. Combination of active substances according to one or more of claims 1-3, characterized in that R3 and R4, identical or different, independently of each other, represent an alkyl radical with 1 to 4 atoms linear or branched carbon or an unsubstituted benzyl radical, preferably an alkyl radical having 1 to 4 linear or branched carbon atoms. 5. Combination of active substances according to one or more of claims 1-4, characterized in that R 5 and R 6 together with the binding nitrogen atom represent a saturated 5- or 6-membered heterocyclic radical , unsubstituted, optionally containing at least one oxygen atom as a member of the ring. 6. A combination of active substances according to one or more of claims 1-5, characterized in that X represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, where in each case the substituents can independently selected from the group consisting of an alkyl radical with 1 to 4 linear or branched carbon atoms, an alkoxy radical with 1 to 4 linear or branched carbon atoms, an alkyl radical with 1 to 4 linear or branched carbon atoms that is at least partially fluorinated, a fluorine atom, a chlorine atom and a bromine atom, preferably represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, where in each case the substituents can be selected independently from the group consisting of a methyl radical, a methoxy radical, a trifluoromethyl radical, a fl atom or, a chlorine atom and a bromine atom. 7. Combination of active substances according to one or more of claims 1-6, characterized in that Y represents an azol radical selected from the group consisting of a) a pyrazole of the general formula (a): 13 in which R 7 represents a alkyl radical with 1 to 12 linear or branched carbon atoms, a benzyl radical or a radical of kind: 14 where n = 1 or 2, Y R 8 represents a hydrogen atom, a methyl radical or a halogen atom, preferably an atom of hydrogen, a methyl radical, a bromine atom or an atom of chlorine, b) an imidazole of the general formula fifteen in which R 9 represents a hydrogen atom, an alkyl radical with 1 to 12 carbon atoms, a benzyl radical or a radical of the general formula (b1): (b1) R 10 - (CH 2) n - in which n is 2, 3 or 4 and R 10 represents a piperidinyl radical, a phenyl radical, a group cyano, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group or a methyl ester group, (CH 3 -O-C (= O) -) Y an imidazole of the following formula: 16 8. Combination of active substances according to one or more of claims 1-7, characterized in that at least one substituted carbinol compound of general formula I is present as component (A). 17 where R 1 represents a hydrogen atom, a methyl radical, an ethyl radical, a radical n-propyl, an iso-propyl radical, a sec-butyl radical, a radical tert-butyl, an n-butyl radical, a vinyl radical, a cyclohexyl radical, a group N-methyl-piperidinyl or a group phenyl, R2 represents a hydrogen atom, a dimethylaminoethyl group, a pyrrolidinylethyl group, a group piperidinylethyl, a group methyl benzyl aminoethyl, a group morpholinyl ethyl, a diisopropylaminoethyl group, a group dimethylaminopropyl, a piperidinylpropyl group, a group pyrrolidinylpropyl, a morpholinylpropyl group, a group N-methyl-2-piperidyl, a group N-ethyl-2-piperidyl, a group N-propyl-2-piperidyl, a group N-methyl-2-pyrrolidinyl, a group N-ethyl-2-pyrrolidinyl, a group N-propyl-2-pyrrolidinyl, or u group 2-dimethylaminoethyl-1-methyl, X represents a phenyl radical, a radical 2-methyl-phenyl, a radical 3-methyl-phenyl, a radical 4-methyl phenyl, a radical 2-chloro-phenyl, a radical 3-chloro-phenyl, a radical 4-chloro-phenyl, a radical 2-fluoro-phenyl, a radical 3-fluoro-phenyl, a radical 4-fluoro-phenyl, a radical 2-trifluoromethyl-phenyl, a radical 3-trifluoromethyl-phenyl, a radical 4-trifluoromethyl-phenyl, a radical 2-methoxy-phenyl, a radical 3-methoxy-phenyl, a radical 4-methoxy-phenyl, a radical 3,4,5-tris-methoxy-phenyl, a 3,4-dichloro-phenyl radical, a 2,4-dichloro-phenyl radical, a Tien-2-yl radical, a radical tien-3-yl, a radical 3-methyl-thien-2-yl, a radical 5-methyl-thien-2-yl, a radical 5-bromo-tien-2-yl or a radical 4-bromo-tien-2-yl, And represents a blue radical selected from the group consisting of a) a pyrazole of the general formula (a): 18 in the that R 7 represents a methyl radical, a radical ethyl, an n-propyl radical, a radical iso-propyl, an n-butyl radical, a sec-butyl radical or a radical tert-butyl, R 8 represents a hydrogen atom, a methyl radical, a bromine atom or a clear atom, b) an imidazole of the general formula 19 in which R 9 represents a hydrogen atom, a methyl radical, an ethyl radical, a radical n-propyl, an iso-butyl radical, a n-butyl radical, a radical sec-butyl, a tert-butyl radical, an n-pentyl radical, a radical n-hexyl, an n-heptyl radical, a n-octyl radical, a radical n-nonyl, an n-decyl radical, a n-undecyl radical, a radical n-dodecil, a radical side or a radical of the General Formula (b1): (b1) R 10 - (CH 2) n - in which n is 2, 3 or 4 and R 10 represents a piperidinyl radical, a phenyl radical, a group cyano, a hydroxyl radical, a carboxy radical, a mino group, a dimethylamino group or a target group ester, Y (c) an imidazole of the following formula: twenty optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, your racemate, or in the form of a mixture of at least two of your stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding salt of the themselves, or a solvate correspondent. 9. Combination of active substances according to one or more of claims 1-8, characterized in that as component (A) one or more compounds selected from the group consisting of [1] 2 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole, [2] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [3] 2- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole, [4] 2- {3-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole, [5] 2- {4-chloro-? - [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [6] 2- {4-fluoro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [7] 2 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole, [8] 2- {3-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [9] 2- {3-chloro- ?- [2- (dimethylamino) ethoxy] -? -Propylbenzyl} -1-methyl-1 H -imidazole, [10] 1-Butyl-2- {4-chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1 H -imidazole, [11] 2 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-4-methoxybenzyl} -1-methyl-1 H -imidazole, [12] 2- {3-Chloro-? -Methyl- ?- [2- (N-pyrrolidinyl) ethoxy] benzyl} -1-methyl-1 H -imidazole, [13] 2 - {α- [2- (dimethylamino) ethoxy] -? -Propyl-3,4,5-trimethoxybenzyl} -1-dodecyl-1 H -imidazole, [14] 1-Butyl-2 - {α- [2- (dimethylamino) ethoxy] -4- (trifluoromethyl) benzyl} -1 H -imidazole, [15] 1-methyl-2 - {? -Methyl- ?- [2- (N-piperidyl) ethoxy] -3- (trifluoromethyl) benzyl} -1 H -imidazole, [16] 2 - {? -Cyclohexyl-3,4-dichloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole, [17] 2- {3,4-dichloro- ?- [2- (dimethylamino) ethoxy] -? -Propylbenzyl} -1-methyl-1 H -imidazole, [18] 2- {3,4-dichloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [19] 2- {3,4-dichloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -imidazole, [20] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1- [2- (N-piperidyl) ethyl] -1 H -imidazole, [21] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1- [2- (N-piperidyl} propyl] -1 H -imidazole, [22] 1- (3-Cyanopropyl) -2- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1 H -imidazole, [23] 2- {4-chloro-? - [2- (dimethylamino) ethoxy] -? - (N-methyl-4-piperidyl) benzyl} -1-methyl-1 H -imidazole, [24] 1-Benzyl-2 - {α- [2- (N-benzyl-N-methylamino) ethoxy] -4-chlorobenzyl} -1 H -imidazole, [25] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -7-methyl-6,7,8,9-tetrahydro-1 H -imidazol [1,5 -a] [1,4] diazepine, [26] 2- {4-Chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -7-methyl-6,7,8,9-tetrahydro-1 H -imidazol [1,5-a] [ 1,4] diazepine, [27] 1-Butyl-5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1 H -pyrazol, [28] 5 - {α- (4-chlorophenyl) - α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [29] 1-Butyl-5 - {α- [2- (dimethylamino) ethoxy] -3,4,5-trimethoxybenzyl} -1 H -pyrazol, [30] 1-Butyl-5- {4-chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1 H -pyrazol, [31] 5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [32] 5 - {α- [2- (dimethylamino} ethoxy} -? -Methylbenzyl} -1-methyl-1 H -pyrazol, [33] 5 - {α- [2- (dimethylamino) ethoxy] -3,4,5-trimethoxybenzyl} -1-methyl-1 H -pyrazol, [34] 1-methyl-5 - {α- [2- (N-pyrrolidinyl) ethoxy] benzyl} -1 H -pyrazol, [35] 1-methyl-5 - {α- [2- (N-morpholinyl) ethoxy] benzyl} -1 H -pyrazol, [36] 5 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-3,4,5-trimethoxybenzyl} -1-methyl-1 H -pyrazol, [37] 4-Bromo-5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [38] 1,3-dimethyl-5 - {α- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1 H -pyrazol, [39] 1,3-dimethyl-5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1 H -pyrazol, [40] 5 - {α- [2- (dimethylamino) ethoxy] -2-methylbenzyl} -1-methyl-1 H -pyrazol, [41] 4-chloro-5- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [42] 5- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [43] 5- {3-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [44] 5 - {α- [2- (dimethylamino) ethoxy] -4-methylbenzyl} -1-methyl-1 H -pyrazol, [45] 5- {2-Chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [46] 1-methyl-5 - {α- [2- (N-piperidyl) ethoxy] benzyl} -1 H -pyrazol, [47] 1-methyl-5 - {α- [2- (N-propyl-2-piperidyl) ethoxy] benzyl} -1 H -pyrazol, [48] 5 - {α- [2- (N-ethyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [49] 1-methyl-5 - {α- [2- (N-methyl-2-pyrrolidinyl) ethoxy] benzyl} -1 H -pyrazol, [50] 5 - {α- [2- (diisopropylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [51] 1-methyl-5 - {α- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1 H -pyrazol, [52] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [53] 2- {3-Chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [54] 2- {4-chloro-? - [3- (dimethylamino) propoxy] -? -Ethylbenzyl} -1-methyl-1 H -imidazole, [55] 2 - {α-butyl-3-chloro-α- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole. [56] 2 - {? -Cyclohexyl-4-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [57] 2 - {α- [3- (dimethylamino) propoxy] -4-fluoro-? -Methylbenzyl} -1-methyl-1 H -imidazole, [58] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole, [59] 2- {2-Chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [60] 2- {3-Chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [61] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-3,4,5-trimethoxybenzyl} -1-methyl-1 H -imidazole, [62] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-4-methoxybenzyl} -1-methyl-1 H -imidazole, [63] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [64] 2 - {α- [3- (dimethylamino) propoxy] -3,4,5-trimethoxybenzyl} -1-methyl-1 H -imidazole, [65] 2 - {α- [3- (dimethylamino) propoxy] -? -Methyl-4- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole, [66] 2 - {α- [3- (dimethylamino) propoxy] -3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole, [67] 2 - {α- [3- (dimethylamino) propoxy] -4- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole, [68] 2 - {α- [3- (dimethylamino) propoxy] -4-methoxybenzyl} -1-methyl-1 H -imidazole, [69] 2 - {α-butyl- ?- [3- (dimethylamino) propoxy] -3- (trifluoromethyl) benzyl} -1-methyl-1 H -imidazole, [70] 1-Butyl-2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1 H -imidazole, [71] 1-Butyl-2 - {? -Butyl- ?- [3- (dimethylamino) propoxy] -3,4,5-trimethoxybenzyl} -1 H -imidazole, [72] 1-Butyl-2 - {α-butyl-2-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1 H -imidazole, [73] 1-Butyl-2 - {? -Butyl-2,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1 H -imidazole, [74] 1-Butyl-2 - {α- [3- (dimethylamino) propoxy] -4- (trifluoromethyl) benzyl} -1 H -imidazole, [75] 2- {4-chloro- ?- [3- (N-piperidyl) propoxy] benzyl} -1-methyl-1 H -imidazole, [76] 1-methyl-2 - {α-methyl- ?- [3- (N-piperidyl) propoxy] -4- (trifluoromethyl) benzyl} -1 H -imidazole, [77] 2 - {α-butyl-2-chloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [78] 2 - {α-butyl-3,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [79] 2- {3,4-dichloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -imidazole, [80] 2- {3,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [81] 2 - {? -Cyclohexyl-3,4-dichloro- ?- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -imidazole, [82] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -? - [2- (N-piperidyl) ethyl] -1 H -imidazole, [83] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1- [2- (N-piperidyl) propyl] -1 H -imidazole, [84] 2- {4-chloro- ?- [3- (dimethylamino) propoxy] -? (N-methyl-4-piperidyl) benzyl} -1-methyl-1 H -imidazole, [85] 1-Butyl-5 - {α- [3- (dimethylamino) propoxy] benzyl} -1 H -pyrazol, [86] 1-Butyl-5- {4-chloro- ?- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1 H -pyrazol, [87] 5 - {α- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -pyrazol, [88] 5 - {α- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1-methyl-1 H -pyrazol, [89] 1,3-dimethyl-5 - {α- [3- (dimethylamino) propoxy] -? -Methylbenzyl} -1 H -pyrazol, [90] 1,3-dimethyl-5 - {α- [3- (dimethylamino) propoxy] benzyl} -1 H -pyrazol, [91] 5 - {α- [3- (dimethylamino) propoxy] -2-methylbenzyl} -1-methyl-1 H -pyrazol, [92] 5-Chloro-5- {4-chloro-? - [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -pyrazol, [93] 1-methyl-5 - {α- [3- (N-piperidyl) propoxy] benzyl} -1 H -pyrazol, [94] 1-methyl-5 - {α- [3- (N-pyrrolidinyl) propoxy] benzyl} -1 H -pyrazol, [95] 4- {4-chloro- ?- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [96] 4- {4-Chloro- ?- [2- (dimethylamino) ethoxy] -? -Methylbenzyl} -1-methyl-1 H -pyrazol, [97] 4- {4-chloro- ?- [2- (N-propyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [98] 4- {4-chloro- ?- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [99] 4- {4-chloro- ?- [2- (N-ethyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [100] 4- {4-chloro- ?- [2- (diisopropylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [101] 4- {4-chloro- ?- [2- (N-methyl-2-pyrrolidinyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [102] 4 - {α- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H -pyrazol, [103] 4- {4-chloro- ?- [3- (N-morpholinyl) propoxy] benzyl} -1-methyl-1 H -pyrazol, [104] 4- {4-chloro- ?- [3- (N-pyrrolidinyl) propoxy] benzyl} -1-methyl-1 H -pyrazol, [105] 2 - (? -Hydroxybenzyl) -1 H -imidazole, [106] 2- (4-Chloro-? -Hydroxybenzyl) -1 H -imidazole, [107] 2- (4-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [108] 2- (3-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [109] 2- (4-Fluoro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [110] 2 - [α-hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole, [111] 2 - [α-hydroxy-4- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole, [112] 2 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1-methyl-1 H -imidazole, [113] 2- (3,4-Dichloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [114] 1-Butyl-2 - [α-hydroxy-4- (trifluoromethyl) benzyl] -1 H -imidazole, [115] 1-Butyl-2- (3,4-dichloro-? -Hydroxybenzyl) -1 H -imidazole, [116] 1-Butyl-2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole, [117] 1-Butyl-2 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole, [118] 1-dodecyl-2 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole, [119] 2 - (? -Butyl-3-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [120] 2- (3-Chloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole, [121] 2- (4-Chloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole, [122] 2- [4-Chloro-? -Hydroxy- ?- (N-methyl-4-piperidyl) benzyl] -1-methyl-1 H -imidazole, [123] 2- (4-Chloro-? -Ethyl-? -Hydroxybenzyl) -1-methyl-1- H -imidazole, [124] 2 - (? -Butyl-4-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [125] 2 - (? -Cyclohexyl-4-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [126] 2- (2-Chloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole, [127] 2 - (? -Butyl-2-chloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [128] 2 - [α-hydroxy-α-methyl-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole, [129] 2 - [α-butyl-? -Hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole, [130] 2 - [α-cyclohexyl-α-hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole, [131] 2 - [α-hydroxy-α-methyl-4- (trifluoromethyl) benzyl] -1-methyl-1 H -imidazole, [132] 2- (4-Fluoro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole, [133] 2 - (? -Hydroxy-? -Methyl-4-methoxybenzyl) -1-methyl-1 H -imidazole, [134] 2- (3,4-Dichloro-? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -imidazole, [135] 2 - (? -Butyl-3,4-dichloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [136] 2 - (? -Cyclohexyl-3,4-dichloro-? -Hydroxybenzyl) -1-methyl-1 H -imidazole, [137] 2 - (? -Hydroxy-? -Methyl-3,4,5-trimethoxybenzyl) -1-methyl-1 H -imidazole, [138] 1-Butyl-2- (4-chloro-? -Hydroxy-? -Methylbenzyl) -1 H -imidazole, [139] 1-Butyl-2 - (? -Butyl-4-chloro-? -Hydroxybenzyl] -1 H -imidazole, [140] 1-Butyl-2- [4-chloro-? -Hydroxy-α- (N-methyl-4-piperidyl) benzyl] -1 H -imidazole, [141] 1-Butyl-2 - (? -Butyl-? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole, [142] 1-Butyl-2 - (? -Butyl-2-chloro-? -Hydroxybenzyl) -1 H -imidazole, [143] 1-Butyl-2 - [α-ethyl-? -Hydroxy-3- (trifluoromethyl) benzyl] -1 H -imidazole, [144] 1-Butyl-2 - (? -Butyl-2,4-dichloro-? -Hydroxybenzyl) -1 H -imidazole, [145] 2- (4-Chloro-? -Hydroxy-? -Methylbenzyl) -1- [2- (N-piperidyl) ethyl] -1 H -imidazole, [146] 2- (4-Chloro-? -Hydroxy-? -Methylbenzyl) -1- (3-dimethylaminopropyl) -1 H -imidazole, [147] 2 - (? -Butyl-? -Hydroxy-3,4,5-trimethoxybenzyl) -1-dodecyl-1 H -imidazole, [148] 1-Benzyl-2 - [α-butyl-? -Hydroxy-3- (trifluoromethyl) benzyl] -1 H -imidazole, [149] 1-benzyl-2- (4-chloro-? -Hydroxy-? -Methylbenzyl) -1 H -imidazole, [150] 1- (2-Cyanoethyl) -2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole, [151] 1- (3-aminopropyl) -2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole, [152] 3- [2- (3-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] propanoic acid, [153] 2- (4-Chloro-? -Hydroxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole, [154] 3- [2- (3-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] methyl propanoate, [155] 2 - (? -Hydroxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole, [156] 2 - (? -Hydroxy-4-methylbenzyl) -1- (3-hydroxypropyl) -1 H -imidazole, [157] 2 - (? -Hydroxy-4-methoxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole, [158] 2- (3,4-Dichloro-? -Hydroxybenzyl) -1- (3-hydroxypropyl) -1 H -imidazole, [159] 3- {2 - (α-hydroxybenzyl) -1 H -imidazol-1-yl} methyl propanoate, [160] 2- (4-Chloro-? -Hydroxybenzyl) -1- (4-hydroxybutyl) -1 H -imidazole, [161] 1- (3-Cyanopropyl) -2- (4-chloro-? -Hydroxybenzyl) -1 H -imidazole, [162] 4- [2- (4-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] butanoic acid, [163] 4- [2- (4-Chloro-? -Hydroxybenzyl) -1 H -imidazol-1-yl] methyl butanoate, [164] 1-Butyl-5 - (? -Hydroxybenzyl) -1 H -pyrazol, [165] 5- (4-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -pyrazol, [166] 5 - (α-hydroxy-3,4,5-trimethoxybenzyl) -1-methyl-1 H -pyrazol, [167] 1-Butyl-5 - (? -Hydroxy-3,4,5-trimethoxybenzyl) -1 H -pyrazol, [168] 4-Bromo-5 - (? -Hydroxybenzyl) -1-methyl-1 H -pyrazol, [169] 5 - [α- (4-chlorophenyl) - α-hydroxybenzyl] -1-methyl-1 H -pyrazol, [170] 1-Butyl-5- (4-chloro-? -Hydroxy-? -Methylbenzyl) -1 H -pyrazol, [171] 5 - (? -Hydroxy-? -Methylbenzyl) -1-methyl-1 H -pyrazol, [172] 5 - (? -Hydroxy-? -Methyl-3,4,5-trimethoxybenzyl) -1-methyl-1 H -pyrazol, [173] 1,3-dimethyl-5 - (? -Hydroxy-? -Methylbenzyl) -1 H -pyrazol, [174] 1-Butyl-5 - (α-hydroxy-α-vinylbenzyl) -1 H -pyrazol, [175] 1-Butyl-5- (4-chloro-? -Hydroxy-α-vinylbenzyl) -1 H -pyrazol, [176] 4-Chloro-5 - (α-hydroxybenzyl) -1-methyl-1 H -pyrazol, [177] 5 - (α-hydroxy-2-methylbenzyl) -1-methyl-1 H -pyrazol, [178] 5- (3-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -pyrazol, [179] 5 - (? -Hydroxy-4-methylbenzyl) -1-methyl-1 H -pyrazol, [180] 5- (2-Chloro-? -Hydroxybenzyl) -1-methyl-1 H -pyrazol, [181] 5 - (α-hydroxy-4-methoxybenzyl) -1-methyl-1 H -pyrazol, [182] 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol, [183] 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol citrate citrate, [184] 5 - {α- [2- (dimethylamino) ethoxy] -3-thienylmethyl} -1-methyl-1 H -pyrazol, [185] 2 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -imidazole, [186] 5 - {α- [2- (dimethylamino) ethoxy] -3-methyl-2-thienylmethyl} -1-methyl-1 H -pyrazol, [187] 5 - {α- [2- (dimethylamino) ethoxy] -5-methyl-2-thienylmethyl} -1-methyl-1 H -pyrazol, [188] 5- {5-bromo- ?- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol, [189] 5- {4-bromo- ?- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol, [190] 5 - {α- [2- (dimethylamino) ethoxy] -? -Methyl-2-thienylmethyl} -1-methyl-1 H -pyrazol, [191] 5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol citrate, [192] (±) -5 - {α- [2- (dimethylamino) -1- (methyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [193] (±) -5 - {α- [2- (dimethylamino) -1- (methyl) ethoxy] benzyl} -1-methyl-1 H -pyrazol, [194] (+) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol, [195] (-) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol, [196] Citrate of (+) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol, [197] (-) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol citrate citrate, [198] (+) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol D-ditholuoyltartrate, [199] (-) - 5 - {α- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H -pyrazol L-ditholuoyltartrate, [200] (+) - 5 - {α- [2-dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol citrate citrate, [201] (-) - 5 - {α- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H -pyrazol citrate citrate, [202] 5 - (? -Hydroxy-2-thienylmethyl) -1-methyl-1 H -pyrazol, [203] 5 - (? -Hydroxy-3-methyl-2-thienylmethyl) -1-methyl-1 H -pyrazol, [204] 5 - (α-hydroxy-5-methyl-2-thienylmethyl) -1-methyl-1 H -pyrazol, [205] 5- (5-Bromo-? -Hydroxy-2-thienylmethyl) -1-methyl-1 H -pyrazol, [206] 5- (4-Bromo-? -Hydroxy-2-thienylmethyl) -1-methyl-1 H -pyrazol and [207] 5 - (? -Hydroxy-? -Methyl-2-thienylmethyl) -1-methyl-1 H -pyrazol, 10. Combination of active substances according to one or more of claims 1-9, characterized in that an opioid with weak analgesic efficacy is present as component (B). 11. Combination of active substances according to claim 10, characterized in that the opioid with weak analgesic efficacy is selected from the group consisting of codeine, dextropropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, loperamide, meptazinol, nalbuphine, pethidine, tilidine, tramadol, viminol and corresponding physiologically acceptable salts of these compounds. 12. Combination of active substances according to claim 10 or 11, characterized in that the molar ratio between component (B) and component (A) is in the range of 1: 1 to 1:20, preferably 1: 1 at 1:10, more preferably from 1: 1 to 1: 5. 13. Combination of active substances according to one or more of claims 1-9, characterized in that as component (B) at least one opioid with analgesic efficacy of medium to high is present. 14. Combination of active substances according to claim 13, characterized in that the opioid with medium to high analgesic efficacy is selected from the group consisting of alfentanil, buprenorphine, butorphanol, dextromoramide, dezocine, diacetylmorphine (heroin), etorphine, fentanyl, hydrocodone, hydromorphone, ketobemidone, levometadone, levometadyl acetate, levorphanol, morphine, 14-methoxymethopon, nalorphine, oxycodone, oxymorphone, pentazocine, piritramide, remifentanil, sufentanil and corresponding physiologically acceptable salts thereof. 15. A combination of active substances according to claim 13 or 14, characterized in that the molar ratio between component (B) and component (A) is in the range of 1: 1 to 1: 400, preferably 1: 1 at 1: 200, more preferably from 1: 1 to 1:40, and even more preferably from 1: 1 to 1: 5. 16. Combination of active substances according to one or more of claims 1 to 15, characterized in that the component (A) and the component (B) are present at least partially in the form of a salt formed from these components. 17. Combination of active substances according to one or more of claims 1 to 16, characterized in that it further comprises as component (C) at least one agent that is suitable for reducing or preventing abuse of component (A) and / or the component (B). 18. A combination of active substances according to claim 17, characterized in that said agent or agents of component (C) are selected from the group consisting of opioid antagonists, aversive agents and gelling agents. 19. Combination of active substances according to claim 18, characterized in that the opioid antagonist is selected from the group consisting of levalorphane, naloxone, naltrexone and physiologically acceptable salts thereof. 20. Medication comprising a combination of active substances according to one or more of the claims 1 to 19 and optionally at least one substance activates additionally and / or optionally at least one substance assistant. 21. Medication according to claim 20 for the treatment of pain, preferably for the pain treatment selected from the group consisting of neuropathic pain, acute pain, chronic pain, postoperative pain, chronic low back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, pain resistant, visceral pain, surgical pain, injury pain bone, pain during childbirth, pain due to burns, pain due to sunburn, postpartum pain, migraine, pain angina, pain related to the genitourinary tract, pain of cystitis and nociceptive pain, or for prophylaxis and / or treatment of urinary incontinence, or for prophylaxis and / or treatment of neurogenic inflammation. 22. Use of a combination of substances active according to one or more of claims 1 to 19 for the manufacture of a medicament for the treatment of pain. 23. Use according to claim 22, characterized in that the pain is selected from the group consisting of neuropathic pain, acute pain, chronic pain, postoperative pain, chronic low back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, resistant pain, visceral pain, surgical pain, bone injury pain, pain during childbirth, pain due to burns, pain due to sunburn, postpartum pain, migraine, angina pain, tract related pain genitourinary, cystitis pain and nociceptive pain. 24. Use of a combination of substances active according to one or more of claims 1 to 19 for the manufacture of a drug for prophylaxis and / or Urinary incontinence treatment. 25. Use of a combination of substances active according to one or more of claims 1 to 19 for the manufacture of a drug for prophylaxis and / or Neurogenic inflammation treatment. 26. Pharmaceutical formulation comprising a combination of active substances according to one or more of the claims 1 to 19 and optionally at least one substance activates additionally and / or optionally at least one substance assistant. 27. Pharmaceutical formulation according to claim 26, characterized in that it is suitable for oral or parenteral administration, preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathecal, rectal, transdermal, transmucosal or nasal administration. 28. Pharmaceutical formulation for oral administration according to claim 27, characterized in that it is in the form of a tablet, a dragee, a capsule, drops, a gel, juice, syrup, solution or suspension. 29. Pharmaceutical formulation for oral administration according to claim 27, characterized in that it is in the form of multiparticulates, preferably pellets or granules, optionally compressed in the form of a tablet, introduced into a capsule or suspended in a suitable liquid. 30. Pharmaceutical formulation for oral administration according to claims 27-29, characterized in that it comprises at least one enteric coating. 31. Pharmaceutical formulation according to claims 26-30, characterized in that it comprises component (A) and / or component (B) at least partially in a sustained release form. 32. Pharmaceutical formulation according to claim 31, characterized in that the sustained release is achieved by at least one coating or matrix comprising at least one sustained release material. 33. Pharmaceutical formulation according to claim 32, characterized in that the sustained-release material is based on a natural, semi-synthetic or synthetic polymer, insoluble in water, optionally modified, or on a natural, semi-synthetic or synthetic wax, fat, fatty alcohol or fatty acid, or in a mixture of at least two of the components mentioned above. 34. Pharmaceutical formulation according to claim 33, characterized in that the water-insoluble polymer is based on an acrylic resin, which is preferably selected from the group of poly (meth) acrylates, dialkyl (meth) acrylates (with 1 to 4 carbon atoms) aminoalkyl (with 1 to 4 carbon atoms) and / or copolymers thereof or a mixture of at least two of the polymers mentioned above. 35. Pharmaceutical formulation according to claim 33, characterized in that the water-insoluble polymers are cellulose derivatives, preferably alkyl cellulose, in a particularly preferred form ethyl cellulose or cellulose esters. 36. Pharmaceutical formulation according to claim 33, characterized in that the wax is carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitoestearate, microcrystalline wax or a mixture of at least two of these components. 37. Pharmaceutical formulation according to any one of claims 33-36, characterized in that the polymers have been used in combination with one or more plasticizers. 38. Pharmaceutical formulation according to any one of claims 31-37, characterized in that it comprises component (A) and / or component (B) in the form of immediate release as well as in the form of sustained release.