WO2013068463A1

WO2013068463A1 - Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an n-cyclic group as vanilloid receptor ligands

Info

Publication number: WO2013068463A1
Application number: PCT/EP2012/072142
Authority: WO
Inventors: Robert Frank; Thomas Christoph; Nils Damann; Bernhard Lesch; Gregor Bahrenberg; Derek John Saunders; Hannelore Stockhausen; Yong-Soo Kim; Myeong-Seop Kim; Jeewoo Lee
Original assignee: Grünenthal GmbH
Priority date: 2011-11-09
Filing date: 2012-11-08
Publication date: 2013-05-16
Also published as: EP2776424A1; KR20140093260A; JP2014532743A

Abstract

The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-cyclic group as vanilloid receptor ligands formula (S) to pharmaceutical compositions containing these compounds of the general formula (S) and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

Description

Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-cyclic group as vanilloid receptor ligands

FIELD OF THE INVENTION

The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-cyclic group as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

BACKGROUND OF THE INVENTION

The treatment of pain, in particular of neuropathic pain, is very important in medicine. There is a worldwide demand for effective pain therapies. The urgent need for action for a patient- focused and target-oriented treatment of chronic and non-chronic states of pain, this being understood to mean the successful and satisfactory treatment of pain for the patient, is also documented in the large number of scientific studies which have recently appeared in the field of applied analgesics or basic research on nociception.

The subtype 1 vanilloid receptor (VR1/TRPV1 ), which is often also referred to as the capsaicin receptor, is a suitable starting point for the treatment of pain, in particular of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain. This receptor is stimulated inter alia by vanilloids such as capsaicin, heat and protons and plays a central role in the formation of pain. In addition, it is important for a large number of further physiological and pathophysiological processes and is a suitable target for the therapy of a large number of further disorders such as, for example, migraine, depression, neurodegenerative diseases, cognitive disorders, states of anxiety, epilepsy, coughs, diarrhoea, pruritus, inflammations, disorders of the cardiovascular system, eating disorders, medication dependency, misuse of medication and urinary incontinence.

Compounds which have an affinity for the subtype 1 vanilloid receptor (VR1/TRPV1 ) are e.g. known from WO 2010/127855-A2 and WO 2010/127856-A2. There is a demand for further compounds having comparable or better properties, not only with regard to affinity to vanilloid receptors 1 (VR1/TRPV1 receptors) per se (potency, efficacy).

Thus, it may be advantageous to improve the metabolic stability, the solubility in aqueous media or the permeability of the compounds. These factors can have a beneficial effect on oral bioavailability or can alter the PK/PD (pharmacokinetic/pharmacodynamic) profile; this can lead to a more beneficial period of effectiveness, for example.

A weak or non-existent interaction with transporter molecules, which are involved in the ingestion and the excretion of pharmaceutical compositions, is also to be regarded as an indication of improved bioavailability and at most low interactions of pharmaceutical compositions. Furthermore, the interactions with the enzymes involved in the decomposition and the excretion of pharmaceutical compositions should also be as low as possible, as such test results also suggest that at most low interactions or no interactions at all, of pharmaceutical compositions are to be expected.

It was therefore an object of the invention to provide novel compounds, preferably having advantages over the prior-art compounds. The compounds should be suitable in particular as pharmacological active ingredients in pharmaceutical compositions, preferably in pharmaceutical compositions for the treatment and/or prophylaxis of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 receptors).

This object is achieved by the subject matter described herein.

It has surprisingly been found that the substituted compounds of general formula (S), as given below, display outstanding affinity to the subtype 1 vanilloid receptor (VR1 /TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and/or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 ).

Particularly suitable are substituted compounds of general formula (S), as given below, that in addition to their activity with regard to the VR1 -receptor show one or more additional advantageous properties, for example, suitable potency, suitable efficacy, no increase in body temperature and/or heat pain threshold; appropriate solubility in biologically relevant media such as aqueous media, in particular in aqueous media at a physiologically acceptable pH value, such as in buffer systems, for instance in phosphate buffer systems; suitable metabolic stability and diversity (e.g. sufficient stability towards the oxidative capabilities of hepatic enzymes such as cytochrome P450 (CYP) enzymes and sufficient diversity with regard to the metabolic elimination via these enzymes); and the like.

The present invention therefore relates to a substituted compound of general formula (S),

(S),

in which

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂CH₂-OH, CH₂-OCH₃, CH₂CH₂- OCH₃, OCFH₂, OCF₂H, OCF₃, OH, NH₂, a d_₄ alkyl, an 0-d_₄ alkyl, a NH-d_₄ alkyl, and a N(Ci_-4 alkyl)₂, wherein the Ci_-4 alkyl is in each case unsubstituted,

R² represents CF₃, an unsubstituted Ci_-4 alkyl or an unsubstituted C₃.₆ cycloalkyl,

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, OH, OCF₃, a d_₄ alkyl, and an 0-d_₄ alkyl, wherein the d_₄ alkyl is in each case unsubstituted,

A denotes N, CH or C(CH₃),

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a 3 to 10 membered heterocyclyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF₃, CH₂OH, CH₂CH₂OH, CH₃, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, =0, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof. DETAILED DESCRIPTION

The term "single stereoisomer" preferably means in the sense of the present invention an individual enantiomer or diastereomer. The term "mixture of stereoisomers" means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.

The term "physiologically acceptable salt" preferably comprises in the sense of this invention a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.

A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid which is physiologically acceptable - in particular when used in human beings and/or other mammals. Examples of physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p- toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, oc-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid, aspartic acid. Citric acid and hydrochloric acid are particularly preferred. Hydrochloride salts and citrate salts are therefore particularly preferred salts.

A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention as an anion with at least one preferably inorganic cation, which is physiologically acceptable - in particular when used in human beings and/or other mammals. Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts [NH_XR₄._X]⁺, in which x = 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Ci_-4 alkyl residue, in particular (mono-) or (di)sodium, (mono-) or (di)potassium, magnesium or calcium salts.

The terms "alkyl" and "Ci_-4 alkyl" preferably comprise in the sense of this invention acyclic saturated aliphatic hydrocarbon residues, which can be respectively branched or unbranched and can be unsubstituted or can be mono- or polysubstituted, e.g. mono-, di- or trisubstituted, and which contain 1 to 4, i.e. 1 , 2, 3 or 4, carbon atoms, i.e. Ci_-4 aliphatic residues, i.e. Ci_-4 alkanyls. Preferred Ci_-4 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, and tert.-butyl.

In relation to the terms "alkyl" and "Ci_-4 alkyl", the term "monosubstituted" or "polysubstituted" such as di- or tri-substituted refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution or trisubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent. The term "polysubstituted" such as di- or tri-substituted with respect to polysubstituted residues and groups such as di- or tri-substituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example trisubstituted on the same carbon atom, as in the case of CF₃ or CH₂CF₃ or at various points, as in the case of CH(OH)-CH₂CH₂-CHCI₂. The multiple substitution can be carried out using the same or using different substituents.

The terms "cycloalkyl" and "C₃.₆ cycloalkyl" preferably mean for the purposes of this invention cyclic aliphatic (cycloaliphatic) hydrocarbons containing 3, 4, 5, or 6 carbon atoms, i.e. C_3-6- cycloaliphatic residues, wherein the hydrocarbons are saturated and which can be unsubstituted or can be mono- or polysubstituted, e.g. mono-, di- or trisubstituted. The cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloalkyl residue. Preferably, cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, more preferably from the group consisting of cyclopropyl and cyclobutyl. A particularly preferred cycloalkyl is cyclopropyl.

The terms "heterocyclyl", "3 to 10 membered heterocyclyl" and "3 to 6 membered heterocyclyl" preferably comprise in the sense of this invention aliphatic saturated heterocycloalkyls having 3 to 6, i.e. 3, 4, 5, or 6, ring members, i.e. a 3 to 6 membered heterocyclyl, or, respectively, having 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 ring members, i.e. 3 to 10 membered heterocyclyl, in which at least one, if appropriate also two or three carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0), S(=0)₂, N, NH and N(Ci_-8 alkyl), wherein the ring members can be unsubstituted or can be mono- or polysubstituted, e.g. mono-, di- or trisubstituted. Heterocyclyls are thus heterocycloaliphatic residues. A heterocyclyl according of the present invention is formed from radicals R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them, i.e. contains at least one N as a ring member. Heterocyclyl residues from the group comprising azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dihydropyridinyl, imidazolidinyl, isoxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, pyrazolidinyl, tetrahydropyrrolyl, tetrahydropyridinyl, thiazolidinyl and thiomorpholinyl are preferred.

In relation to the terms "cycloalkyl, "C₃-₆ cycloalkyl", "heterocyclyl", "3 to 10 membered heterocyclyl", and "3 to 6 membered heterocyclyl", the term "monosubstituted" or "polysubstituted" such as di- or tri-substituted refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution or trisubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent. The term "polysubstituted" such as di- or tri-substituted with respect to polysubstituted residues and groups such as di- or tri- substituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example disubstituted on the same carbon atom, as in the case of 1 ,1 -difluorocyclohexyl, or at various points, as in the case of 1 -chloro- 3-fluorocyclohexyl. The multiple substitution can be carried out using the same or using different substituents.

Within the scope of the present invention, the symbol

used in the formulae denotes a link of a corresponding residue to the respective superordinate general structure.

In a preferred embodiment of the compound according to the present invention

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂.

Preferably,

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, O- CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂.

More preferably, R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, CFH₂, CF₂H, CF₃, CN, CH₂-OCH₃, OCF₃, CH₃, 0-CH₃, 0-CH₂CH₃ and N(CH₃)₂.

Even more preferably,

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, CFH₂, CF₂H, CF₃, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃.

Still more preferably,

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, CF₃, OCF₃, CH₃ and 0-CH₃.

Particularly,

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, CF₃ and 0-CH₃.

Even more particularly preferred

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI and 0-CH₃.

In a preferred embodiment of the compound according to the present invention at least one of R¹⁰¹ , R¹⁰² and R¹⁰³ is≠ H.

In another preferred embodiment of the compound according to the present invention one or two of R¹⁰¹ , R¹⁰² and R¹⁰³, preferably R¹⁰² and/or R¹⁰³, denote(s) H.

In another preferred embodiment of the compound according to the present invention one of R¹⁰¹ , R¹⁰² and R¹⁰³ represents H, preferably R¹⁰³ represents H.

In another preferred embodiment of the compound according to the present invention R¹⁰¹ and R¹⁰² are independently of one another selected from the group consisting of

H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, and R¹⁰³ represents H.

Preferably,

R¹⁰¹ and R¹⁰² are independently of one another selected from the group consisting of

H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, more preferably are independently of one another selected from the group consisting of H, F, CI, CFH₂, CF₂H, CF₃, CN, CH₂-OCH₃, OCF₃, CH₃, 0-CH₃, O- CH₂CH₃ and N(CH₃)₂, even more preferably are independently of one another selected from the group consisting of H, F, CI, CFH₂, CF₂H, CF₃, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃, still more preferably are independently of one another selected from the group consisting of H, F, CI, CF₃, OCF₃, CH₃ and 0-CH₃, in particular are independently of one another selected from the group consisting of H, F, CI, CF₃ and 0-CH₃, even more particularly preferred are independently of one another selected from the group consisting of H, F, CI, and 0-CH₃, and R¹⁰³ represents H.

In yet another preferred embodiment of the compound according to the present invention

R¹⁰¹ is selected from the group consisting of F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂- OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, and both R¹⁰² and R¹⁰³ represents H.

Preferably,

R¹⁰¹ is selected from the group consisting of F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂- OCH₃, OCF₃, OH, CH₃, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, more preferably is selected from the group consisting of F, CI, CFH₂, CF₂H, CF₃, CN, CH₂-OCH₃, OCF₃, CH₃, O- CH₃, 0-CH₂CH₃ and N(CH₃)₂, even more preferably is selected from the group consisting of F, CI, CFH₂, CF₂H, CF₃, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃, still more preferably is selected from the group consisting of F, CI, CF₃, OCF₃, CH₃ and 0-CH₃, in particular is selected from the group consisting of F, CI, CF₃ and 0-CH₃, even more particularly preferred is selected from the group consisting of F, CI, and 0-CH₃, and both R¹⁰² and R¹⁰³ represents H.

In still another preferred embodiment of the compound according to the present invention

R¹⁰² is selected from the group consisting of F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂- OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, and both R¹⁰¹ and R¹⁰³ represents H.

Preferably,

R¹⁰² is selected from the group consisting of F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂- OCH₃, OCF₃, OH, CH₃, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, more preferably is selected from the group consisting of F, CI, CFH₂, CF₂H, CF₃, CN, CH₂-OCH₃, OCF₃, CH₃, O- CH₃, 0-CH₂CH₃ and N(CH₃)₂, even more preferably is selected from the group consisting of F, CI, CFH₂, CF₂H, CF₃, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃, still more preferably is selected from the group consisting of F, CI, CF₃, OCF₃, CH₃ and 0-CH₃, in particular is selected from the group consisting of F, CI, CF₃ and 0-CH₃, even more particularly preferred is selected from the group consisting of F, CI, and 0-CH₃, and both R¹⁰¹ and R¹⁰³ represents H.

In yet a further preferred embodiment of the compound according to the present invention

R¹⁰¹ is selected from the group consisting of F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂- OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂,

R¹⁰² is selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, and R¹⁰³ represents H. Preferably,

R¹⁰¹ is selected from the group consisting of F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂- OCH₃, OCF₃, OH, CH₃, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, more preferably is selected from the group consisting of F, CI, CFH₂, CF₂H, CF₃, CN, CH₂-OCH₃, OCF₃, CH₃, O- CH₃, O-CH₂CH₃ and N(CH₃)₂, even more preferably is selected from the group consisting of F, CI, CFH₂, CF₂H, CF₃, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃, still more preferably is selected from the group consisting of F, CI, CF₃, OCF₃, CH₃ and 0-CH₃, in particular is selected from the group consisting of F, CI, CF₃ and 0-CH₃, even more particularly preferred is selected from the group consisting of F, CI, and 0-CH₃,

R¹⁰² is selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, more preferably is selected from the group consisting of H, F, CI, CFH₂, CF₂H, CF₃, CN, CH₂- OCH₃, OCF₃, CH₃, 0-CH₃, 0-CH₂CH₃ and N(CH₃)₂, even more preferably is selected from the group consisting of H, F, CI, CFH₂, CF₂H, CF₃, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃, still more preferably is selected from the group consisting of H, F, CI, CF₃, OCF₃, CH₃ and O- CH₃, in particular is selected from the group consisting of H, F, CI, CF₃ and 0-CH₃, even more particularly preferred is selected from the group consisting of H, F, CI, and 0-CH₃, and R¹⁰³ represents H.

In another particularly preferred embodiment according to the present invention the part structure (SS2)

(SS2), is selected from the group consisting of

(SS2), is selected from the group consisting of

Most preferred, the part structure (SS2)

is selected from the group consisting of

preferably is selected from the group consisting of

In another preferred embodiment of the compound according to the present invention

R² represents CF₃, methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec-butyl, tert.- butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Preferably,

R² represents CF₃, 2-propyl, n-butyl, iso-butyl, sec-butyl, tert.-butyl, cyclopropyl, or cyclobutyl.

More preferably,

R² represents CF₃, tert.-butyl or cyclopropyl.

In a particularly preferred embodiment of the compound according to the present invention R² represents CF₃.

In another particularly preferred embodiment of the compound according to the present invention R² represents tert.-butyl.

In another particularly preferred embodiment of the compound according to the present invention R² represents cyclopropyl.

In a further preferred embodiment of the compound according to the present invention

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, Br, CF₃, CN, OH, OCF₃, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, and 0-CH₂CH₃.

Preferably,

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, CF₃, CN, OH, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃.

More preferably, R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, CF₃, O-CH3, and 0-CH₂CH₃.

Even more preferably,

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, and 0-CH₃, still more preferably are independently of one another selected from the group consisting of H, F and CI.

In yet a further preferred embodiment of the compound according to the present invention at least one of R⁷ and R⁹ is≠ H.

In a further preferred embodiment of the compound according to the present invention R⁹ denotes H.

R⁷ is selected from the group consisting of F, CI, Br, CF₃, CN, OH, OCF₃, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, and 0-CH₂CH₃, preferably is selected from the group consisting of F, CI, CF₃, CN, OH, OCF₃, CH₃, 0-CH₃, and 0-CH₂CH₃, more preferably is selected from the group consisting of F, CI, CF₃, 0-CH₃, and 0-CH₂CH₃, even more preferably is selected from the group consisting of F, CI, and 0-CH₃, still more preferably is selected from the group consisting of F and CI, and R⁹ represents H.

In another preferred embodiment of the compound according to the present invention A denotes N or C(CH₃).

In a particularly preferred embodiment of the compound according to the present invention A denotes N.

In another particularly preferred embodiment of the compound according to the present invention A denotes C(CH₃).

In another preferred embodiment of the compound according to the present invention R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form the part structure (SS1 )

(SS1 ),

wherein r denotes 0, 1 , 2 or 3, s denotes 0, 1 , 2 or 3,

R^111a, R^{111 b} and R^111c are independently of one another selected from the group consisting of H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, preferably are independently of one another selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) and

N(CH₃)₂, or two of R^111a, R^{111 b} and R^111c together denote =0 and the remaining residue of R^111a, R^{111 b} and R^111c represents H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) or N(CH₃)₂, preferably represents H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂, or, when A denotes N,

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a 3 to 10 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of S, S(=0), S(=0)₂, N, NH and N(d.4 alkyl), which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.- butyl, cyclopropyl, OH, =0, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, preferably which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OI-l, CH₂CH₃, CH(CH₃)₂, OH, =0, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂, more preferably which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, CH₃, CH₂OH, CH₂CH₂OH, OH, =0, and OCH₃, even more preferably which is unsubstituted, or, when A denotes CH or C(CH₃),

R¹⁰⁹ and R^{1 10} together with the nitrogen atom connecting them form a 3 to 1 0 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH and N(Ci_-4 alkyl), unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, =0, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, preferably which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, =0, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂, more preferably which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, CH₃, CH₂OH, CH₂CH₂OH, OH, =0, and OCH₃, even more preferably which is unsubstituted.

R¹⁰⁹ and R^{1 10} together with the nitrogen atom connecting them form the part structure (SS1 )

1 1 1 a

1 1 1 c

R

(SS1 ),

wherein r denotes 0, 1 or 2, s denotes 0, 1 or 2,

R^111a, R^{111 b} and R^{111 c} are independently of one another selected from the group consisting of H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, preferably are independently of one another selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂, or two of R^111a, R^{111 b} and R^111c together denote =0 and the remaining residue of R^111a, R^{111 b} and R^111c represents H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) or N(CH₃)₂, preferably represents H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂.

Preferably,

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form the part structure (SS1 )

(SS1 ),

wherein r denotes 0, 1 or 2, s denotes 0 or 1 ,

R^111a and R^{111 b} are independently of one another selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂, preferably are independently of one another selected from the group consisting of H, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, even more preferably are independently of one another selected from the group consisting of H, OH and OCH₃, and R^111c denotes H, or R^111a and R^{111 b} together denote =0 and R^111c denotes H. More preferably,

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a part structure selected from the group consisting of

(SS1 -C) (SS1 -d) wherein R^{1 11a} and R^{111 b} are independently of one another selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, and OCH₃, preferably are independently of one another selected from the group consisting of H, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, even more preferably are

independently of one another selected from the group consisting of H, OH and OCH₃, or R^111a and R^{111 b} together denote =0.

Even more preferably, R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a part structure selected from the group consisting of

(SS1 -a) (SS1 -b)

(SS1 -C) (SS1 -d) wherein R^{1 11a} is selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH,

CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, and OCH₃, preferably is selected from the group consisting of H, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, even more preferably is selected from the group consisting of H, OH and OCH₃, and R^{111 b} denotes H.

Particularly,

(SS1 -b)

(SS1 -C) wherein R^{1 11a} is selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH,

In a particularly preferred embodiment of the present invention,

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂, preferably, wherein at least one of R¹⁰¹ , R¹⁰² and R¹⁰³ is≠ H,

R² represents CF₃, tert.-butyl or cyclopropyl,

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, Br, CF₃, CN, OH, OCF₃, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, and 0-CH₂CH₃, preferably, wherein at least one of R⁷ and R⁹ is≠ H,

A denotes N, CH or C(CH₃), and

(SS1 -C) (SS1 -d) wherein R^111a is selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH,

CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, and OCH₃, preferably are independently of one another selected from the group consisting of H, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, even more preferably are independently of one another selected from the group consisting of H, OH and OCH₃, and R^{111 b} denotes H, or R^111a and R^{111 b} together denote =0.

Preferred embodiments of the compound according to the invention of general formula (S) have general formulae (SO-a) and/or (SO-b):

(SO-a) (SO-b), wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

Further preferred embodiments of the compound according to the invention of general formula (S) have general formulae (S1 -a), (S1 -a-1 ) and/or (S1 -a-2):

(S1 -a),

(S1 -a-2), wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof, preferably wherein R^{111 a} denotes OH, R^{111 b} and R^111c both denote H, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

Moreover, preferred embodiments of the compound according to the invention of general formula (S) have general formulae (S1 -b), (S1 -b-1 ) and/or (S1 -b-2):

(S1 -b),

-D-1 ),

(S1 -D-2), wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof, preferably wherein R^111a denotes OH, R^{111 b} denotes H, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

In addition, preferred embodiments of the compound according to the invention of general formula (S) have general formulae (S1 -c), (S1 -c-1 ) and/or (S1 -c-2):

(S1 -c),

-C-1 ),

(S1 -C-2), wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof, preferably wherein R^111a denotes OH, R^{111 b} denotes H, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

Yet further preferred embodiments of the compound according to the invention of general formula (S) have general formulae (S1 -d), (S1 -d-1 ) and/or (S1 -d-2):

(S1 -d),

-d-1 ),

(SI -d-2), wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof, preferably wherein R^111a denotes OH, R^{111 b} denotes H, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

Further preferred embodiments of the compound according to the invention of general formula (S) have general formulae (S1 -e), (S1 -e-1 ) and/or (S1 -e-2):

(S1 -e),

(S1 -e-2), wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof, preferably wherein R^111a denotes OH, R^{111 b} denotes H, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

Embodiments of the compound according to the invention general formulae (S1 -d), (S1 -d-1 ) and/or (S1 -d-2) are especially preferred.

In particularly preferred embodiments of the present invention radical R¹⁰¹ in the compound of general formula (S), (S1 -a), (S1 -a-1 ), (S1 -a-2), (S1 -b), (S1 -b-1 ), (S1 -b-2), (S1 -c), (S1 -c-1 ), (S1 -C-2), (S1 -d), (S1 -d-1 ), (S1 -d-2), (S1 -e), (S1 -e-1 ) and/or (S1 -e-2) represents F, CI, CF₃ or O-CH3, preferably F or CI, most preferably CI - preferably when R¹⁰³ is H and R¹⁰² represents H, F, CI, CF₃ or OCH₃, more preferably when R¹⁰³ is H and R¹⁰² represents H, F or CI, even more preferably when both R¹⁰² and R¹⁰³ denote H, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof. Particularly preferred are compounds according to the invention from the group

C1 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1 ,1 - dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide;

C2 N-[[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1 ,1 - dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide;

C3 N-[[2-(3,4-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-

(1 ,1 -dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide;

C4 1 -[[2-(3-Fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3-fluoro-

4-pyrrolidin-1 -yl-phenyl)-urea;

C5 1 -[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3-fluoro-

4-morpholin-4-yl-phenyl)-urea;

C6 1 -[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-

4-(3-hydroxy-azetidin-1 -yl)-phenyl]-urea;

C7 1 -[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(3- hydroxy-azetidin-1 -yl)-phenyl]-urea;

C8 1 -[[5-tert-Butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(3- hydroxy-azetidin-1 -yl)-phenyl]-urea;

C9 1 -[3-Fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-3-[[2-(3-fluorophenyl)-5-

(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

C10 1 -[[2-(3,4-Dif luoro-phenyl)-5-(trif luoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3- fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-urea;

C11 1 -[[5-tert-Butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(3- hydroxy-azetidin-1 -yl)-phenyl]-urea;

C12 1 -[3-Fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-3-[[2-(m-tolyl)-5-

(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; and

C13 1 -[[2-(3-Chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(3- hydroxy-azetidin-1 -yl)-phenyl]-urea; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.

Furthermore, preference may be given to compounds according to the invention that cause a 50% displacement of capsaicin, which is present at a concentration of 100 nM, in a FLIPR assay with CHO K1 cells which were transfected with the human VR1 gene at a concentration of less than 2 000 nM, preferably less than 1 000 nM, particularly preferably less than 300 nM, most particularly preferably less than 100 nM, even more preferably less than 75 nM, additionally preferably less than 50 nM, most preferably less than 10 nM.

In the process, the Ca²⁺ influx is quantified in the FLIPR assay with the aid of a Ca²⁺- sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described hereinafter.

The substituted compounds according to the invention and corresponding stereoisomers and also the respective corresponding acids, bases, salts and solvates are toxicologically safe and are therefore suitable as pharmaceutical active ingredients in pharmaceutical compositions.

The present invention therefore further relates to a pharmaceutical composition containing at least one compound according to the invention, in each case if appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or respectively in the form of a corresponding salt, or respectively in the form of a corresponding solvate, and also if appropriate one or more pharmaceutically compatible auxiliaries.

These pharmaceutical compositions according to the invention are suitable in particular for vanilloid receptor 1 -(VR1/TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, i.e. they exert an agonistic or antagonistic effect.

Likewise, the pharmaceutical compositions according to the invention are preferably suitable for the prophylaxis and/or treatment of disorders or diseases which are mediated, at least in part, by vanilloid receptors 1 .

The pharmaceutical composition according to the invention is suitable for administration to adults and children, including toddlers and babies.

The pharmaceutical composition according to the invention may be found as a liquid, semisolid or solid pharmaceutical form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and also be administered as much.

In addition to at least one substituted compound according to the invention, if appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemate or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio, or if appropriate in the form of a corresponding salt or respectively in the form of a corresponding solvate, the pharmaceutical composition according to the invention conventionally contains further physiologically compatible pharmaceutical auxiliaries which can for example be selected from the group consisting of excipients, fillers, solvents, diluents, surface-active substances, dyes, preservatives, blasting agents, slip additives, lubricants, aromas and binders.

The selection of the physiologically compatible auxiliaries and also the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneal^, intradermal^, intramuscularly, intranasally, buccally, rectally or locally, for example to infections of the skin, the mucous membranes and of the eyes. Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral application; solutions, suspensions, easily reconstitutable dry preparations and also sprays are preferably suitable for parenteral, topical and inhalative application. The substituted compounds according to the invention used in the pharmaceutical composition according to the invention in a repository in dissolved form or in a plaster, agents promoting skin penetration being added if appropriate, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the respective substituted compound according to the invention also in a delayed manner.

The pharmaceutical compositions according to the invention are prepared with the aid of conventional means, devices, methods and process known in the art, such as are described for example in„Remington's Pharmaceutical Sciences", A.R. Gennaro (Editor), 17^th edition, Mack Publishing Company, Easton, Pa, 1985, in particular in Part 8, Chapters 76 to 93. The corresponding description is introduced herewith by way of reference and forms part of the disclosure. The amount to be administered to the patient of the respective substituted compounds according to the invention of the above-indicated general formula I may vary and is for example dependent on the patient's weight or age and also on the type of application, the indication and the severity of the disorder. Conventionally 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg of at least one such compound according to the invention are applied per kg of the patient's body weight.

The pharmaceutical composition according to the invention is preferably suitable for the treatment and/or prophylaxis of one or more disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eating disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating movement activity; for anxiolysis; for local anaesthesia and/or for inhibiting undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 /TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Particularly preferably, the pharmaceutical composition according to the invention is suitable for the treatment and/or prophylaxis of one or more disorders and/or diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; migraine; depression; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; urinary incontinence; overactive bladder (OAB); medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably development of tolerance to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency.

Most particularly preferably, the pharmaceutical composition according to the invention is suitable for the treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain.

The present invention further relates to a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in vanilloid receptor 1 -(VR1 /TRPV1 ) regulation, preferably for use in vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation.

The present invention therefore further relates to a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by vanilloid receptors 1 .

In particular, the present invention therefore further relates to a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eating disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating movement activity; for anxiolysis; for local anaesthesia and/or for inhibiting undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 /TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Most particularly preferred is a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain.

The present invention further relates to the use of at least one substituted compound according to the present invention and also if appropriate to the use of at least one substituted compound according to the present invention of one or more pharmaceutically acceptable auxiliaries for the preparation of a pharmaceutical composition for vanilloid receptor 1 -(VR1 /TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, and, further for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by vanilloid receptors 1 , such as e.g. disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eating disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating movement activity; for anxiolysis; for local anaesthesia and/or for inhibiting undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 /TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Another aspect of the present invention is a method for vanilloid receptor 1 -(VR1/TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1 /TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, and, further, a method of treatment and/or prophylaxis of disorders and/or diseases, which are mediated, at least in part, by vanilloid receptors 1 , in a mammal, preferably of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eating disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating movement activity; for anxiolysis; for local anaesthesia and/or for inhibiting undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil, which comprises administering an effective amount of at least one substituted compound according to the invention to the mammal.

The effectiveness against pain can be shown, for example, in the Bennett or Chung model (Bennett, G.J. and Xie, Y.K., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 1988, 33(1 ), 87-107; Kim, S.H. and Chung, J.M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363), by tail flick experiments (e.g. according to D'Amour und Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941 )) or by the formalin test (e.g. according to D. Dubuisson et al., Pain 1977, 4, 161 -174).

The present invention further relates to processes for preparing substituted compounds according to the invention.

In particular, the compounds according to the present invention of can be prepared by a process according to which at least one compound of general formula (S- II),

(S-ll), in which R¹⁰¹ , R¹⁰², R¹⁰³ and R² have one of the foregoing meanings, is reacted in a reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, with a compound of general formula (S-lll) with D = OH or Hal,

(S-lll), in which Hal represents a halogen, preferably Br or CI, and R⁷, R⁹, R¹⁰⁹ and R¹¹⁰ each have one of the foregoing meanings and A denotes CH or C(CH₃), in a reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, to form a compound of general formula (S),

(S), in which A represents CH or C(CH₃) and R¹⁰¹ , R¹⁰², R¹⁰³ and R² as well as R⁷, R⁹, R¹⁰⁹ and R¹¹⁰ have one of the foregoing meanings; or in that at least one compound of general formula (S-ll),

(S-ll), in which R¹⁰¹ , R¹⁰², R¹⁰³ and R² have one of the foregoing meanings, is reacted to form a compound of general formula (S-IV),

(S-IV), in which R¹⁰¹ , R¹⁰², R¹⁰³ and R² have one of the foregoing meanings, in a reaction medium, in the presence of phenyl chloroformiate, if appropriate in the presence of at least one base and/or at least one coupling reagent, and said compound is if appropriate purified and/or isolated, and a compound of general formula (S-IV) is reacted with a compound of general formula (S-V),

(S-V), in which R⁷, R⁹, R¹⁰⁹ and R¹¹⁰ have one of the foregoing meanings, and A denotes N, in a reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, to form a compound of general formula (S),

(S), in which A represents N and R¹⁰¹ , R¹⁰², R¹⁰³ and R² as well as R⁷, R⁹, R¹⁰⁹ and R¹¹⁰ have one of the foregoing meanings.

The reaction of compounds of the above-indicated general formula (S-ll) with carboxylic acids of the above- indicated general formula (S-ll I), particularly with D = OH, to form compounds of the above-indicated general formula (S) is carried out preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1 ,2)-dichloroethane, dimethylformamide, dichloromethane and corresponding mixtures, if appropriate in the presence of at least one coupling reagent, preferably selected from the group consisting of l -benzotriazolyloxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'-(3- dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), diisopropylcarbodiimide, 1 ,1 '- carbonyldiimidazole (CDI), N-[(dimethylamino)-1 H-1 , 2, 3-triazolo[4, 5-b]pyridino-1 -yl- methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), 0-(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxybenzotriazole (HOBt) and 1 -hydroxy-7-azabenzotriazole (HOAt), if appropriate in the presence of at least one organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and diisopropylethylamine, preferably at temperatures of from -70 °C to 100 °C.

Alternatively, the reaction of compounds of the above-indicated general formulae (S-ll) with carboxylic acid halides of the above-indicated general formula (S - III) with D = Hal, in which Hal represents a halogen as the leaving group, preferably a chlorine or bromine atom, to form compounds of the above- indicated general formula (S) is carried out in a reaction medium preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, if appropriate in the presence of an organic or inorganic base, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine, at temperatures of from -70 °C to 100 °C.

The compounds of the above- indicated formulae (S-ll), (S-lll), (S-IV), and (S-V) are each commercially available and/or can be prepared using conventional processes known to the person skilled in the art. In particular, processes to prepare these compounds are e.g. disclosed in WO 2010/127855-A2, and WO 2010/127856-A2. The corresponding parts of these references are hereby deemed to be part of the disclosure.

All reactions which can be applied for synthesizing the compounds according to the present invention can each be carried out under the conventional conditions with which the person skilled in the art is familiar, for example with regard to pressure or the order in which the components are added. If appropriate, the person skilled in the art can determine the optimum procedure under the respective conditions by carrying out simple preliminary tests. The intermediate and end products obtained using the reactions described hereinbefore can each be purified and/or isolated, if desired and/or required, using conventional methods known to the person skilled in the art. Suitable purifying processes are for example extraction processes and chromatographic processes such as column chromatography or preparative chromatography. All of the process steps of the reaction sequences which can be applied for synthesizing the compounds according to the present invention as well as the respective purification and/or isolation of intermediate or end products, can be carried out partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.

The substituted compounds according to the invention can be isolated both in the form of their free bases, and also in the form of corresponding salts, in particular physiologically acceptable salts, and further in the form of a solvate such as hydrate.

The free bases of the respective substituted compounds according to the invention can be converted into the corresponding salts, preferably physiologically acceptable salts, for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, oc-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid and/or aspartic acid. The free bases of the respective inventive substituted compounds and of corresponding stereoisomers can likewise be converted into the corresponding physiologically acceptable salts using the free acid or a salt of a sugar additive, such as for example saccharin, cyclamate or acesulphame.

Accordingly, the substituted compounds according to the invention such as the free acids of the substituted compounds according to the invention can be converted into the corresponding physiologically acceptable salts by reaction with a suitable base. Examples include the alkali metal salts, alkaline earth metals salts or ammonium salts [NH_XR₄._X]⁺, in which x = 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Ci_-4 alkyl residue.

The substituted compounds according to the invention and of corresponding stereoisomers can if appropriate, like the corresponding acids, the corresponding bases or salts of these compounds, also be obtained in the form of their solvates, preferably in the form of their hydrates, using conventional methods known to the person skilled in the art.

If the substituted compounds according to the invention are obtained, after preparation thereof, in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and/or diastereomers, they can be separated and if appropriate isolated using conventional processes known to the person skilled in the art. Examples include chromatographic separating processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallisation processes. These processes allow individual enantiomers, for example diastereomeric salts formed by means of chiral stationary phase HPLC or by means of crystallisation with chiral acids, for example (+)- tartaric acid, (-)-tartaric acid or (+)-10-camphorsulphonic acid, to be separated from one another.

The chemicals and reaction components used in the reactions and schemes described below are available commercially or in each case can be prepared by conventional methods known to the person skilled in the art. General reaction scheme 1 (Scheme 1):

In step j01 an acid halide J-0, in which Hal preferably represents CI or Br, can be esterified using methanol to form the compound J-l by means of methods with which the person skilled in the art is familiar.

In step j02 the methyl pivalate J-l can be converted into an oxoalkylnitrile J-l I by means of methods known to the person skilled in the art, such as for example using acetonitrile CH₃- CN, if appropriate in the presence of a base.

In step j03 the compound J-ll can be converted into an amino-substituted pyrazolyl derivative J-lll by means of methods known to the person skilled in the art, such as for example using hydrazine hydrate, with cyclization.

In step j04 the amino compound J-lll can first be converted into a diazonium salt by means of methods known to the person skilled in the art, such as for example using nitrite, and the diazonium salt can be converted into a cyano-substituted pyrazolyl derivative J-IV with elimination of nitrogen using a cyanide, if appropriate in the presence of a coupling reagent.

In step j05 the compound J-IV can be substituted in the N position by means of methods known to the person skilled in the art, for example using a halide of part structure (SS2), i.e. Hal-(SS2), if appropriate in the presence of a base and/or a coupling reagent, wherein Hal is preferably CI, Br or I, or using a boronic acid B(OH)₂(SS2) or a corresponding boronic acid ester, if appropriate in the presence of a coupling reagent and/or a base and the compound J-V can in this way be obtained.

Alternatively, a second synthesis pathway, in which in step k01 an ester K-0 is first reduced to form the aldehyde K-l by means of methods known to the person skilled in the art, for example using suitable hydrogenation reagents such as metal hydrides, is suitable for preparing the compound J-V.

In step k02 the aldehyde K-l can then be reacted with a hydrazine K-V, which can be obtained in step k05, starting from the primary amine K-IV, by means of methods known to the person skilled in the art, to form the hydrazine K-ll by means of methods known to the person skilled in the art with elimination of water.

In step k03 the hydrazine K-ll can be halogenated, preferably chlorinated, by means of methods known to the person skilled in the art with the double bond intact, such as for example using a chlorination reagent such as NCS, and the compound K-lll can in this way be obtained.

In step k04 the hydrazonoyl halide K-lll can be converted into a cyano-substituted compound J-V by means of methods known to the person skilled in the art, such as for example using a halogen-substituted nitrile, with cyclisation.

In step j06 the compound J-V can be hydrogenated by means of methods known to the person skilled in the art, for example using a suitable catalyst such as palladium/activated carbon or using suitable hydrogenation reagents, and the compound (S-ll) can in this way be obtained.

In step j07 the compound (S-ll) can be converted into the compound (S-IV) by means of methods known to the person skilled in the art, such as for example using phenyl chloroformate, if appropriate in the presence of a coupling reagent and/or a base. In addition to the methods disclosed in the present document for preparing unsymmetrical ureas using phenyl chloroformate, there are further processes with which the person skilled in the art is familiar, based on the use of activated carbonic acid derivatives or isocyanates, if appropriate.

In step j08 the amine (S-V) can be converted into the urea compound (S) (wherein A = N). This can be achieved by reaction with (S-IV) by means of methods with which the person skilled in the art is familiar, if appropriate in the presence of a base.

In step j09 the amine (S-ll) can be converted into the amide (S) (wherein A = CH or C(CH₃)). This can for example be achieved by reaction with an acid halide, preferably a chloride of formula (S-lll) with D = Hal by means of methods with which the person skilled in the art is familiar, if appropriate in the presence of a base or by reaction with an acid of formula (S-lll) with D = OH, if appropriate in the presence of a suitable coupling reagent, for example HATU or CDI, if appropriate with the addition of a base. Further, the amine (S-ll) may be converted into the amide (S) (wherein A = CH or C(CH₃)) by reaction of a compound (S-llla) by means of methods with which the person skilled in the art is familiar, if appropriate in the presence of a base.

The compounds according to general formula (S), wherein A = N, may be further prepared by a reaction sequence according to general reaction scheme 2. eneral reaction scheme 2 (scheme 2)

wherein A = N

In step v1 the compound (S-V) can be converted into the compound (S-Va) by means of methods known to the person skilled in the art, such as for example using phenyl chloroformate, if appropriate in the presence of a coupling reagent and/or a base. In addition to the methods disclosed in the present document for preparing unsymmetrical ureas using phenyl chloroformate, there are further processes with which the person skilled in the art is familiar, based on the use of activated carbonic acid derivatives or isocyanates, if appropriate.

In step v2 the amine (S-ll) can be converted into the urea compound (S) (wherein A = N). This can be achieved by reaction with (S-Va) by means of methods with which the person skilled in the art is familiar, if appropriate in the presence of a base.

The methods with which the person skilled in the art is familiar for carrying out the reaction steps j01 to j09 and also k01 to k05 as well as v1 and v2 may be inferred from the standard works on organic chemistry such as, for example, J. March, Advanced Organic Chemistry, Wiley & Sons, 6th edition, 2007; F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Parts A and B, Springer, 5th edition, 2007; team of authors, Compendium of Organic Synthetic Methods, Wiley & Sons. In addition, further methods and also literature references can be issued by the common databases such as, for example, the Reaxys® database of Elsevier, Amsterdam, NL or the SciFinder® database of the American Chemical Society, Washington, US. EXAMPLES

The following examples further illustrate the invention but are not to be construed as limiting its scope.

The indication ..equivalents" ("eq." or "eq" or "equiv." or "equiv") means molar equivalents, „RT" or "rt" means room temperature (23 ± 7 °C), „M" are indications of concentration in mol/l, „aq." means aqueous, „sat." means saturated, „sol." means solution, "cone." means concentrated.

Further abbreviations: d days

BH₃ ^«S(CH₃)2 borane-methyl sulfide complex (BH₃-DMS)

brine saturated aqueous sodium chloride solution

CC column chromatography on silica gel

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-en

DCM dichloromethane

DMF N,N-dimethylformamide

EDCI N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride

ether diethyl ether

EtOAc ethyl acetate

h hour(s)

GC gas chromatography

HBTU 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HOBt N-hydroxybenzotriazole

H₂0 water

m/z mass-to-charge ratio

MeOH methanol

min or min. minutes

MS mass spectrometry

Pd / C palladium on charcoal

PE petroleum ether

TBTU 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

TLC thin layer chromatography

THF tetrahydrofuran

v/v volume to volume

w/w weight in weight The yields of the compounds prepared were not optimized. All temperatures are uncorrected.

All starting materials which are not explicitly described were either commercially available (the details of suppliers such as for example Acros, Avocado, Aldrich, Apollo, Bachem, Fluka, FluoroChem, Lancaster, Manchester Organics, MatrixScientific, Maybridge, Merck, Rovathin, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington DC, US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington DC, US, repspectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

The stationary phase used for the column chromatography was silica gel 60 (0.04 - 0.063 mm) from E. Merck, Darmstadt.

The mixing ratios of solvents or eluents for chromatography are specified in v/v.

All the intermediate products and exemplary compounds were analytically characterized by means of ¹ H-NMR spectroscopy. In addition, mass spectrometry tests (MS, m/z for [M+H]⁺) were carried out for all the exemplary compounds and selected intermediate products.

Synthesis of selected intermediate products:

1. Synthesis of (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (steps i01 -i06)

Step j01 : Pivaloyl chloride (J-0) (1 eq., 60 g) was added dropwise to a solution of methanol (120 mL) within 30 min at 0 °C and the mixture was stirred for 1 h at room temperature. After the addition of water (120 mL), the separated organic phase was washed with water (120 mL), dried over sodium sulphate and codistilled with dichloromethane (150 mL). The liquid product J-l was able to be obtained at 99 % purity (57 g).

Step j02: NaH (50 % in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 % yield) was able to be obtained as a solid brown substance.

Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-ll I ) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n- hexane (200 mL).

Step j04: 3-Tert-butyl-1 H-pyrazol-5-amine (J-lll) (1 equivalents, 40 g) was dissolved in diluted HCI (120 mL of HCI in 120 mL of water) and mixed dropwise with NaN0₂ (1 .03 equivalents, 25 g in 100 mL) at 0 - 5 °C over a period of 30 min. After stirring for 30 minutes, the reaction mixture was neutralised with Na₂C0₃. A diazonium salt obtained by reaction of KCN (2.4 equivalents, 48 g), water (120 mL) and CuCN (1 .12 equivalents, 31 g) was added dropwise to the reaction mixture within 30 min and the mixture was stirred for a further 30 min at 75 °C. After complete reaction, the reaction mixture was extracted with ethyl acetate (3 x 500 mL), the combined organic phases were dried over sodium sulphate and the solvent was removed under vacuum. The purification (silica gel: 100-200 mesh, eluent: 20 % ethyl acetate/n-hexane) of the residue by column chromatography produced a white solid (J-IV) (6.5 g, 15 %).

Step j05 (method 1):

3-tert.-butyl-1 H-pyrazol-5-carbonitrile (J-IV) (10 mmol) was added to a suspension of NaH (60 %) (12.5 mmol) in dimethylformamide (20 mL) at room temperature while stirring. After stirring for 15 minutes, 1 -iodo-3-chlorobenzene (37.5 mmol) was added dropwise to this reaction mixture at room temperature. After stirring for 30 min at 100 °C, the reaction mixture was mixed with water (150 mL) and extracted with dichloromethane (3 x 75 mL). The combined organic extracts were washed with water (100 mL) and sat. NaCI solution (100 mL) and dried over magnesium sulphate. After removal of the solvent under vacuum, the residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: various mixtures of ethyl acetate and cyclohexane as the mobile solvent) and the product J-V was obtained.

Step j05 [method 2):

A mixture of 3-tert-butyl-1 H-pyrazol-5-carbonitrile (J-IV) (10 mmol), a boronic acid B(OH)₂(3- chlorophenyl) or a corresponding boronic acid ester (20 mmol) and copper (II) acetate (15 mmol) is placed in dichloromethane (200 mL), mixed with pyridine (20 mmol) while stirring at room temperature and the mixture is stirred for 16 h. After removal of the solvent under vacuum, the residue obtained is purified by column chromatography (silica gel: 100-200 mesh, eluent: various mixtures of ethyl acetate and cyclohexane as the mobile solvent) and the product J-V is in this way obtained.

Step j06: (method 1):

J-V was dissolved together with palladium on carbon (10 %, 500 mg) and concentrated HCI (3 mL) in methanol (30 mL) and exposed to a hydrogen atmosphere for 6 h at room temperature. The reaction mixture was filtered over celite and the filtrate was concentrated under vacuum. The residue was purified by means of flash chromatography (silica gel: 100- 200 mesh, eluent: ethyl acetate) and the product (U-ll) was in this way obtained.

Step j06: (method 2):

J-V was dissolved in tetrahydrofuran (10 mL) and BH₃ ^»S(CH₃)2 (2.0 M in tetrahydrofuran, 3 mL, 3 equivalents) was added thereto. The reaction mixture was heated to reflux for 8 h, aq. 2 N HCI (2 N) was added thereto and the reaction mixture was refluxed for a further 30 minutes. The reaction mixture was mixed with aq. NaOH solution (2N) and washed with ethyl acetate. The combined organic phases were washed with sat. aq. NaCI solution and dried over magnesium sulphate. The solvent is removed under vacuum and the residue is purified by column chromatography (silica gel: 100-200 mesh, eluent: various mixtures of dichloromethane and methanol as the mobile solvent) and the product (U-ll) is in this way obtained.

The following further intermediate products were/can be synthesised in a similar manner using the process described hereinbefore under 1.:

(3-tert-butyl-1 -(3-chloro-4-fluorophenyl)-1 H-pyrazol-5-yl)methanamine

(3-tert-butyl-1 -(3,4-difluorophenyl)-1 H-pyrazol-5-yl)methanamine

2. Synthesis of 1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl-methanamine (steps k01 -k05 and i06)

Step k01 : LAIH (lithium aluminium hydride) (0.25 equivalents, 0.7g) was dissolved in dry diethyl ether (30 mL) under a protective gas atmosphere and stirred for 2 h at room temperature. The suspension obtained was taken up in diethyl ether (20 mL). Ethyl-2,2,2- trifluoroacetate (K-0) (1 equivalent, 10 g) was taken up in dry diethyl ether (20 mL) and added dropwise to the suspension at -78 °C over a period of 1 h. The mixture was then the stirred for a further 2 h at -78 °C. ethanol (95 %) (2.5 mL) was then added dropwise, the reaction mixture was heated to room temperature and placed on iced water (30 mL) with concentrated H₂S0₄ (7.5 mL). The organic phase was separated and concentrated under vacuum and the reaction product K-l was immediately introduced into the next reaction step k02.

Step k05: 3-chloroaniline (K-IV) (1 equivalent, 50 g) was dissolved at -5 to 0 °C in concentrated HCI (300 mL) and stirred for 10 min. A mixture of NaN0₂ (1 .2 equivalents, 32.4 g), water (30 mL), SnCI₂-2H₂0 (2.2 equivalents, 70.6 g) and concentrated HCI (100 mL) was added dropwise over a period of 3 h while maintaining the temperature. After stirring for a further 2 h at -5 to 0 °C, the reaction mixture was set to pH 9 using NaOH solution and extracted with ethyl acetate (250 mL). The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. The purification by column chromatography (silica gel: 100-200 mesh, eluent: 8 % ethyl acetate/n-hexane) produced 40 g (72 %) of (3-chlorophenyl)hydrazine (K-IV) as a brown oil. Step k02: The aldehyde (K-l) (2 equivalents, 300 mL) obtained from k01 and (3- chlorophenyl)hydrazine (K-IV) (1 equivalent, 20 g) were placed in ethanol (200 mL) and refluxed for 5 h. The solvent was removed under vacuum, the residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) and the product (25 g, 72 %) K-ll was obtained as a brown oil.

Step k03: The hydrazine K-ll (1 equivalent, 25 g) was dissolved in dimethylformamide (125 mL). N-chlorosuccinimide (1 .3 equivalents, 19.5 g) was added portionwise at room temperature within 15 min and the mixture was stirred for 3 h. The dimethylformamide was removed by distillation and the residue was taken up in ethyl acetate. The ethyl acetate was removed under vacuum, the residue obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) and the product K-lll (26.5 g, 92 %) was obtained as a pink-coloured oil.

Step k04: At room temperature the hydrazonoyl chloride K-lll (1 equivalent, 10 g) was taken up in toluene (150 mL) and mixed with 2-chloroacrylonitrile (2 equivalents, 6.1 mL) and triethylamine (2 equivalents, 10.7 mL). This reaction mixture was stirred for 20 h at 80 °C. The mixture was then diluted with water (200 mL) and the phases were separated. The organic phase was dried over magnesium sulphate and the solvent was removed under vacuum. The residue was purified by means of column chromatography (silica gel: 100-200 mesh, eluent: 5 % ethyl acetate/n-hexane) and the product (5.5 g, 52 %) was obtained as a white solid J-V.

Step j06 {method 3):

The carbonitrile J-V (1 equivalent, 1 g) was dissolved in methanolic ammonia solution (150 mL, 1 :1 ) and hydrogenated in an H-cube (10 bar, 80 °C, 1 mL/min, 0.25 mol/L). After removal of the solvent under vacuum, (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine (II) was able to be obtained as a white solid (0.92 g, 91 %).

The following further intermediate products were/can be synthesized in a similar manner using the process described hereinbefore under 2.:

(1 -(3-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine

(1 -(3,4-difluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine

(1 -(3-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine 3. Preparation of methyl phenyl (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5- vDmethylcarbamate

Step a: To a solution of (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (5 g, 18 mmol) in dimethylformamide (25 mL), potassium carbonate (9.16 g, 66 mmol, 3.5 eq) was added and cooled the contents to 0°C. Then phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1 .1 equivalents) was added dropwise for 15 minutes and the overall reaction mixture was stirred for another 15 minutes at 0 °C. Progress of the reaction was monitored by TLC (20 % ethyl acetate-n-hexane). On completion of the reaction, reaction contents were filtered, filtrate was diluted with cold water (100 mL) and the product extracted with ethyl acetate (3 ^χ 25 mL). Combined organic layer was washed with brine solution (100 mL), dried over sodium sulphate and concentrated under reduced pressure. Crude obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: 10% ethyl acetate in n-hexane) to yield the required product as a white solid (3.2 g, 45 %).

4. Preparation of (1 -(3-chlorophenyl)-3-cvclopropyl-1 H-pyrazol-5-yl)methanamine hydrochloride

Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 ^χ 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %).

Step b: To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 % solution in water, 0.4 mL, 0.651 mmol, 1 .2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 %).

Step c: A mixture of step-b product (1 .1 g, 5.164 mmol, 1 equivalent) and 3-chlorophenyl hydrazine hydrochloride (1 .84 g, 10.27 mmol, 2 equivalents) was taken in acetic acid (20 mL), 2-methoxy ethanol (10 mL) and the reaction mixture was heated at 105 °C for 3 h. Solvent was evaporated and the residue was extracted with ethyl acetate (60 mL). The organic layer washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography (silica gel: 100-200 mesh; eluent: ethyl acetate-petroleum ether (4:96)) afforded a pale brown semi solid (1 .15g, 77 %).

Step d: To a solution of step-c product (2.5 g, 8.62 mmol, 1 eq) in tetrahydrofuran (15 mL) - methanol (9 mL) - water (3 mL), lithium hydroxide (1 .08 g, 25.71 mmol, 3 equivalents) was added at 0 °C and the reaction mixture was stirred for 2 h at room temperature. Solvent was evaporated and pH of the residue was adjusted to ~3 sing 2 N aqueous HCI (1 .2 mL). The acidic aqueous layer was extracted with ethyl acetate (2 ^χ 60 mL); the combined organic layer washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give an off white solid (1 .4 g, 62 %).

Step e: To a solution of step-d product (1 .4 g, 5.34 mmol, 1 equivalent) in 1 ,4-dioxane (30 mL), pyridine (0.25 mL, 3.2 mmol, 0.6 equivalents) and di-tert-butyl dicarbonate (1 .4 mL, 6.37 mmol, 1 .2 equivalents) were added at 0 °C and the resulting mixture was stirred for 30 minutes at the same temperature. Ammonium bicarbonate (0.84 g, 10.63 mmol, 2 equivalents) was added at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (2 ^χ 30 mL). The organic layer was washed with 2N HCI (20 mL), water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography (silica gel: 100-200 mesh; eluent: ethyl acetate-petroleum ether (16:84)) gave a white solid (1 g, 72 %).

Step f: To a solution of step-e product (2 g, 7.66 mmol, 1 equivalent) in tetrahydrofuran (25 mL), BH₃.DMS (1 .44 mL, 15.32 mmol, 2 equivalents) was added at 0 °C and the reaction mixture was heated at 70°C for 3 h. The reaction mixture was cooled to 0 °C and methanol (15 mL) was added and reaction mixture heated at reflux for 1 h. The reaction mixture was brought to room temperature and solvent was evaporated under reduced pressure. The residue was dissolved in ether (15 mL), cooled to 0 °C and a solution of HCI in 1 ,4-dioxane (3 mL) was added (pH of the reaction mixture ~4). The precipitated solid was filtered and washed with diethyl ether (5 mL, thrice) to give the hydrochloride salt compound as a white solid (600 mg, 28 %). Synthesis of exemplary compounds:

1. Preparation of amides (A = CH or C{CH?))

General directions for reacting amines of general formula (S-ll) with carboxylic acids of general formula or carboxylic acid derivatives of general formula (S-lll) to form compounds of general formula (S), wherein A = CH or C(CH₃) (amides), as in scheme 1 (step j09).

1. 1 Method A:

The acid of general formula (S-lll) (1 equivalent), the amine of general formula (S-ll) (1 .2 equivalents) and EDCI (1 .2 equivalents) are stirred in DMF (10 mmol of acid/20 ml_) for 12 hours at RT and water is subsequently added thereto. The reaction mixture is repeatedly extracted with EtOAc, the aqueous phase is saturated with NaCI and subsequently reextracted with EtOAc. The combined organic phases are washed with 1 N HCI and brine, dried over magnesium sulphate and the solvent is removed under vacuum. The residue is purified by means of flash chromatography (Si0₂, EtOAc/hexane in different ratios such as 1 :2) and the product (S) is in this way obtained.

1.2 Method B:

The acid of general formula (S-lll) (1 equivalent) and the amine of general formulae (S-ll) (1 .1 equivalents) are dissolved in dichloromethane (1 mmol of acid in 6 ml_) and mixed with EDCI (1 .5 equivalents), HOBt (1 .4 equivalents) and triethylamine (3 equivalents) at 0 °C. The reaction mixture is stirred for 20 h at room temperature and the crude product is purified by means of column chromatography (Si0₂, n-hexane/EtOAc in different ratios such as 2:1 ) and (S) is in this way obtained.

1.3 Method C:

The acid of general formula (S-lll) (1 equivalent) is first mixed with a chlorinating agent, preferably with thionyl chloride and the mixture obtained in this way is boiled under reflux and the acid (S-lll) is in this way converted into the corresponding acid chloride. The amine of general formulae (S-ll) (1 .1 equivalents) is dissolved in dichloromethane (1 mmol of acid in 6 ml_) and mixed with triethylamine (3 equivalents) at 0 °C. The reaction mixture is stirred for 20 h at room temperature and the crude product is purified by means of column chromatography (Si0₂, n-hexane/EtOAc in different ratios such as 2:1 ) and (S) is in this way obtained.

1.4 Method D:

The phenyl ester (S-llla) (1 equivalent) and the corresponding amine (S-ll) (1 .1 equivalents) are dissolved in THF (10 mmol of the reaction mixture in 120 mL) and stirred for 16 h at room temperature after addition of DBU (1 .5 equivalents). After removal of the solvent under vacuum, the residue obtained is purified by means of flash chromatography (Si0₂, EtOAc/hexane in different ratios such as 1 :1 ) and (S) is in this way obtained.

The exemplary compounds C1 -C3 were obtained using one of the methods described hereinbefore.

2. Preparation of ureas (A = N)

General directions for reacting amines of general formula (S-ll) or (S-V) with phenyl chloroformate to form compounds of formula (S-IV) or (S-Va) (scheme 1 , step j07 and scheme 2, step v1 ) and subsequent reaction of compounds of formula (S-IV) with amines of general formula (S-V) (scheme 1 , step j08) or of compounds of formula (S-Va) with amines of general formula (S-ll) (scheme 2, step v2) to form compounds of general formula (S), wherein A = N:

Step j07/step v1 : The amine of general formula (S-ll) or (S-V) (1 equivalent) is placed in dichloromethane (10 mmol of amine in 70 mL) and phenyl chloroformate (1 .1 equivalents) is added thereto at room temperature and the mixture is stirred for 30 min. After removal of the solvent under vacuum, the residue is purified by means of flash chromatography (Si0₂, diethyl ether/hexane in different ratios such as 1 :2) and (S-IV) or (S-Va) is in this way obtained.

Step j08/step v2: The carbamic acid phenyl ester (S-IV) or (S-Va) obtained (1 equivalent) and the corresponding amine (S-V) or (S-ll) (1 .1 equivalents) are dissolved in THF (10 mmol of the reaction mixture in 120 mL) and stirred for 16 h at room temperature after addition of DBU (1 .5 equivalents). After removal of the solvent under vacuum, the residue obtained is purified by means of flash chromatography (Si0₂, EtOAc/hexane in different ratios such as 1 :1 ) and (S) is in this way obtained. The exemplary compounds C4-C13 were obtained using one of the methods described hereinbefore.

Detailed synthesis of selected exemplary compounds

Synthesis of example C1 : N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]- methyl]-2-[4-(1 ,1 -dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide

Stepl : Under a nitrogen atmosphere, potassium tert. butyloxide (8.2 g, 73 mmol) was slurried in DMF and cooled to -45 °C. A mixture of o-fluoronitrobenzene (3.88 mL, 36.6 mmol) and ethyl-2-chloropropionate (4.66 mL, 36.6 mmol) was added while maintaining this temperature and the mixture was stirred for 15 min. The reaction mixture was adjusted with HCI (16%) to pH = 4 and diluted with water (250 mL). The aqueous phase was repeatedly extracted with ethyl acetate (3 x 100 mL), the combined organic phases are washed with water (3 x 100 mL) and brine (1 x 100 mL) and dried over magnesium sulfate. After concentration in vacuo ethyl 2-(3-fluoro-4-nitrophenyl)propanoate was obtained (8.47 g, 96 %). Step 2: A suspension of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate (8.3 g, 34,41 mmol) and Pd/C (10 % Pd) in EtOH (170 mL) was hydrogenated for 1 h under a hydrogen atmosphere (2.5 bar, 22 °C). The suspension was removed by filtration, concentrated under vacuum and purified by column chromatography (Si0₂, ethyl acetate/hexane 1 :5) to obtain ethyl 2-(4- amino-3-fluorophenyl)propanoate (6.4 g, 77 %).

Step3: Chloropropanesulfonyl chloride (0.576 mL, 4.73 mmol) was added to a solution of ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 4.735 mmol) and pyridine (0.382 mL, 4.735 mmol) in DCM (18 mL) at 0 °C. The reaction mixture was stirred for 1 h, after it was partitioned between DCM (10 mL) and 1 N hydrochloric acid (10 mL). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated in vacuo to afford ethyl 2-(4-(3-chloropropylsulfonamido)-3-fluorophenyl)propanoate as an oil (1 .5 g).

Step4: Potassium carbonate (881 mg, 6.39 mmol) and ethyl 2-(4-(3- chloropropylsulfonamido)-3-fluorophenyl)propanoate (1 .5 g, 4.264 mmol) were dissolved in DMF (9 mL) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 24 h after which time it was partitioned between diethyl ether (50 mL) and water (50 mL). The organic phases were washed with 1 N HCI (30 mL) and water (30 mL) and dried over magnesium sulfate. After filtration and concentration in vacuo 2-[4-(1 ,1 -dioxo- [1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid ethyl ester was obtained (598 mg, 44 %).

Step5: 2-[4-(1 ,1 -Dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid ethyl ester (448 mg, 1 .42 mmol) was dissolved in a 2:1 mix of THF/water (2.8 mL + 1 .4 mL) and stirred for 15 min. 3 equivalents of LiOH (98 mg, 4.26 mmol), which is also dissolved in a 2:1 THF/water mix (1 mL + 0.5 mL), are added to this solution. The reaction mixture was stirred overnight under reflux. While cooling, the aqueous phase is set to pH 1 using 4 N aq. HCI and repeatedly extracted with ethyl acetate (3 x 10 mL). The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to afford 2-[4-(1 ,1 -dioxo- [1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (350 mg, 86 %).

Step 6: To a solutionof 2-[4-(1 ,1 -Dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (50 mg, 0.174 mmol) in THF(1 .3 mL) wasadded 1 -hydroxybenzotriazole (23 mg, 0.174 mmol), 0-(1 H-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate (56 mg, 0.174 mmol), n-ethyldiisopropylamine (0.059 mL, 0.348 mmol) and (1 -(3-chlorophenyl)-3- (trif luoromethyl)- 1 H-pyrazol-5-yl)methanamine (47 mg, 0.174 mmol). Thereaction mixture wasstirredfor 48 h at roomtemperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate/cyclohexan (2:1 )) to give pure N- [[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1 ,1 -dioxo- [1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide (example compound C1 ) (68 mg, 72 %).

Synthesis of example C2: N-[[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]- methyl]-2-[4-(1 ,1 -dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamid

Steps 1-5: as described for example compound C1

Step 6: To a solution of 2-[4-(1 ,1 -dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (50 mg, 0.174 mmol) in THF(1 .3 ml_) was added 1 -hydroxybenzotriazole (23 mg, 0.174 mmol), 0-(1 H-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate (56 mg, 0.174 mmol), n-ethyldiisopropylamine (0.059 ml_, 0.348 mmol) and (3-tert-butyl-1 -(3-chloro-4- fluorophenyl)-1 H-pyrazol-5-yl)methanamine (81 mg, 0.174 mmol). The reaction mixture was stirredfor 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate/cyclohexan (2:1 )) to give pure example compound C2 (75 mg, 78 %).

Exemplary compound 3 was prepared analogously according to example C1 . Synthesis of example C6: 1 -[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]- methyl]-3-[3-fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-urea

Step 1 : To a stirred solution of 1 ,2-difluoro-4-nitrobenzene (200mg, 1 .25 mmol, 1 eq) in THF (5 mL) was added TEA (0.26 mL, 1 .88 mmol, 1 .5 eq) and 3-hydroxyazetidine.HCI (205 mg, 1 .88 mmol, 1 .5 eq) at RT and refluxed for 24h. THF was evaporated and the residue was washed with water (10 mL) to obtain 1 -(2-fluoro-4-nitrophenyl)azetidin-3-ol (200 mg, 75%) as a solid (TLC: EtOAc/PE (3:7), R_f: 0.30).

Step 2: To a stirred solution of 1 -(2-fluoro-4-nitrophenyl)azetidin-3-ol (160 mg, 0.75 mmol, 1 .0 eq) in ethanol (10 mL) was added 10% Pd-C (20 mg) and stirred under H₂ gas balloon at RT for 5 h. The reaction mixture was passed through celite and concentrated to obtain 1 -(4- amino-2-fluorophenyl)azetidin-3-ol (1 10 mg, 80.0%, viscous oil) (TLC: EtOAc/PE (1 :1 ), R_f: 0.1 ).

Step 3: To a stirred solution of 1 -(4-amino-2-fluorophenyl)azetidin-3-ol (1 .8 g, 9.94 mmol, 1 .0 eq) in acetone (50 mL) was added pyridine (1 .57 g, 19.87 mmol, 2.0 eq) and phenyl chloroformate (1 .71 g, 10.89 mmol, 1 .1 eq) and stirred at RT for 2h. The reaction mixture was evaporated, diluted with EtOAc (100 mL), washed with water (100 mL) followed by brine and evaporated. The residue obtained was purified by CC (eluent: EtOAc/PE (1 :4)) to obtain phenyl 3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenylcarbamate (2.3 g, 76%, brown solid) (TLC: EtOAc/PE (1 :1 ), R_f: 0.45).

Step 4: To a stirred solution of (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine hydrochloride (103 mg, 0.33 mmol, 1 .0 eq) in DCM (10 mL) was added TEA (0.10 mL, 0.66 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1 - yl)phenylcarbamate (100 mg, 0.33mmol, 1 .0 eq) at RT and stirred for 48 h. The reaction mixture was diluted with water (5 ml_) and extracted with DCM (20 ml_), washed with brine, dried over Na₂S0₄ and evaporated. The residue was purified by CC using 1 .0% MeOH in EtOAc as eluent to obtain 1 -((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methyl)- 3-(3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)urea (100 mg; 63%, light brown solid) (TLC: EtOAc/PE 3:2; R_f: 0.3).

Synthesis of example C7: 1 -[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3- fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-urea

Steps 1-3: as described for example compound C6

Step 4: To a stirred solution of (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (106 mg, 0.398 mmol, 1 .0 eq) in acetonitrile (9 ml_) was added TEA (0.22 ml_, 1 .6 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenylcarbamate (122 mg, 0.406 mmol, 1 .02 eq) and the mixture was stirred at reflux for 16 h. The reaction mixture was evaporated and the residue was purified by CC (EtOAc/n-hexane 2:1 as eluent) to obtain 1 - ((3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1 - yl)phenyl)urea (183 mg; 97%).

Exemplary compounds C8 - C9 were prepared in a similar manner according to C6. Synthesis of example C10: 1 -((1 -(3,4-difluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)urea

Step 1 :To a stirred solution of ((1 -(3,4-difluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine hydrochloride (75 mg, 0.239 mmol, 1 .0 eq) in acetonitrile (5.5 mL) was added TEA (0.13 mL, 0.96 mmol, 4.0 eq.) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1 - yl)phenylcarbamate (73 mg, 0.244 mmol, 1 .02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column

chromatography (EtOAc/cyclohexane (4:1 ) as eluent) to get 1 -((1 -(3,4-difluorophenyl)-3- (trifluoromethyl)-1 H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)urea (102mg, 88 %).

Synthesis of example C11 : 1 -((3-tert-butyl-1 -(3,4-difluorophenyl)-1 H-pyrazol-5-yl)methyl)-3- (3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)urea

Step 1 :To a stirred solution of (3-tert-butyl-1 -(3,4-difluorophenyl)-1 H-pyrazol-5- yl)methanamine hydrochloride (85 mg, 0.282 mmol, 1 .0 eq) in acetonitrile (6.7 mL) was added TEA (0.16 mL, 1 .1 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1 - yl)phenylcarbamate (86 mg, 0.287 mmol, 1 .02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column

chromatography (EtOAc/cyclohexane (1 :2) as eluent) to get 1 -((3-tert-butyl-1 -(3,4- difluorophenyl)-1 H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)urea (62

Synthesis of example C12: 1 -(3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)-3-((1 -m-tolyl-3- (trifluoromethyl)-1 H-pyrazol-5-yl)methyl)urea

Step 1 :To a stirred solution of (1 -m-tolyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine hydrochloride (75 mg, 0.257 mmol, 1 .0 eq) in acetonitrile (6 mL) was added TEA (0.14 mL, 1 .0 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenylcarbamate (78 mg, 0.262 mmol, 1 .02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography

(EtOAc/cyclohexane (4:1 ) as eluent) to get 1 -(3-fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)-3- ((1 -m-tolyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methyl)urea (71 mg, 71 %).

Synthesis of C13: 1 -((3-cyclopropyl-1 -(3,4-difluorophenyl)-1 H-pyrazol-5-yl)methyl)-3-(3- fluoro-4-(3-hydroxyazetidin-1 -yl)phenyl)urea

Step 1 :To a stirred solution of (1 -(3-chlorophenyl)-3-cyclopropyl-1 H-pyrazol-5- yl)methanamine hydrochloride (101 mg, 0.408 mmol, 1 .0 eq) in acetonitrile (9.5 mL) was added TEA (0.23 mL, 1 .6 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1 - yl)phenylcarbamate (124 mg, 0.416 mmol, 1 .02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column

chromatography (EtOAc/cyclohexane (1 :1 ) as eluent). The collected fractions were evaporated, the residue was treated with ether and filtered. The filter cake was dried to give 1 -((3-cyclopropyl-1 -(3,4-difluorophenyl)-1 H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3- hydroxyazetidin-1 -yl)phenyl)urea.

Mass spectrometric data are cited hereinafter by way of example for the following exemplary compounds (Table 1 ):

Table 1

Exemplary [M+H]

compound

C1 545.2

C2 551 .3

C3 547.1

C4 466.2

C5 498.0

C6 484.0

C7 472.1

C8 489.0

C9 468.1

C10 486.1

C11 474.2

C12 464.2

C13 456.2

Pharmacological methods

I. Functional testing carried out on the vanilloid receptor 1 (VRI/TRPV1 receptor)

The agonistic or antagonistic effect of the substances to be tested on the rat-species vanilloid receptor 1 (VR1/TRPV1 ) can be determined using the following assay. In this assay, the influx of Ca²⁺ through the receptor channel is quantified with the aid of a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).

Method:

Complete medium: 50 ml_ HAMS F12 nutrient mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) with 10 % by volume of FCS (foetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heat-inactivated); 2mM L-glutamine (Sigma, Munich, Germany); 1 % by weight of AA solution (antibiotic/antimyotic solution, PAA, Pasching, Austria) and 25 ng/mL NGF medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany)

Cell culture plate: Poly-D-lysine-coated, black 96-well plates having a clear base (96-well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Karlsruhe, Germany), the laminin being diluted with PBS (Ca-Mg- free PBS, Gibco Invitrogen GmbH, Karlsruhe, Germany) to a concentration of 100 μg/mL. Aliquots having a laminin concentration of 100 μg mL are removed and stored at -20 °C. The aliquots are diluted with PBS in a ratio of 1 : 10 to 10 μg mL of laminin and respectively 50 μ\- of the solution are pipetted into a recess in the cell culture plate. The cell culture plates are incubated for at least two hours at 37 °C, the excess solution is removed by suction and the recesses are each washed twice with PBS. The coated cell culture plates are stored with excess PBS which is not removed until just before the feeding of the cells.

Preparation of the cells:

The vertebral column is removed from decapitated rats and placed immediately into cold HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany), i.e. buffer located in an ice bath, mixed with 1 % by volume (per cent by volume) of an AA solution (antibiotic/antimyotic solution, PAA, Pasching, Austria). The vertebral column is cut longitudinally and removed together with fasciae from the vertebral canal. Subsequently, the dorsal root ganglia (DRG) are removed and again stored in cold HBSS buffer mixed with 1 % by volume of an AA solution. The DRG, from which all blood remnants and spinal nerves have been removed, are transferred in each case to 500 μΙ_ of cold type 2 collagenase (PAA, Pasching, Austria) and incubated for 35 minutes at 37 °C. After the addition of 2.5 % by volume of trypsin (PAA, Pasching, Austria), incubation is continued for 10 minutes at 37 °C. After complete incubation, the enzyme solution is carefully pipetted off and 500 μΙ_ of complete medium are added to each of the remaining DRG. The DRG are respectively suspended several times, drawn through cannulae No. 1 , No. 12 and No. 1 6 using a syringe and transferred to a 50 ml_ Falcon tube which is filled up to 15 ml_ with complete medium. The contents of each Falcon tube are respectively filtered through a 70 μηι Falcon filter element and centrifuged for 1 0 minutes at 1 ,200 rpm and room temperature. The resulting pellet is respectively taken up in 250 μΙ_ of complete medium and the cell count is determined.

The number of cells in the suspension is set to 3 x 1 0⁵ per ml_ and 1 50 μΙ_ of this suspension are in each case introduced into a recess in the cell culture plates coated as described hereinbefore. In the incubator the plates are left for two to three days at 37 °C, 5 % by volume of C0₂ and 95 % relative humidity. Subsequently, the cells are loaded with 2 μΜ of Fluo-4 and 0.01 % by volume of Pluronic F1 27 (Molecular Probes Europe BV, Leiden, the Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) for 30 min at 37 °C, washed 3 times with HBSS buffer and after further incubation for 1 5 minutes at room temperature used for Ca²⁺ measurement in a FLIPR assay. The Ca²⁺-dependent fluorescence is in this case measured before and after the addition of substances ( ex = 488 nm, em = 540 nm). Quantification is carried out by measuring the highest fluorescence intensity (FC, fluorescence counts) over time.

FLIPR assay:

The FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 μΜ) are pipetted onto the cells and the Ca²⁺ influx is compared with the control (capsaicin 1 0 μΜ). This provides the result in % activation based on the Ca²⁺ signal after the addition of 1 0 μΜ of capsaicin (CP). After 5 minutes' incubation, 100 nM of capsaicin are applied and the Ca²⁺ influx is also determined.

Desensitising agonists and antagonists lead to suppression of the Ca²⁺ influx. The % inhibition is calculated compared to the maximum achievable inhibition with 1 0 μΜ of capsazepine. Triple analyses (n=3) are carried out and repeated in at least 3 independent experiments (N=4).

Starting from the percentage displacement caused by different concentrations of the compounds to be tested of general formula I, IC₅o inhibitory concentrations which cause a 50- % displacement of capsaicin were calculated. K values for the test substances were obtained by conversion by means of the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

II. Functional testing carried out on the vanilloid receptor 1 (VRI/TRPV1 receptor)

The agonistic or antagonistic effect of the substances to be tested on the vanilloid receptor 1 (VR1 ) can also be determined using the following assay. In this assay, the influx of Ca²⁺ through the channel is quantified with the aid of a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).

Method:

Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) United Kingdom) are stably transfected with the VR1 gene. For functional testing, these cells are plated out on poly-D-lysine-coated black 96-well plates having a clear base (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells/well. The cells are incubated overnight at 37 °C and 5 % C0₂ in a culture medium (Ham's F12 nutrient mixture, 1 0 % by volume of FCS (foetal calf serum), 1 8 μg ml of L-proline). The next day the cells are incubated with Fluo-4 (Fluo-4 2 μΜ, 0.01 % by volume of Pluronic F1 27, Molecular Probes in HBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH, Karlsruhe, Germany) for 30 minutes at 37 °C. Subsequently, the plates are washed three times with HBSS buffer and after further incubation for 15 minutes at RT used for Ca²⁺ measurement in a FLIPR assay. The Ca²⁺-dependent fluorescence is measured before and after the addition of the substances to be tested ( ex wavelength = 488 nm, e m = 540 nm). Quantification is carried out by measuring the highest fluorescence intensity (FC, fluorescence counts) over time. FLIPR assay:

The FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 μΜ) are pipetted onto the cells and the Ca²⁺ influx is compared with the control (capsaicin 10 μΜ) (% activation based on the Ca²⁺ signal after the addition of 10 μΜ of capsaicin). After 5 minutes' incubation, 100 nM of capsaicin are applied and the Ca²⁺ influx is also determined.

Desensitising agonists and antagonists led to suppression of the Ca²⁺ influx. The % inhibition is calculated compared to the maximum achievable inhibition with 10 μΜ of capsazepine.

Starting from the percentage displacement caused by different concentrations of the compounds to be tested of general formula I, IC₅₀ inhibitory concentrations which cause a 50- per cent displacement of capsaicin were calculated. K, values for the test substances were obtained by conversion by means of the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

Pharmacological data

The affinity of the compounds according to the invention for the vanilloid receptor 1 (VR1/TRPV1 receptor) was determined as described hereinbefore (pharmacological method I or II).

The compounds according to the invention display outstanding affinity to the VR1 /TRPV1 receptor (Table 2).

In Table 2 the abbreviations below have the following meanings: Cap = capsaicin

The value after the „@"symbol indicates the concentration at which the inhibition (as a percentage) was respectively determined.

Table 2

Claims

Patent claims:

1 . A substituted compound of general formula (S),

(S),

in which

R 101 103

, R and R are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂CH₂-OH, CH₂- OCH₃, CH₂CH₂-OCH₃, OCFH₂, OCF₂H, OCF₃, OH, NH₂, a d-₄ alkyl, an 0-d-₄ alkyl, a NH-C1-4 alkyl, and a N(Ci-₄ alkyl)₂, wherein the C1-4 alkyl is in each case unsubstituted,

R² represents CF₃, an unsubstituted C1-4 alkyl or an unsubstituted C₃-₆ cycloalkyl,

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, OH, OCF₃, a d-₄ alkyl, and an O-d-4 alkyl, wherein the C1-4 alkyl is in each case unsubstituted,

A denotes N, CH or C(CH₃),

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a 3 to 10 membered heterocyclyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF₃, CH₂OH, CH₂CH₂OH, CH₃, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, =0, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.

2. The compound according to claim 1 , characterized in that

R² represents CF₃, tert.-butyl or cyclopropyl.

3. The compound according to claim 1 or 2, characterized in that

R 101 103

, R¹⁰² and R are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂.

4. The compound according to any of the preceding claims, characterized in that at least one of R¹⁰¹ , R¹⁰² and R¹⁰³ is≠ H.

5. The compound according to any of the preceding claims, characterized in that

6. The compound according to any of the preceding claims, characterized in that at least one of R⁷ and R⁹ is≠ H.

7. The compound according to any of the preceding claims, characterized in that

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form the part structure

(SS1 )

(SS1 ),

wherein r denotes 0, 1 , 2 or 3, s denotes 0, 1 , 2 or 3, R^111a, R^{111 b} and R^{111 c} are independently of one another selected from the group consisting of H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, or two of R^111a, R^{111 b} and R^111c together denote =0 and the remaining residue of R^111a, R^{111 b} and R^111c represents H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) or N(CH₃)₂, or, when A denotes N,

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a 3 to 10 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of S, S(=0), S(=0)₂, N, NH and N(Ci_-4 alkyl), which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, =0, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, or, when A denotes CH or C(CH₃),

R¹⁰⁹ and R¹¹⁰ together with the nitrogen atom connecting them form a 3 to 10 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH and N(Ci_-4 alkyl), unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, =0, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂.

8. The compound according to any of the preceding claims, characterized in that

(SS1 )

R 1 1 1 c

(SS1 ),

wherein r denotes 0, 1 or 2, s denotes 0, 1 or 2,

R^111a, R^{111 b} and R^{111 c} are independently of one another selected from the group consisting of H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂, or two of R^111a, R^{111 b} and R^111c together denote =0 and the remaining residue of R^111a, R^{111 b} and R^111c represents H, F, CI, Br, CN, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, tert.-butyl, cyclopropyl, OH, OCH₃, OCF₃, NH₂, NH(CH₃) or N(CH₃)₂.

9. The compound according to any of the preceding claims, characterized in that

(SS1 )

R 1 1 1 c

(SS1 ),

wherein r denotes 0, 1 or 2, s denotes 0 or 1 ,

R^111a, R^{111 b} and R^{111 c} are independently of one another selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃,

CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) and N(CH₃)₂, or two of R^111a, R^{111 b} and R^111c together denote =0 and the remaining residue of R^111a, R^{111 b} and R^111c represents H, F, CI, CH₂OH, CH₂CH₂OH, CF₃, CH₃, CH₂CH₃, CH(CH₃)₂, OH, OCH₃, NH₂, NH(CH₃) or N(CH₃)₂.

10. The compound according to any of the preceding claims, characterized in that

(SS1 -C) (SS1 -d) wherein R^111a and R^{111 b} are independently of one another selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, and OCH₃, or R^111a and R^{111 b} together denote =0.

1 1 . The compound according to any of the preceding claims, characterized in that A denotes N or C(CH₃).

12. The compound according to any one of claims 1 -10, characterized in that

R¹⁰¹ , R¹⁰² and R¹⁰³ are independently of one another selected from the group consisting of H, F, CI, Br, CFH₂, CF₂H, CF₃, CN, CH₂-OH, CH₂-OCH₃, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, 0-CH₂CH₃, NH₂, NH(CH₃), and N(CH₃)₂,

R² represents CF₃, tert.-butyl or cyclopropyl,

R⁷ and R⁹ are independently of one another selected from the group consisting of H, F, CI, Br, CF₃, CN, OCF₃, OH, CH₃, CH₂CH₃, CH(CH₃)₂, 0-CH₃, and 0-CH₂CH₃,

A denotes N, CH or C(CH₃), and

(SS1 -a) (SS1

(SS1 -C) (SS1 -d) wherein R^111a is selected from the group consisting of H, F, CI, CF₃, CH₃, CH₂OH, CH₂CH₂OH, CH₂CH₃, CH(CH₃)₂, OH, and OCH₃, and R^{111 b} denotes H.

13. The compound according to any one of the preceding claims, selected from the group consisting of

(1 ,1 -dioxo-[1 ,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide;

4-pyrrolidin-1 -yl-phenyl)-urea;

4-morpholin-4-yl-phenyl)-urea;

4-(3-hydroxy-azetidin-1 -yl)-phenyl]-urea;

C9 1 -[3-Fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-3-[[2-(3-fluorophenyl)-5-

(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

C10 1 -[[2-(3,4-Difluoro-phenyl)-5-(trif luoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3- fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-urea;

C12 1 -[3-Fluoro-4-(3-hydroxy-azetidin-1 -yl)-phenyl]-3-[[2-(m-tolyl)-5-

(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; and

14. A pharmaceutical composition comprising at least one substituted compound according to any one of claims 1 to 13.

15. A substituted compound according to any one of claims 1 to 13 for use in the treatment and/or prophylaxis of one or more diseases and/or disorders selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eating disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating movement activity; for anxiolysis; for local anaesthesia and/or for inhibiting undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 /TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ- 249665, SDZ-249482, nuvanil and capsavanil.