HK1163104B

HK1163104B - N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor

Info

Publication number: HK1163104B
Application number: HK12103943.8A
Authority: HK
Inventors: Andreas Haupt; Frauke Pohlki; Karla Drescher; Karsten Wicke; Liliane Unger; Ana-Lucia Relo; Anton Bespalov; Barbara Vogg; Gisela Backfisch; Juergen Delzer; Min Zhang; Yanbin Lao
Original assignee: Abbott Gmbh & Co. Kg; Abbott Laboratories
Priority date: 2009-04-30
Filing date: 2010-04-29
Publication date: 2016-10-21

Description

BACKGROUND OF THE INVENTION

The present invention relates to N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating diseases that respond to modulation of the serotonin 5-HT₆ receptor.

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter and local hormone, is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration is found in the enterochromaffin cells of the gastrointestinal tract, the remainder being predominantly present in platelets and in the Central Nervous System (CNS). 5-HT is implicated in a vast array of physiological and pathophysiological pathways. In the periphery, it contracts a number of smooth muscles and induces endothelium-dependent vasodilation. In the CNS, it is believed to be involved in a wide range of functions, including the control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.

Neurons that secrete 5-HT are termed serotonergic. The function of 5-HT is exerted upon its interaction with specific (serotonergic) neurons. Until now, seven types of 5-HT receptors have been identified: 5-HT₁ (with subtypes 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E and 5-HT_1F), 5-HT₂ (with subtypes 5-HT_2A, 5-HT_2B and 5-HT_2C), 5-HT₃, 5-HT₄, 5-HT₅ (with subtypes 5-HT_5A and 5-HT_5B), 5-HT₆ and 5-HT₇. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cy.

The human 5-HT₆ receptors are positively coupled to adenylyl cyclase. They are distributed throughout the limbic, striatal and cortical regions of the brain and show a high affinity to antipsychotics.

The modulation of the 5-HT₆ receptor by suitable substances is expected to improve certain disorders including cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowel Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, addiction diseases and obesity (see e.g. A. Meneses, Drug News Perspect 14(7) (2001) pp. 396-400 and literature cited therein; J. Pharmacol. Sci. Vol. 101 (Suppl. 1), 2006, p. 124. Modulators of the 5HT₆-receptor such as PRX-07034 (Epix Pharmaceuticals) have been found in preclinical and clinical studies to be particular useful in the treatment of cognitive dysfunctions, in particular associated with Alzheimer's disease or schizophrenia or in the treatment of obesity (see e.g. http://www.epixpharma.com/products/prx-07034.asp).

WO 98/027081 , WO 99/02502 , WO 00/12623 , WO 00/12073 , US 2003/0069233 , WO 02/08179 , WO 02/92585 , WO 2006/010629 describe certain benzenesulfonanilide compounds having 5HT₆ receptor antagonist activity and suggest the use of these compounds for the treatment of medical disorders which are susceptible to the treatment with 5HT₆ receptor antagonists such as certain CNS disorders, drug abuse, ADHD, obesity and type II diabetes. WO 2004/080986 and WO 03/014097 describe certain diarylsulfone compounds, suggesting the use of these compounds for the treatment of medical disorders which are susceptible to the treatment with 5HT₆ receptor antagonists such as certain CNS disorders, drug abuse, ADHD, obesity and type II diabetes. WO 2008087123 suggests compounds having 5HT₆ receptor antagonist activity for preventing relapse into addiction.

However, there is still an ongoing need for providing compounds having high affinity for the 5-HT₆ receptor and which show high selectivity to this receptor. In particular the compounds should have low affinity to adrenergic receptors, such as α₁-adrenergic receptor, histamine receptors, such as H₁-receptor, and dopaminergic receptors, such as D₂-receptor, in order to avoid or reduce considerable side effects associated with modulation of these receptors, such as postural hypotension, reflex tachycardia, potentiation of the antihypertensive effect of prazosin, terazosin, doxazosin and labetalol or dizziness associated to the blockade of the α₁-adrenergic receptor, weight gain, sedation, drowsiness or potentiation of central depressant drugs associated to the blockade of the H₁-receptor, or extrapyramidal movement disorder, such as dystonia, parkinsonism, akathisia, tardive dyskinesia or rabbit syndrome, or endocrine effects, such as prolactin elevation (galactorrhea, gynecomastia, menstruyl changes, sexual dysfunction in males), associated to the blockade of the D₂-receptor.

It is one object of the present invention to provide compounds which have a high affinity for the 5-HT₆ receptor. It is a further object of the present invention to provide compounds which selectively bind to the 5-HT₆ receptor.

The compounds should also have good pharmacological profile, e.g. a good bioavailability and/or a good metabolic stability.

SUMMARY OF THE INVENTION

The present invention relates to N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamides or benzenesulfonyl-phenyl-(piperazines or homopiperazines) of formula (I) or (I') wherein

X: is a bond or a group N-R4;
R1: is hydrogen or methyl;
R2: is hydrogen or methyl;
R3: is hydrogen, C1-C3 alkyl (e.g. methyl), fluorine, C1-C2 alkoxy (e.g. methoxy) or fluorinated C1-C2 alkoxy;
R4: is hydrogen C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), C3-C4 cycloalkyl, or-CH2-C3-C4 cycloalkyl (e.g. cyclopropylmethyl);
R5: is hydrogen, fluorine, chlorine, C1-C2 alkyl (e.g. methyl), fluorinated C1-C2 alkyl, C1-C2 alkoxy (e.g. methoxy) or fluorinated C1-C2 alkoxy;
R6: is hydrogen, fluorine or chlorine; and
n: is 1 or 2,

and physiologically tolerated acid addition salts and the N-oxides thereof.

Said compounds, i.e., the N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamides or benzenesulfonyl-phenyl-piperazines or -homopiperazines and their physiologically tolerated acid addition salts and the N-oxides thereof, exhibit to a surprising and unexpected degree, a high binding affinity to the 5-HT₆ receptor and are thus useful as pharmaceuticals.

The present invention thus further relates to the compounds of formula (I) or (I') for use in therapy.

The present invention also relates to pharmaceutical compositions which comprise a compound of formula (I) or (I') and, optionally, a physiologically acceptable carrier and/or an auxiliary substance.

In particular, said compounds, i.e., the N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamides or benzenesulfonyl-phenyl-(piperazines or homopiperazines) and their physiologically tolerated acid addition salts and the N-oxides thereof, are modulators of the 5-HT₆ receptor.

The present invention thus further relates to the compounds of formula (I) or (I') for use in modulating the 5-HT₆ receptor.

The present invention also relates to the use of the compounds of formula (I) or (I') in the manufacture of a medicament for modulating the 5-HT₆ receptor and corresponding methods of modulating the 5-HT₆ receptor.

Modulators of the 5-HT₆ receptor and in particular antagonists of the 5-HT₆ receptor are known to be useful in treating a variety of disorders.

The present invention thus further relates to the compounds of formula (I) or (I') for use in treating said disorders.

The present invention also relates to the use of the compounds of formula (I) or (I') in the manufacture of a medicament for treating said disorders and corresponding methods of treating said disorders.

DETAILED DESCRIPTION OF THE INVENTION

The disorders diseases which are susceptible to treatment with a compound of the formula (I) or (I') include, e.g., disorders and diseases of the central nervous system, in particular cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome (ADHD), personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowel Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, including hydrocephalus, drug addiction and obesity.

Provided the compounds of the formula (I) or (I') of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, the invention also relates to enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers (ennatiomerically pure), diastereomers and tautomers of the compounds of formula (I) or (I') and/or of their salts and/or their N-oxides.

The invention also relates to physiologically tolerated salts of the compounds of the formula (I) or (I'), especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966.

The invention also relates to N-oxides of the compounds of the formula (I) or (I'), provided that those compounds contain a basic nitrogen atom, such as the nitrogen atom of the piperazine moiety.

The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix C_n-C_m indicates in each case the possible number of carbon atoms in the group.

As used herein, C₁-C₄ alkyl is a straight-chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms. Examples of such a group include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (= 2-butyl), 2-methylpropyl (= isobutyl) and 1,1-dimethylethyl (= tert.-butyl).

As used herein, fluorinated C₁-C₂ alkyl is a straight-chain alkyl group having 1 or 2 carbon atoms, wherein at least one hydrogen atom, e.g. 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine. Examples of such a group include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl and 1,1,2,2,2-pentafluoroethyl.

As used herein, C₁-C₂ alkoxy is a straight-chain alkyl group having 1 or 2 carbon atoms which is bound to the remainder of the molecule via an oxygen atom, i.e., methoxy and ethoxy.

As used herein, fluorinated C₁-C₂ alkoxy is an alkoxy group as defined above, wherein at least one, e.g. 1, 2, 3, 4 or 5 hydrogen atoms are replaced by fluorine atoms. Examples of such a group are fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and 1,1,2,2-tetrafluoroethoxy.

As used herein, C₃-C₄-cycloalkyl is a cycloaliphatic radical having from 3 to 4 carbon atoms, i.e. cyclopropyl and cyclobutyl.

With respect to the compounds' capability of modulating the 5-HT₆ receptor, the variables X, R¹, R², R³, R⁴, R⁵, R⁶ and n preferably have the following meanings which, when taken alone or in combination, represent particular embodiments of the compounds of the formula (I) or (I').

X is a bond or a group N-R⁴. A first preferred embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein X is a group N-R⁴.

R¹ is hydrogen or methyl. A second preferred embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen. Another embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is methyl.

R² is hydrogen or methyl. A third preferred embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R² is hydrogen.

Another embodiment of the invention relates to compounds of the formula I or I', wherein R² is methyl. If R² is methyl, the carbon atom that carries R² creates a center of chirality. Thus, a specific embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R² is methyl and wherein the carbon atom that carries R² has S-configuration. Another specific embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R² is methyl and wherein the carbon atom that carries R² has R-configuration.

Likewise preferred are mixtures of compounds of the present invention, wherein the carbon atom that carries R² has S-configuration or R-configuration, respectively. These mixtures may contain equal amounts or non-equal amounts of the compound I, or equal amounts or non-equal amounts of the compound I', respectively, that have R-configuration with regard to the moiety CH-R² and of the compound I or I' that have S-configuration with regard to CH-R².

The term "enantiomerically pure" means that the mixture contains the respective compound in an entaniomeric excess of at least 80 %, in particular at least 90 % (ee).

R³ is hydrogen, C₁-C₃ alkyl (e.g. methyl), fluorine, C₁-C₂ alkoxy (e.g. methoxy) or fluorinated C₁-C₂ alkoxy.

Preference is given to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R³ is methyl or methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy, and most preferably methyl. The invention also relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R³ is hydrogen or fluorine, in particular hydrogen.

R⁴ is hydrogen, C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂- (e.g. cyclopropylmethyl).

Preference is given to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropylmethyl. More preference is given to the compounds of the present invention, wherein R⁴ is hydrogen.

R⁵ is hydrogen, fluorine, C₁-C₂ alkyl (e.g. methyl), fluorinated C₁-C₂ alkyl, C₁-C₂ alkoxy (e.g. methoxy) or fluorinated C₁-C₂ alkoxy.

R⁵ is preferably selected from the group consisting of hydrogen, fluorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and more preferably from hydrogen, methoxy and difluoromethoxy. Likewise, preference is given to the compounds of the formula I or I', wherein R⁵ is chlorine. In a particular preferred embodiment of the invention, R⁵ is hydrogen. In another particular preferred embodiment of the invention, R⁵ is selected from fluorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and more preferably from methyl, methoxy and difluoromethoxy. Likewise, more preference is given to the compounds of the formula I or I', wherein R⁵ is fluorine. Likewise, more preference is given to the compounds of the formula I or I', wherein R⁵ is chlorine.

R⁶ is hydrogen, fluorine or chlorine, preferably hydrogen or fluorine. In a particular preferred embodiment of the invention, R⁶ is hydrogen. In another particular embodiment of the invention R⁶ is different from hydrogen, in particular fluorine. If R⁶ is different from hydrogen it is preferably located in the 5- or 6-postion of the benzene ring.

Preference is given to those compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R³ is methyl or methoxy and R⁶ is hydrogen, or R³ is methyl or methoxy and R⁶ is fluorine being located in the 5- or 6-position of the benzene ring, or both R³ and R⁶ are hydrogen or R³ is hydrogen and R⁶ is fluorine being located in the 5- or 6-position of the benzene ring.

According to a further particular embodiment, R⁵ and R⁶ are hydrogen, R³ is selected from the group consisting of C₁-C₂ alkyl (e.g. methyl) and C₁-C₂ alkoxy (e.g. methoxy), and R⁴ is selected from the group consisting of hydrogen, C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), or cyclopropylmethyl.

n is 1 or 2, thus forming a piperazine or a homopiperazine moiety. Preference is give to n being 1, i.e. compounds having a piperazine moiety.

A particular preferred embodiment la of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is hydrogen.

A further particular preferred embodiment Ib of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is methyl.

A further particular preferred embodiment Ic of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is methyl; R² is hydrogen; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is hydrogen.

A further particular preferred embodiment Id of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is methyl; R² is hydrogen; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is methyl.

A particular preferred embodiment le of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is hydrogen.

A further particular preferred embodiment If of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is methyl.

A further particular preferred embodiment Ig of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is methyl; R² is hydrogen; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is hydrogen.

A further particular preferred embodiment Ih of the invention relates to compounds of the formula I, to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is methyl; R² is hydrogen; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is methyl.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, preference is given to those, where the radicals R⁵ and R⁶ in formula I are both hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is hydrogen and where the radical R⁶ in formula I is fluorine, which is located in the 5-position or in the 6-position of the benzene ring.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is methoxy and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is methoxy and where the radical R⁶ in formula I is fluorine, which is located in the 5-position or in the 6-position of the benzene ring.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is difluoromethoxy and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is difluoromethoxy and where the radical R⁶ in formula I is fluorine, which is located in the 5-position or in the 6-position of the benzene ring.

Amongst the compounds of embodiments IKa, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is chlorine and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, where the radical R⁵ in formula I is fluorine and where the radical R⁶ in formula I is hydrogen.

A particular preferred embodiment I'a of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is hydrogen.

A further particular preferred embodiment I'b of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is methyl; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is hydrogen.

A further particular preferred embodiment I'c of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is methyl.

A further particular preferred embodiment I'd of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is methyl; R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl or methoxy; and R⁴ is methyl.

A particular preferred embodiment I'e of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is hydrogen.

A further particular preferred embodiment I'f of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is methyl; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is hydrogen.

A further particular preferred embodiment I'g of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is hydrogen; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is methyl.

A further particular preferred embodiment I'h of the invention relates to compounds of the formula I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen; R² is methyl; R³ is hydrogen or fluorine, in particular hydrogen; and R⁴ is methyl.

Amongst the compounds of embodiments I'a, I'b, I'c, I'd, I'e, I'f, I'g and I'h, preference is given to those, where the radicals R⁵ and R⁶ in formula I' are both hydrogen.

Amongst the compounds of embodiments I'a, I'b, I'c, I'd, I'e, I'f, I'g and I'h, likewise preference is given to those, where the radical R⁵ in formula I is hydrogen and where the radical R⁶ in formula I' is fluorine, which is located in the 5-position or in the 6-position of the benzene ring.

Amongst the compounds of the formula I, in particular amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, particular preference is given to those, wherein the OCHF₂-radical is located on the benzene ring in the meta-position with respect to X. Amongst these compounds, particular preference is given to those compounds of the formula I, wherein R⁵ is hydrogen. Amongst these compounds, likewise preference is given to those compounds of the formula I, wherein R⁵ is different from hydrogen and in particular selected from fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and more preferably from methyl, methoxy and difluoromethoxy, and located in the para-position, with respect to X, or in the para-position, with respect to the OCHF₂-radical.

Amongst the compounds of the formula I, in particular amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, wherein the OCHF₂-radical is located on the benzene ring in the ortho-position with respect to X. Amongst these compounds, particular preference is given to those compounds of the formula I, wherein R⁵ is hydrogen. Amongst these compounds, likewise preference is given to those compounds of the formula I, wherein R⁵ is different from hydrogen and in particular selected from fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and more preferably from methyl, methoxy and difluoromethoxy, and located in the para-position, with respect to X, or in the para-position, with respect to the OCHF₂-radical.

Amongst the compounds of the formula I, in particular amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewise preference is given to those, wherein the OCHF₂-radical is located on the benzene ring in the para-position with respect to X. Amongst these compounds, particular preference is given to those compounds of the formula I, wherein R⁵ is hydrogen. Amongst these compounds, likewise preference is given to those compounds of the formula I, wherein R⁵ is different from hydrogen and in particular selected from fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and more preferably from methyl, methoxy and difluoromethoxy, and located in the meta-position, with respect to X.

Amongst the compounds of the formula I', in particular amongst the compounds of embodiments I'a, I'b, I'c, I'd, I'e, I'f and I'g, particular preference is given to those, wherein X is attached to the benzene ring in the α-position with respect to the 1,3-dioxole ring. Amongst these compounds, particular preference is given to those compounds of the formula I', wherein R⁵ is hydrogen.

Amongst the compounds of the formula I', in particular amongst the compounds of embodiments I'a, I'b, I'c, I'd, I'e, I'f and I'g, particular preference is given to those, wherein X is attached to the benzene ring in the ß-position with respect to the 1,3-dioxole ring. Amongst these compounds, particular preference is given to those compounds of the formula I', wherein R⁵ is hydrogen.

A particular preferred embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein

X: is a bond or a group N-R4;
R1: is hydrogen or methyl;
R2: is hydrogen or methyl, in particular hydrogen;
R3: is hydrogen, C1-C2 alkyl, fluorine, C1-C2 alkoxy or fluorinated C1-C2 alkoxy, preferably hydrogen, methyl, methoxy, difluoromethoxy or trifluoromethoxy, in particular hydrogen, methyl or methoxy;
R4: is hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropylmethyl;
R5: is hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and more preferably hydrogen, methyl or methoxy;
R6: is hydrogen or fluorine, which is located in the 5- or 6-position of the benzene ring; and
n: is 1 or 2.

A further particular preferred embodiment of the invention relates to compounds of the formula I or I', to their pharmacologically tolerated salts and to the N-oxides thereof, wherein

X: is a bond or a group N-R4;
R1: is hydrogen or methyl, preferably hydrogen;
R2: is hydrogen;
R3: is hydrogen, C1-C2 alkyl or C1-C2 alkoxy, preferably hydrogen, methyl or methoxy, in particular methyl or methoxy;
R4: is hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropylmethyl, preferably hydrogen;
R5: is hydrogen, chlorine, fluorine, difluoromethoxy, methyl or methoxy, preferably hydrogen, methyl or methoxy, in particular hydrogen;
R6: is hydrogen; and
n: is 1 or 2, preferably 1.

X: is a group N-R4;
R1: is hydrogen;
R2: is hydrogen;
R3: is C1-C2 alkyl or C1-C2 alkoxy, preferably methyl or methoxy;
R4: is hydrogen;
R5: is hydrogen;
R6: is hydrogen; and
n: is 1.

X: is a group N-R4;
R1: is hydrogen;
R2: is hydrogen;
R3: is C1-C2 alkyl or C1-C2 alkoxy, preferably methyl or methoxy;
R4: is hydrogen;
R5: is chlorine;
R6: is hydrogen; and
n: is 1.

X: is a group N-R4;
R1: is hydrogen;
R2: is hydrogen;
R3: is C1-C2 alkyl or C1-C2 alkoxy, preferably methyl or methoxy;
R4: is hydrogen;
R5: is fluorine;
R6: is hydrogen; and
n: is 1.

X: is a group N-R4;
R1: is hydrogen;
R2: is hydrogen;
R3: is C1-C2 alkyl or C1-C2 alkoxy, preferably methyl or methoxy;
R4: is hydrogen;
R5: is difluoromethoxy;
R6: is hydrogen; and
n: is 1.

Examples of compounds according to the present invention are the compounds of the formula I, their pharmacologically tolerated salts and the N-oxides thereof, wherein R⁶ is hydrogen, and the meanings of X, R¹, R², R³, R⁴ and R⁵ and the position of R⁵ and of the moiety OCHF₂ on the benzene ring is given in the following table A:

Table A

No.	n				X
1.	1	H	H	NH	ortho	H
2.	1	H	H	NH	meta	H
3.	1	H	H	NH	para	H
4.	1	H	H	NH	ortho
5.	1	H	H	NH	ortho
6.	1	H	H	NH	meta
7.	1	H	H	NH	meta
8.	1	H	H	NH	meta
9.	1	H	H	NH	ortho	CI (para to NH)
10.	1	H	H	NH	ortho
11.	1	H	H	NH	ortho	F (para to NH)
12.	1	H	H	NH	ortho
13.	1	H	H	NH	meta
14.	1	H	NH	ortho	H
15.	1	H	NH	meta	H
16.	1	H	NH	para	H
17.	1	H	NH	ortho
18.	1	H	NH	ortho
19.	1	H	NH	meta
20.	1	H	NH	meta
21.	1	H	NH	meta
22.	1	H	NH	ortho	Cl (para to NH)
23.	1	H	NH	ortho
24.	1	H	NH	ortho	F (para to NH)
25.	1	H	NH	ortho
26.	1	H	NH	meta
27.	1	H	H	ortho	H
28.	1	H	H	meta	H
29.	1	H	H	para	H
30.	1	H	H	ortho
31.	1	H	H	ortho
32.	1	H	H	meta
33.	1	H	H	meta
34.	1	H	H	meta
35.	1	H	H	ortho	Cl (para to X)
36.	1	H	H	ortho
37.	1	H	H	ortho	F (para to X)
38.	1	H	H	ortho
39.	1	H	H	meta
40.	1	H	ortho	H
41.	1	H	meta	H
42.	1	H	para	H
43.	1	H	ortho
44.	1	H	ortho
45.	1	H	meta
46.	1	H	meta
47.	1	H	meta
48.	1	H	ortho	Cl (para to X)
49.	1	H	ortho
50.	1	H	ortho	F (para to X)
51.	1	H	ortho
52.	1	H	meta
53.	1	H	H	ortho	H
54.	1	H	H	meta	H
55.	1	H	H	para	H
56.	1	H	H	ortho
57.	1	H	H	ortho
58.	1	H	H	meta
59.	1	H	H	meta
60.	1	H	H	meta
61.	1	H	ortho	H
62.	1	H	meta	H
63.	1	H	para	H
64.	1	H	ortho
65.	1	H	ortho
66.	1	H	meta
67.	1	H	meta
68.	1	H	meta
69.	1	H	H	ortho	H
70.	1	H	H	meta	H
71.	1	H	H	para	H
72.	1	H	H	ortho
73.	1	H	H	ortho
74.	1	H	H	meta
75.	1	H	H	meta
76.	1	H	H	meta
77.	1	H	ortho	H
78.	1	H	meta	H
79.	1	H	para	H
80.	1	H	ortho
81.	1	H	ortho
82.	1	H	meta
83.	1	H	meta
84.	1	H	meta
85.	1	H	H	ortho	H
86.	1	H	H	meta	H
87.	1	H	H	para	H
88.	1	H	H	ortho
89.	1	H	H	ortho
90.	1	H	H	meta
91.	1	H	H	meta
92.	1	H	H	meta
93.	1	H	ortho	H
94.	1	H	meta	H
95.	1	H	para	H
96.	1	H	ortho
97.	1	H	ortho
98.	1	H	meta
99.	1	H	meta
100.	1	H	meta
101.	1	H	H	bond	ortho	H
102.	1	H	H	bond	meta	H
103.	1	H	H	bond	para	H
104.	1	H	H	bond	ortho
105.	1	H	H	bond	ortho
106.	1	H	H	bond	meta
107.	1	H	H	bond	meta
108.	1	H	H	bond	meta
109.	1	H	bond	ortho	H
110.	1	H	bond	meta	H
111.	1	H	bond	para	H
112.	1	H	bond	ortho
113.	1	H	bond	ortho
114.	1	H	bond	meta
115.	1	H	bond	meta
116.	1	H	bond	meta
117.	2	H	H	NH	ortho	H
118.	2	H	H	NH	meta	H
119.	2	H	H	NH	para	H
120.	2	H	H	NH	ortho
121.	2	H	H	NH	ortho
122.	2	H	H	NH	meta
123.	2	H	H	NH	meta
124.	2	H	H	NH	meta
125.	2	H	H	NH	ortho	Cl (para to NH)
126.	2	H	H	NH	ortho
127.	2	H	H	NH	ortho	F (para to NH)
128.	2	H	H	NH	ortho
129.	2	H	H	NH	meta
130.	2	H	NH	ortho	H
131.	2	H	NH	meta	H
132.	2	H	NH	para	H
133.	2	H	NH	ortho
134.	2	H	NH	ortho
135.	2	H	NH	meta
136.	2	H	NH	meta
137.	2	H	NH	meta
138.	2	H	NH	ortho	Cl (para to NH)
139.	2	H	NH	ortho
140.	2	H	NH	ortho	F (para to NH)
141.	2	H	NH	ortho
142.	2	H	NH	meta
143.	2	H	H	ortho	H
144.	2	H	H	meta	H
145.	2	H	H	para	H
146.	2	H	H	ortho
147.	2	H	H	ortho
148.	2	H	H	meta
149.	2	H	H	meta
150.	2	H	H	meta
151.	2	H	H	ortho	Cl (para to X)
152.	2	H	H	ortho
153.	2	H	H	ortho	F (para to X)
154.	2	H	H	ortho
155.	2	H	H	meta
156.	2	H	ortho	H
157.	2	H	meta	H
158.	2	H	para	H
159.	2	H	ortho
160.	2	H	ortho
161.	2	H	meta
162.	2	H	meta
163.	2	H	meta
164.	2	H	ortho	Cl (para to X)
165.	2	H	ortho
166.	2	H	ortho	F (para to X)
167.	2	H	ortho
168.	2	H	meta
169.	2	H	H	ortho	H
170.	2	H	H	meta	H
171.	2	H	H	para	H
172.	2	H	H	ortho
173.	2	H	H	ortho
174.	2	H	H	meta
175.	2	H	H	meta
176.	2	H	H	meta
177.	2	H	ortho	H
178.	2	H	meta	H
179.	2	H	para	H
180.	2	H	ortho
181.	2	H	ortho
182.	2	H	meta
183.	2	H	meta
184.	2	H	meta
185.	2	H	H	ortho	H
186.	2	H	H	meta	H
187.	2	H	H	para	H
188.	2	H	H	ortho
189.	2	H	H	ortho
190.	2	H	H	meta
191.	2	H	H	meta
192.	2	H	H	meta
193.	2	H	ortho	H
194.	2	H	meta	H
195.	2	H	para	H
196.	2	H	ortho
197.	2	H	ortho
198.	2	H	meta
199.	2	H	meta
200.	2	H	meta
201.	2	H	H	ortho	H
202.	2	H	H	meta	H
203.	2	H	H	para	H
204.	2	H	H	ortho
205.	2	H	H	ortho
206.	2	H	H	meta
207.	2	H	H	meta
208.	2	H	H	meta
209.	2	H	mrtho	H
210.	2	H	meta	H
211.	2	H	para	H
212.	2	H	ortho
213.	2	H	ortho
214.	2	H	meta
215.	2	H	meta
216.	2	H	meta
217.	2	H	H	bond	ortho	H
218.	2	H	H	bond	meta	H
219.	2	H	H	bond	para	H
220.	2	H	H	bond	ortho
221.	2	H	H	bond	ortho
222.	2	H	H	bond	meta
223.	2	H	H	bond	meta
224.	2	H	H	bond	meta
225.	2	H	bond	ortho	H
226.	2	H	bond	meta	H
227.	2	H	bond	para	H
228.	2	H	bond	ortho
229.	2	H	bond	ortho
230.	2	H	bond	meta
231.	2	H	bond	meta
232.	2	H	bond	meta
233.	1	H	H	NH	ortho	H
234.	1	H	H	NH	meta	H
235.	1	H	H	NH	para	H
236.	1	H	H	NH	ortho
237.	1	H	H	NH	ortho
238.	1	H	H	NH	meta
239.	1	H	H	NH	meta
240.	1	H	H	NH	meta
241.	1	H	H	NH	ortho	Cl (para to NH)
242.	1	H	H	NH	ortho
243.	1	H	H	NH	ortho	F (para to NH)
244.	1	H	H	NH	ortho
245.	1	H	H	NH	meta
246.	1	H	NH	ortho	H
247.	1	H	NH	meta	H
248.	1	H	NH	para	H
249.	1	H	NH	ortho
250.	1	H	NH	ortho
251.	1	H	NH	meta
252.	1	H	NH	meta
253.	1	H	NH	meta
254.	1	H	NH	ortho	Cl (para to NH)
255.	1	H	NH	ortho
256.	1	H	NH	ortho	F (para to NH)
257.	1	H	NH	ortho
258.	1	H	NH	meta
259.	1	H	H	ortho	H
260.	1	H	H	meta	H
261.	1	H	H	para	H
262.	1	H	H	ortho
263.	1	H	H	ortho
264.	1	H	H	meta
265.	1	H	H	meta
266.	1	H	H	meta
267.	1	H	H	ortho	Cl (para to X)
268.	1	H	H	ortho
269.	1	H	H	ortho	F (para to X)
270.	1	H	H	ortho
271.	1	H	H	meta
272.	1	H	ortho	H
273.	1	H	meta	H
274.	1	H	para	H
275.	1	H	ortho
276.	1	H	ortho
277.	1	H	meta
278.	1	H	meta
279.	1	H	meta
280.	1	H	ortho	Cl (para to X)
281.	1	H	ortho
282.	1	H	ortho	F (para to X)
283.	1	H	ortho
284.	1	H	meta
285.	1	H	H	ortho	H
286.	1	H	H	meta	H
287.	1	H	H	para	H
288.	1	H	H	ortho
289.	1	H	H	ortho
290.	1	H	H	meta
291.	1	H	H	meta
292.	1	H	H	meta
293.	1	H	ortho	H
294.	1	H	meta	H
295.	1	H	para	H
296.	1	H	ortho
297.	1	H	ortho
298.	1	H	meta
299.	1	H	meta
300.	1	H	meta
301.	1	H	H	ortho	H
302.	1	H	H	meta	H
303.	1	H	H	para	H
304.	1	H	H	ortho
305.	1	H	H	ortho
306.	1	H	H	meta
307.	1	H	H	meta
308.	1	H	H	meta
309.	1	H	ortho	H
310.	1	H	meta	H
311.	1	H	para	H
312.	1	H	ortho
313.	1	H	ortho
314.	1	H	meta
315.	1	H	meta
316.	1	H	meta
317.	1	H	H	ortho	H
318.	1	H	H	meta	H
319.	1	H	H	para	H
320.	1	H	H	ortho
321.	1	H	H	ortho
322.	1	H	H	meta
323.	1	H	H	meta
324.	1	H	H	meta
325.	1	H	ortho	H
326.	1	H	meta	H
327.	1	H	para	H
328.	1	H	ortho
329.	1	H	ortho
330.	1	H	meta
331.	1	H	meta
332.	1	H	meta
333.	1	H	H	bond	ortho	H
334.	1	H	H	bond	meta	H
335.	1	H	H	bond	para	H
336.	1	H	H	bond	ortho
337.	1	H	H	bond	ortho
338.	1	H	H	bond	meta
339.	1	H	H	bond	meta
340.	1	H	H	bond	meta
341.	1	H	bond	ortho	H
342.	1	H	bond	meta	H
343.	1	H	bond	para	H
344.	1	H	bond	ortho
345.	1	H	bond	ortho
346.	1	H	bond	meta
347.	1	H	bond	meta
348.	1	H	bond	meta
349.	2	H	H	NH	ortho	H
350.	2	H	H	NH	meta	H
351.	2	H	H	NH	para	H
352.	2	H	H	NH	ortho
353.	2	H	H	NH	ortho
354.	2	H	H	NH	meta
355.	2	H	H	NH	meta
356.	2	H	H	NH	meta
357.	2	H	H	NH	ortho	CI (para to NH)
358.	2	H	H	NH	ortho
359.	2	H	H	NH	ortho	F (para to NH)
360.	2	H	H	NH	ortho
361.	2	H	H	NH	meta
362.	2	H	NH	ortho	H
363.	2	H	NH	meta	H
364.	2	H	NH	para	H
365.	2	H	NH	ortho
366.	2	H	NH	ortho
367.	2	H	NH	meta
368.	2	H	NH	meta
369.	2	H	NH	meta
370.	2	H	NH	ortho	CI (para to NH)
371.	2	H	NH	ortho
372.	2	H	NH	ortho	F (para to NH)
373.	2	H	NH	ortho
374.	2	H	NH	meta
375.	2	H	H	ortho	H
376.	2	H	H	meta	H
377.	2	H	H	para	H
378.	2	H	H	ortho
379.	2	H	H	ortho
380.	2	H	H	meta
381.	2	H	H	meta
382.	2	H	H	meta
383.	2	H	H	ortho	Cl (para to X)
384.	2	H	H	ortho
385.	2	H	H	ortho	F (para to X)
386.	2	H	H	ortho
387.	2	H	H	meta
388.	2	H	ortho	H
389.	2	H	meta	H
390.	2	H	para	H
391.	2	H	ortho
392.	2	H	ortho
393.	2	H	meta
394.	2	H	meta
395.	2	H	meta
396.	2	H	ortho	CI (para to X)
397.	2	H	ortho
398.	2	H	ortho	F (para to X)
399.	2	H	ortho
400.	2	H	meta
401.	2	H	H	ortho	H
402.	2	H	H	meta	H
403.	2	H	H	para	H
404.	2	H	H	ortho
405.	2	H	H	ortho
406.	2	H	H	meta
407.	2	H	H	meta
408.	2	H	H	meta
409.	2	H	ortho	H
410.	2	H	meta	H
411.	2	H	para	H
412.	2	H	ortho
413.	2	H	ortho
414.	2	H	meta
415.	2	H	meta
416.	2	H	meta
417.	2	H	H	ortho	H
418.	2	H	H	meta	H
419.	2	H	H	para	H
420.	2	H	H	ortho
421.	2	H	H	ortho
422.	2	H	H	meta
423.	2	H	H	meta
424.	2	H	H	meta
425.	2	H	ortho	H
426.	2	H	meta	H
427.	2	H	para	H
428.	2	H	ortho
429.	2	H	ortho
430.	2	H	meta
431.	2	H	meta
432.	2	H	meta
433.	2	H	H	ortho	H
434.	2	H	H	meta	H
435.	2	H	H	para	H
436.	2	H	H	ortho
437.	2	H	H	ortho
438.	2	H	H	meta
439.	2	H	H	meta
440.	2	H	H	meta
441.	2	H	ortho	H
442.	2	H	meta	H
443.	2	H	para	H
444.	2	H	ortho
445.	2	H	ortho
446.	2	H	meta
447.	2	H	meta
448.	2	H	meta
449.	2	H	H	bond	ortho	H
450.	2	H	H	bond	meta	H
451.	2	H	H	bond	para	H
452.	2	H	H	bond	ortho
453.	2	H	H	bond	ortho
454.	2	H	H	bond	meta
455.	2	H	H	bond	meta
456.	2	H	H	bond	meta
457.	2	H	bond	ortho	H
458.	2	H	bond	meta	H
459.	2	H	bond	para	H
460.	2	H	bond	ortho
461.	2	H	bond	ortho
462.	2	H	bond	meta
463.	2	H	bond	meta
464.	2	H	bond	meta
465.	1	H	H	NH	ortho	H
466.	1	H	H	NH	meta	H
467.	1	H	H	NH	para	H
468.	1	H	H	NH	ortho
469.	1	H	H	NH	ortho
470.	1	H	H	NH	meta
471.	1	H	H	NH	meta
472.	1	H	H	NH	meta
473.	1	H	H	NH	ortho	CI (para to NH)
474.	1	H	H	NH	ortho
475.	1	H	H	NH	ortho	F (para to NH)
476.	1	H	H	NH	ortho
477.	1	H	H	NH	meta
478.	1	H	NH	ortho	H
479.	1	H	NH	meta	H
480.	1	H	NH	para	H
481.	1	H	NH	ortho
482.	1	H	NH	ortho
483.	1	H	NH	meta
484.	1	H	NH	meta
485.	1	H	NH	meta
486.	1	H	NH	ortho	CI (para to NH)
487.	1	H	NH	ortho
488.	1	H	NH	ortho	F (para to NH)
489.	1	H	NH	ortho
490.	1	H	NH	meta
491.	1	H	H	ortho	H
492.	1	H	H	meta	H
493.	1	H	H	para	H
494.	1	H	H	ortho
495.	1	H	H	ortho
496.	1	H	H	meta
497.	1	H	H	meta
498.	1	H	H	meta

Table A

No.	n				X
499.	1	H	H	ortho	Cl (para to X)
500.	1	H	H	ortho
501.	1	H	H	ortho	F (para to X)
502.	1	H	H	ortho
503.	1	H	H	meta
504.	1	H	ortho	H
505.	1	H	meta	H
506.	1	H	para	H
507.	1	H	ortho
508.	1	H	ortho
509.	1	H	meta
510.	1	H	meta
511.	1	H	meta
512.	1	H	ortho	Cl (para to X)
513.	1	H	ortho
514.	1	H	ortho	F (para to X)
515.	1	H	ortho
516.	1	H	meta
517.	1	H	H	ortho	H
518.	1	H	H	meta	H
519.	1	H	H	para	H
520.	1	H	H	ortho
521.	1	H	H	ortho
522.	1	H	H	meta
523.	1	H	H	meta
524.	1	H	H	meta
525.	1	H	ortho	H
526.	1	H	meta	H
527.	1	H	para	H
528.	1	H	ortho
529.	1	H	ortho
530.	1	H	meta
531.	1	H	meta
532.	1	H	meta
533.	1	H	H	ortho	H
534.	1	H	H	meta	H
535.	1	H	H	para	H
536.	1	H	H	ortho
537.	1	H	H	ortho

Table A

No.	n				X
538.	1	H	H	meta
539.	1	H	H	meta
540.	1	H	H	meta
541.	1	H	ortho	H
542.	1	H	meta	H
543.	1	H	para	H
544.	1	H	ortho
545.	1	H	ortho
546.	1	H	meta
547.	1	H	meta
548.	1	H	meta
549.	1	H	H	ortho	H
550.	1	H	H	meta	H
551.	1	H	H	para	H
552.	1	H	H	ortho
553.	1	H	H	ortho
554.	1	H	H	meta
555.	1	H	H	meta
556.	1	H	H	meta
557.	1	H	ortho	H
558.	1	H	meta	H
559.	1	H	para	H
560.	1	H	ortho
561.	1	H	ortho
562.	1	H	meta
563.	1	H	meta
564.	1	H	meta
565.	1	H	H	bond	ortho	H
566.	1	H	H	bond	meta	H
567.	1	H	H	bond	para	H
568.	1	H	H	bond	ortho
569.	1	H	H	bond	ortho
570.	1	H	H	bond	meta
571.	1	H	H	bond	meta
572.	1	H	H	bond	meta
573.	1	H	bond	ortho	H
574.	1	H	bond	meta	H
575.	1	H	bond	para	H
576.	1	H	bond	ortho
577.	1	H	bond	ortho
578.	1	H	bond	meta
579.	1	H	bond	meta
580.	1	H	bond	meta
581.	2	H	H	NH	ortho	H
582.	2	H	H	NH	meta	H
583.	2	H	H	NH	para	H
584.	2	H	H	NH	ortho
585.	2	H	H	NH	ortho
586.	2	H	H	NH	meta
587.	2	H	H	NH	meta
588.	2	H	H	NH	meta
589.	2	H	H	NH	ortho	CI (para to NH)
590.	2	H	H	NH	ortho
591.	2	H	H	NH	ortho	F (para to NH)
592.	2	H	H	NH	ortho
593.	2	H	H	NH	meta
594.	2	H	NH	ortho	H
595.	2	H	NH	meta	H
596.	2	H	NH	para	H
597.	2	H	NH	ortho
598.	2	H	NH	ortho
599.	2	H	NH	meta
600.	2	H	NH	meta
601.	2	H	NH	meta
602.	2	H	NH	ortho	Cl (para to NH)
603.	2	H	NH	ortho
604.	2	H	NH	ortho	F (para to NH)
605.	2	H	NH	ortho
606.	2	H	NH	meta
607.	2	H	H	ortho	H
608.	2	H	H	meta	H
609.	2	H	H	para	H
610.	2	H	H	ortho
611.	2	H	H	ortho
612.	2	H	H	meta
613.	2	H	H	meta
614.	2	H	H	meta
615.	2	H	H	ortho	Cl (para to X)

Table A

No.	n				X
616.	2	H	H	ortho
617.	2	H	H	ortho	F (para to X)
618.	2	H	H	ortho
619.	2	H	H	meta
620.	2	H	ortho	H
621.	2	H	meta	H
622.	2	H	para	H
623.	2	H	ortho
624.	2	H	ortho
625.	2	H	meta
626.	2	H	meta
627.	2	H	meta
628.	2	H	ortho	Cl (para to X)
629.	2	H	ortho
630.	2	H	ortho	F (para to X)
631.	2	H	ortho
632.	2	H	meta
633.	2	H	H	ortho	H
634.	2	H	H	meta	H
635.	2	H	H	para	H
636.	2	H	H	ortho
637.	2	H	H	ortho
638.	2	H	H	meta
639.	2	H	H	meta
640.	2	H	H	meta
641.	2	H	ortho	H
642.	2	H	meta	H
643.	2	H	para	H
644.	2	H	ortho
645.	2	H	ortho
646.	2	H	meta
647.	2	H	meta
648.	2	H	meta
649.	2	H	H	ortho	H
650.	2	H	H	meta	H
651.	2	H	H	para	H
652.	2	H	H	ortho
653.	2	H	H	ortho
654.	2	H	H	meta

Table A

No.	n				X
655.	2	H	H	meta
656.	2	H	H	meta
657.	2	H	ortho	H
658.	2	H	meta	H
659.	2	H	para	H
660.	2	H	ortho
661.	2	H	ortho
662.	2	H	meta
663.	2	H	meta
664.	2	H	meta
665.	2	H	H	ortho	H
666.	2	H	H	meta	H
667.	2	H	H	para	H
668.	2	H	H	ortho
669.	2	H	H	ortho
670.	2	H	H	meta
671.	2	H	H	meta
672.	2	H	H	meta
673.	2	H	ortho	H
674.	2	H	meta	H
675.	2	H	para	H
676.	2	H	ortho
677.	2	H	ortho
678.	2	H	meta
679.	2	H	meta
680.	2	H	meta
681.	2	H	H	bond	ortho	H
682.	2	H	H	bond	meta	H
683.	2	H	H	bond	para	H
684.	2	H	H	bond	ortho
685.	2	H	H	bond	ortho
686.	2	H	H	bond	meta
687.	2	H	H	bond	meta
688.	2	H	H	bond	meta
689.	2	H	bond	ortho	H
690.	2	H	bond	meta	H
691.	2	H	bond	para	H
692.	2	H	bond	ortho
693.	2	H	bond	ortho
694.	2	H	bond	meta
695.	2	H	bond	meta
696.	2	H	bond	meta
697.	1	H	H	F	NH	ortho	H
698.	1	H	H	F	NH	meta	H
699.	1	H	H	F	NH	para	H
700.	1	H	H	F	NH	ortho
701.	1	H	H	F	NH	ortho
702.	1	H	H	F	NH	meta
703.	1	H	H	F	NH	meta
704.	1	H	H	F	NH	meta
705.	1	H	H	F	NH	ortho	Cl (para to NH)
706.	1	H	H	F	NH	ortho
707.	1	H	H	F	NH	ortho	F (para to NH)
708.	1	H	H	F	NH	ortho
709.	1	H	H	F	NH	meta
710.	1	H	F	NH	ortho	H
711.	1	H	F	NH	meta	H
712.	1	H	F	NH	para	H
713.	1	H	F	NH	ortho
714.	1	H	F	NH	ortho
715.	1	H	F	NH	meta
716.	1	H	F	NH	meta
717.	1	H	F	NH	meta
718.	1	H	F	NH	ortho	Cl (para to NH)
719.	1	H	F	NH	ortho
720.	1	H	F	NH	ortho	F (para to NH)
721.	1	H	F	NH	ortho
722.	1	H	F	NH	meta
723.	1	H	H	F	ortho	H
724.	1	H	H	F	meta	H
725.	1	H	H	F	para	H
726.	1	H	H	F	ortho
727.	1	H	H	F	ortho
728.	1	H	H	F	meta
729.	1	H	H	F	meta
730.	1	H	H	F	meta
731.	1	H	H	F	ortho	Cl (para to X)
732.	1	H	H	F	ortho
733.	1	H	H	F	ortho	F (para to X)
734.	1	H	H	F	ortho
735.	1	H	H	F	meta
736.	1	H	F	ortho	H
737.	1	H	F	meta	H
738.	1	H	F	para	H
739.	1	H	F	ortho
740.	1	H	F	ortho
741.	1	H	F	meta
742.	1	H	F	meta
743.	1	H	F	meta
744.	1	H	F	ortho	Cl (para to X)
745.	1	H	F	ortho
746.	1	H	F	ortho	F (para to X)
747.	1	H	F	ortho
748.	1	H	F	meta
749.	1	H	H	F	ortho	H
750.	1	H	H	F	meta	H
751.	1	H	H	F	para	H
752.	1	H	H	F	ortho
753.	1	H	H	F	ortho
754.	1	H	H	F	meta
755.	1	H	H	F	meta
756.	1	H	H	F	meta
757.	1	H	F	ortho	H
758.	1	H	F	meta	H
759.	1	H	F	para	H
760.	1	H	F	ortho
761.	1	H	F	ortho
762.	1	H	F	meta
763.	1	H	F	meta
764.	1	H	F	meta
765.	1	H	H	F	ortho	H
766.	1	H	H	F	meta	H
767.	1	H	H	F	para	H
768.	1	H	H	F	ortho
769.	1	H	H	F	ortho
770.	1	H	H	F	meta
771.	1	H	H	F	meta
772.	1	H	H	F	meta
773.	1	H	F	ortho	H
774.	1	H	F	meta	H
775.	1	H	F	para	H
776.	1	H	F	ortho
777.	1	H	F	ortho
778.	1	H	F	meta
779.	1	H	F	meta
780.	1	H	F	meta
781.	1	H	H	F	ortho	H
782.	1	H	H	F	meta	H
783.	1	H	H	F	para	H
784.	1	H	H	F	ortho
785.	1	H	H	F	ortho
786.	1	H	H	F	meta
787.	1	H	H	F	meta
788.	1	H	H	F	meta
789.	1	H	F	ortho	H
790.	1	H	F	meta	H
791.	1	H	F	para	H
792.	1	H	F	ortho
793.	1	H	F	ortho
794.	1	H	F	meta
795.	1	H	F	meta
796.	1	H	F	meta
797.	1	H	H	F	bond	ortho	H
798.	1	H	H	F	bond	meta	H
799.	1	H	H	F	bond	para	H
800.	1	H	H	F	bond	ortho
801.	1	H	H	F	bond	ortho
802.	1	H	H	F	bond	meta
803.	1	H	H	F	bond	meta
804.	1	H	H	F	bond	meta
805.	1	H	F	bond	ortho	H
806.	1	H	F	bond	meta	H
807.	1	H	F	bond	para	H
808.	1	H	F	bond	ortho
809.	1	H	F	bond	ortho
810.	1	H	F	bond	meta
811.	1	H	F	bond	meta
812.	1	H	F	bond	meta
813.	2	H	H	F	NH	ortho	H
814.	2	H	H	F	NH	meta	H
815.	2	H	H	F	NH	para	H
816.	2	H	H	F	NH	ortho
817.	2	H	H	F	NH	ortho
818.	2	H	H	F	NH	meta
819.	2	H	H	F	NH	meta
820.	2	H	H	F	NH	meta
821.	2	H	H	F	NH	ortho	Cl (para to NH)
822.	2	H	H	F	NH	ortho
823.	2	H	H	F	NH	ortho	F (para to NH)
824.	2	H	H	F	NH	ortho
825.	2	H	H	F	NH	meta
826.	2	H	F	NH	ortho	H
827.	2	H	F	NH	meta	H
828.	2	H	F	NH	para	H
829.	2	H	F	NH	ortho
830.	2	H	F	NH	ortho
831.	2	H	F	NH	meta
832.	2	H	F	NH	meta
833.	2	H	F	NH	meta
834.	2	H	F	NH	ortho	Cl (para to NH)
835.	2	H	F	NH	ortho
836.	2	H	F	NH	ortho	F (para to NH)
837.	2	H	F	NH	ortho
838.	2	H	F	NH	meta
839.	2	H	H	F	ortho	H
840.	2	H	H	F	meta	H
841.	2	H	H	F	para	H
842.	2	H	H	F	ortho
843.	2	H	H	F	ortho
844.	2	H	H	F	meta
845.	2	H	H	F	meta
846.	2	H	H	F	meta
847.	2	H	H	F	ortho	Cl (para to X)
848.	2	H	H	F	ortho
849.	2	H	H	F	ortho	F (para to X)
850.	2	H	H	F	ortho
851.	2	H	H	F	meta
852.	2	H	F	ortho	H
853.	2	H	F	meta	H
854.	2	H	F	para	H
855.	2	H	F	ortho
856.	2	H	F	ortho
857.	2	H	F	meta
858.	2	H	F	meta
859.	2	H	F	meta
860.	2	H	F	NH	ortho	Cl (para to X)
861.	2	H	F	NH	ortho
862.	2	H	F	NH	ortho	F (para to X)
863.	2	H	F	NH	ortho
864.	2	H	F	NH	meta
865.	2	H	H	F	ortho	H
866.	2	H	H	F	meta	H
867.	2	H	H	F	para	H
868.	2	H	H	F	ortho
869.	2	H	H	F	ortho
870.	2	H	H	F	meta
871.	2	H	H	F	meta
872.	2	H	H	F	meta
873.	2	H	F	ortho	H
874.	2	H	F	meta	H
875.	2	H	F	para	H
876.	2	H	F	ortho
877.	2	H	F	ortho
878.	2	H	F	meta
879.	2	H	F	meta
880.	2	H	F	meta
881.	2	H	H	F	ortho	H
882.	2	H	H	F	meta	H
883.	2	H	H	F	para	H
884.	2	H	H	F	ortho
885.	2	H	H	F	ortho
886.	2	H	H	F	meta
887.	2	H	H	F	meta
888.	2	H	H	F	meta
889.	2	H	F	ortho	H
890.	2	H	F	meta	H
891.	2	H	F	para	H
892.	2	H	F	ortho
893.	2	H	F	ortho
894.	2	H	F	meta
895.	2	H	F	meta
896.	2	H	F	meta
897.	2	H	H	F	ortho	H
898.	2	H	H	F	meta	H
899.	2	H	H	F	para	H
900.	2	H	H	F	ortho
901.	2	H	H	F	ortho
902.	2	H	H	F	Meta
903.	2	H	H	F	meta
904.	2	H	H	F	meta
905.	2	H	F	ortho	H
906.	2	H	F	meta	H
907.	2	H	F	para	H
908.	2	H	F	ortho
909.	2	H	F	ortho
910.	2	H	F	meta
911.	2	H	F	meta
912.	2	H	F	meta
913.	2	H	H	F	bond	ortho	H
914.	2	H	H	F	bond	meta	H
915.	2	H	H	F	bond	para	H
916.	2	H	H	F	bond	ortho
917.	2	H	H	F	bond	ortho
918.	2	H	H	F	bond	meta
919.	2	H	H	F	bond	meta
920.	2	H	H	F	bond	meta
921.	2	H	F	bond	ortho	H
922.	2	H	F	bond	meta	H
923.	2	H	F	bond	para	H
924.	2	H	F	bond	ortho
925.	2	H	F	bond	ortho
926.	2	H	F	bond	meta
927.	2	H	F	bond	meta
928.	2	H	F	bond	meta

Table A

Examples of compounds according to the present invention are the compounds of the formula I', their pharmacologically tolerated salts and the N-oxides thereof, wherein R⁵ and R⁶ are hydrogen, and the meanings of X, R¹, R², R³, R⁴ and n and the position of X is given in the following table B:

Table B:

	n				X	Position of X vs. difluorodioxolan
929.	1	H	H	NH	ortho
930.	1	H	H	NH	meta
931.	1	H	NH	ortho
932.	1	H	NH	meta
933.	2	H	H	NH	ortho
934.	2	H	H	NH	meta
935.	2	H	NH	ortho
936.	2	H	NH	meta
937.	1	H	H	ortho
938.	1	H	H	meta
939.	1	H	ortho
940.	1	H	meta
941.	2	H	H	ortho
942.	2	H	H	meta
943.	2	H	ortho
944.	2	H	meta
945.	1	H	H	ortho
946.	1	H	H	meta
947.	1	H	ortho
948.	1	H	meta
949.	2	H	H	ortho
950.	2	H	H	meta
951.	2	H	ortho
952.	2	H	meta
953.	1	H	H	ortho
954.	1	H	H	meta
955.	1	H	ortho
956.	1	H	meta
957.	2	H	H	ortho
958.	2	H	H	meta
959.	2	H	ortho
960.	2	H	meta
961.	1	H	H	Bond	meta
962.	1	H	Bond	ortho
963.	1	H	Bond	meta
964.	2	H	H	Bond	ortho
965.	2	H	H	Bond	meta
966.	2	H	Bond	ortho
967.	2	H	Bond	meta
968.	1	H	H	ortho
969.	1	H	H	meta
970.	1	H	ortho
971.	1	H	meta
972.	2	H	H	ortho
973.	2	H	H	meta
974.	2	H	ortho
975.	2	H	meta
976.	1	H	H	ortho
977.	1	H	H	meta
978.	1	H	ortho
979.	1	H	meta
980.	2	H	H	ortho
981.	2	H	H	meta
982.	2	H	ortho
983.	2	H	meta
984.	1	H	H	ortho
985.	1	H	H	meta
986.	1	H	ortho
987.	1	H	meta
988.	2	H	H	ortho
989.	2	H	H	meta
990.	2	H	ortho
991.	2	H	meta
992.	1	H	H	Bond	meta
993.	1	H	Bond	ortho
994.	1	H	Bond	meta
995.	2	H	H	Bond	ortho
996.	2	H	H	Bond	meta
997.	2	H	Bond	ortho
998.	2	H	Bond	meta
999.	1	H	H	ortho
1000.	1	H	H	meta
1001.	1	H	ortho
1002.	1	H	meta
1003.	2	H	H	ortho
1004.	2	H	H	meta
1005.	2	H	ortho
1006.	2	H	meta
1007.	1	H	H	ortho
1008.	1	H	H	meta
1009.	1	H	ortho
1010.	1	H	meta
1011.	2	H	H	ortho
1012.	2	H	H	meta
1013.	2	H	ortho
1014.	2	H	meta
1015.	1	H	H	ortho
1016.	1	H	H	meta
1017.	1	H	ortho
1018.	1	H	meta
1019.	2	H	H	ortho
1020.	2	H	H	meta
1021.	2	H	ortho
1022.	2	H	meta
1023.	1	H	H	Bond	meta
1024.	1	H	Bond	ortho
1025.	1	H	Bond	meta
1026.	2	H	H	Bond	ortho
1027.	2	H	H	Bond	meta
1028.	2	H	Bond	ortho
1029.	2	H	Bond	meta
1030.	1	H	H	F	ortho
1031.	1	H	H	F	meta
1032.	1	H	F	ortho
1033.	1	H	F	meta
1034.	2	H	H	F	ortho
1035.	2	H	H	F	meta
1036.	2	H	F	ortho
1037.	2	H	F	meta
1038.	1	H	H	F	ortho
1039.	1	H	H	F	meta
1040.	1	H	F	ortho
1041.	1	H	F	meta
1042.	2	H	H	F	ortho
1043.	2	H	H	F	meta
1044.	2	H	F	ortho
1045.	2	H	F	meta
1046.	1	H	H	F	ortho
1047.	1	H	H	F	meta
1048.	1	H	F	ortho
1049.	1	H	F	meta
1050.	2	H	H	F	ortho
1051.	2	H	H	F	meta
1052.	2	H	F	ortho
1053.	2	H	F	meta
1054.	1	H	H	F	Bond	meta
1055.	1	H	F	Bond	ortho
1056.	1	H	F	Bond	meta
1057.	2	H	H	F	Bond	ortho
1058.	2	H	H	F	Bond	meta
1059.	2	H	F	Bond	ortho
1060.	2	H	F	Bond	meta

Table C:

Further examples are compounds of the formula I, where R⁶ is hydrogen, n, R¹, R³, X and R⁵ are as defined in the rows of Table A, wherein R² is methyl instead of hydrogen (compounds 1061 to 1988) and the physiologically tolerated acid addition salts or the N-oxides thereof.

Table D:

Further examples are compounds of the formula I', where R⁵ and R⁶ are hydrogen, n, R¹, R³ and X are as defined in the rows of Table B, wherein R² is methyl instead of hydrogen (compounds 1989 to 2120) and the physiologically tolerated acid addition salts or the N-oxides thereof.

The compounds I and I' according to the invention are prepared in analogy with methods known from the literature. An important approach to the compounds according to the invention is offered by the reaction of a 1-(piperazin-1-yl) or 1-(homopiperazin-1-yl) compound II where R³ is e.g. methyl or methoxy with chlorosulfonic acid and subsequent reaction of the intermediate sulfonyl chloride with an aniline derivative IV as depicted in scheme 1 or with a 2,2-difluorobenzo[1,3]dioxolane derivative IVa as depicted in scheme 1 a.

In schemes 1 and 1a, n, R² and R³ are as defined herein. R^a is a nitrogen protecting group or methyl. Suitable N-protecting groups are described, for example, in P.J. Kocienski "Protecting Groups", 2nd ed., Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in the literature cited therein. Preferred examples of N-protecting groups are e.g. oxycarbonyl groups such as C₁-C₆-alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl and Boc (tert-butoxycarbonyl) and other oxycarbonyl groups such as benzyloxycarbonyl (Cbz), allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and 2-trimethylsilylethoxycarbonyl (Teoc), or 2-propenyl (allyl). Especially preferred for introduction of a sulfonylchoride group is the trifluoroacetyl group as a protecting group for the piperazine or homopiperazine nitrogen. X¹ is a nucleophilically displaceable leaving group, in particular a halogen atom and, especially, chlorine or bromine.

Sulfone compounds of the present invention where X is a bond can be prepared according to schemes 2 and 3, either from compounds VI (which in itself can be prepared from aniline compounds VI where the NH₂ group is transformed into a group X² which can either be e.g. iodine or bromine, via a Sandmeyer reaction) by reaction with a thiophenol compound VIIIa and subsequent oxidation of the sulfide (scheme 2) with suitable oxidizing agents such as oxone or peracids, or by reaction of a compound VII with the salt of a sulfinic acid derivative VIIIb (usually the sodium salt) without the further need for an oxidative step (scheme 3; e.g. Synlett, 2003, 361 Cacchi et al.).

In schemes 2 and 3, n, R² and R³ are as defined herein. R^a is a nitrogen protecting group or methyl.

Compounds of formula (IX) can be prepared by the palladium-catalyzed reaction of the sulfinic acid salt Vlllb with compounds VII, wherein X² is bromine or iodine. A suitable palladium catalyst is tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃).The sulfone (IX) is usually prepared in the presence of Xantphos, a rigid bidendate ligand. The reaction is also usually carried out in the presence of n-tetrabutylammonium chloride. Sulfinate compounds VIIIb are either commercially available or can e.g. be prepared from the corresponding sulfonyl chlorides by reaction with sodium sulfite under basic conditions.

Compounds VIIa, wherein R³ is as defined above, can also be prepared from suitable aniline compounds by reaction with a suitably protected bis(2-chloroethyl)-amine where R^a can e.g. be the p-tolyl-sulfonyl group.

Compounds of the formulae V and Va, wherein R^a is a nitrogen protecting group, in particular trifluoroacetyl, a C₁-C₆-alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl and Boc (tert-butoxycarbonyl), are novel and thus form also part of the present invention.

Compounds of the formula V, wherein R^a is methyl correspond to compounds I, wherein R¹ is methyl. Compounds of the formula Va, wherein R^a is methyl correspond to compounds I', wherein R¹ is methyl.

The reaction depicted in schemes 1 and 1a takes place under the reaction conditions which are customary for preparing arylsulfonamide compounds or arylsulfonic esters, respectively, and which are described, for example, in J. March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, New York, 1985 p 444 and the literature cited therein, European J. Org. Chem. 2002 (13), pp. 2094-2108, Tetrahedron 2001, 57 (27) pp. 5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000, 10(8), pp. 835-838 and Synthesis 2000 (1), pp. 103-108.

The reaction customarily takes place in an inert solvent, for example in an ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether ortetrahydrofuran, a halohydrocarbon, such as dichloromethane, an aliphatic or cycloaliphatic hydrocarbon, such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumene and the like, or in a mixture of the abovementioned solvents. The reaction of compound III with compound IV (or compound IVa) is customarily carried out in the presence of an auxiliary base. Suitable bases are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogen carbonate or potassium hydrogen carbonate, and organic bases, for example trialkylamines, such as triethylamine, or pyridine compounds, such as pyridine, lutidine, 4-dimethylaminopyridine and the like. The latter compounds can at the same time serve as solvents. The auxiliary base is customarily employed in at least equimolar quantities, based on the amine compound II.

The reaction of compound III with compound IV or IVa, respectively yields compound V or Va, respectively, which, in case R^a is an N-protecting group, is deprotected to yield the compound of the general formula I or I', wherein R¹ is hydrogen. Deprotection of the compound V or Va, respectively, can be achieved by standard methods, e.g. by the methods as described in P.J. Kocienski "Protecting Groups", 2nd ed., Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in the literature cited therein.

Customary methods can then be used to react these compounds with a methylating agent such as methyl iodide or dimethyl sulfate resulting in a compound of the formula I or I', respectively, in which R¹ is methyl. The reaction conditions which are required for this methylating reaction are disclosed, for example, in WO 02/083652 , Tetrahedron 2000, 56(38) pp. 7553-7560 and Synlett. 2000 (4), pp. 475-480.

For preparing a compound of formula I or I', respectively, in which R¹ is methyl, it is likewise possible to react a compound of formula I or I', in which R¹ is hydrogen, with formaldehyde in the presence of a reducing agent in a sense of a reductive amination. Suitable reducing agents are borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or borane-pyridine. The reductive amination is usually carried out in an organic solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran or acetonitrile.

Reaction of the compound V or Va with an alkylating agent yields a compound of the formula V' or V'a, respectively, wherein n, R^a, R² and R³ are as defined above. In the compound of the formula V' or V'a, respectively, the sulfonamide hydrogen is replaced by C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂-.

It is possible to react the compound V or Va with a methylating agent such as methyl iodide or dimethyl sulfate to yield a compound of the formula Vc or Vd, respectively, wherein n, R^a, R² and R³ are as defined above.

If R^a in formulae Vc or Vd is an N-protecting group, compound Vc or Vd, respectively is deprotected to yield the compound of the general formula I, wherein R¹ is hydrogen. Deprotection of the compound Vc or Vd can be achieved by standard methods, e.g. by the methods as described in P.J. Kocienski "Protecting Groups", 2nd ed., Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in the literature cited therein.

Compounds V and IX where R^a is methyl can best be prepared by reaction of compounds V and IX where R^a is hydrogen with formaldehyde under reducing conditions as described above.

The compounds of the general formula VI are known per se or can be prepared in the manner shown in scheme 4.

In scheme 4, n, R^a, R² and R³ are as defined herein.

In step i) of scheme 4, the compound X is subjected to a nitration under standard conditions thereby yielding compound XI. Reaction conditions can be taken e.g. from US 6,599,904 or from the working examples of the present application.

In step ii) of scheme 4, the NH-group of compound XI is protected, either by a conventional N-protecting group as defined above or by introducing a methyl group via a methylating agent such as methyl bromide, methyl iodide or dimethyl sulfate. Introduction of an N-protecting group into compound XI can be achieved by standard methods, e.g. by the methods as described in P.J. Kocienski "Protecting Groups", 2nd ed., Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in the literature cited therein. Methylation of compound XI is likewise achieved by standard methods of Organic chemistry.

In step iii), the nitro group in compound XII is reduced to the NH₂ group to yield compound VI. The reaction conditions which are required for step iii) correspond to the customary conditions for reducing aromatic nitro groups which have been described extensively in the literature (see, for example, J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, New-York, 1985, p. 1183 and the literature cited in this reference). The reduction can be achieved, for example, by reacting the nitro compound XII with a metal such as iron, zinc or tin under acidic reaction conditions, i.e. using nascent hydrogen, or using a complex hydride such as lithium aluminum hydride or sodium borohydride, preferably in the presence of transition metal compounds of nickel or cobalt such as NiCl₂(P(phenyl)₃)₂, or CoCl₂, (see Ono et al. Chem. Ind. (London), 1983 p.480), or using NaBH₂S₃ (see Lalancette et al. Can. J. Chem. 49, 1971, p. 2990), with it being possible to carry out these reductions, depending on the given reagent, in substance or in a solvent or diluent. Alternatively, the reduction of XII to VI can be carried out with hydrogen in the presence of a transition metal catalyst, e.g. using hydrogen in the presence of catalysts based on platinum, palladium, nickel, ruthenium or rhodium. The catalysts can contain the transition metal in elemental form or in the form of a complex compound, of a salt or of an oxide of the transition metal, with it being possible, for the purpose of modifying the activity, to use customary coligands, e.g. organic phosphine compounds, such as triphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphines or phosphites. The catalyst is customarily employed in quantities of from 0.001 to 1 mol per mol of compound XII, calculated as catalyst metal. In a preferred variant, the reduction is effected using tin(II) chloride in analogy with the methods described in Bioorganic and Medicinal Chemistry Letters, 2002, 12(15), pp. 1917-1919 and J. Med. Chem. 2002, 45(21), pp. 4679-4688. The reaction of XII with tin(II) chloride is preferably carried out in an inert organic solvent, preferably an alcohol such as methanol, ethanol, isopropanol or butanol.

If not indicated otherwise, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, "Microwaves in Organic Synthesis", André Loupy (Ed.), Wiley-VCH 2002.

The acid addition salts of compounds I and I' are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example acetonitrile, a lower alcohol, such as methanol, ethanol or propanol, an ether, such as diethyl ether, methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, an ester, such as ethyl acetate, mixtures thereof as well as mixtures thereof with water.

The compounds of the present invention can be a 5-HT₆ receptor agonist, including partial agonistic activity, or a 5-HT₆ receptor antagonist, including inverse agonist activity.

The compounds of formulae I and I' according to the present invention, as well as their salts and their N-oxides, have a surprisingly high affinity for 5-HT₆ receptors. The high affinity of the compounds according to the invention for 5-HT₆ receptors is reflected in very low in-vitro receptor binding constants (K_i(5-HT₆) values) of as a rule less than 500, 100 or 50 nM (nmol/l), preferably of less than 10 nM and, in particular of less than 5 nM. The displacement of ³H-LSD can, for example, be used in receptor binding studies for determining binding affinities to 5-HT₆ receptors.

Furthermore the compounds of formulae I and I', as well as their salts and their N-oxides, are highly selective 5-HT₆ receptor ligands which, because of their low affinity for other receptors such as dopamine receptors, adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors, in particular dopamine D₂, α₁-adrenergic and histamine H₁ receptors, give rise to fewer side-effects than other, less selective 5-HT₆ ligands.

For instance the 5-HT₆/D₂, 5-HT₆/α₁-adrenergic or 5-HT₆/H₁selectivities of the compounds according to the present invention, i.e. the ratios K_i(D₂)/K_i(5-HT₆), K_i(α₁-adrenergic)/K_i(5-HT₆) or K_i(H₁)/K_i(5-HT₆) of the receptor binding constants, is as a rule at least 25, preferably at least 50, even better at least 100.

The displacement of [³H]SCH23390 or [¹²⁵I]spiperone can be used, for example, for carrying out receptor binding studies on D₁, D₂ and D₄ receptors.

Furthermore the compounds of the present invention because of their structural features are susceptible to display an enhanced brain penetration than other known 5-HT₆ receptor ligands.

Because of their binding profile, the compounds of the present invention can be used for treating diseases which respond to 5-HT₆ receptor ligands (or which are susceptible to treatment with a 5-HT₆ receptor ligand), i.e. they are effective for treating those medical disorders or diseases in which exerting an influence on (modulating) the 5-HT₆ receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of these diseases are disorders or diseases of the central nervous system.

Disorders or diseases of the central nervous system are understood as meaning disorders which affect the spinal cord and, in particular, the brain. Within the meaning of the invention, the term "disorder" denotes disturbances and/or anomalies which are as a rule regarded as being pathological conditions or functions and which can manifest themselves in the form of particular signs, symptoms and/or malfunctions. While the treatment according to the invention can be directed toward individual disorders, i.e. anomalies or pathological conditions, it is also possible for several anomalies, which may be causatively linked to each other, to be combined into patterns, i.e. syndromes, which can be treated in accordance with the invention.

The disorders which can be treated in accordance with the invention are in particular disorders which respond to a modulation of the 5-HT₆ receptor. They include cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowel Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, addiction diseases including e.g. drug addiction and obesity.

The addiction diseases include psychic disorders and behavioral disturbances which are caused by the abuse of psychotropic substances, including certain pharmaceuticals, such as sedative, anxiolytica, hypnotics or narcotics (hereinafter also referred to as drug addiction), and also other addiction diseases, such as addiction to gaming (gambling; impulse control disorders not elsewhere classified). Examples of addictive substances are: opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics and tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate and other stimulants including caffeine. Addictive substances which come particularly into consideration are opioids, cocaine, amphetamine or amphetamine-like substances, hallucinogens, NMDA-receptor antagonists such phencyclidine and related cyclidines, dextrometorphan, dextrorphan, ibogaine, ketimine and tiletamine, cannabis, nicotine and alcohol. Other addiction diseases include gaming (gambling), including problem gambling (compulsive gambling, ludomania), computer or video game addiction and internet addiction.

With regard to the treatment of addiction diseases, particular preference is given to those compounds according to the present invention which themselves do not possess any psychotropic effect. This can also be observed in a test using rats, which, after having been administered compounds which can be used in accordance with the invention, reduce their self administration of psychotropic substances, for example cocaine or alcohol.

According to another aspect of the present invention, the compounds according to the invention are suitable for treating disorders whose causes can at least partially be attributed to an anomalous activity of 5-HT₆ receptors.

According to another aspect of the present invention, the treatment is directed, in particular, toward those disorders which can be influenced, within the sense of an expedient medicinal treatment, by the binding of preferably exogeneously administered binding partners (ligands) to 5-HT₆ receptors.

The diseases which can be treated with the compounds according to the invention are frequently characterized by progressive development, i.e. the above-described conditions change over the course of time; as a rule, the severity increases and conditions may possibly merge into each other or other conditions may appear in addition to those which already exist.

The compounds of the present invention can be used to treat a large number of signs, symptoms and/or malfunctions which are connected with the disorders of the central nervous system and, in particular, the abovementioned conditions. These signs, symptoms and/or malfunctions include, for example, a disturbed relationship to reality, lack of insight and ability to meet customary social norms or the demands made by life, changes in temperament, changes in individual drives, such as hunger, sleep, thirst, etc., and in mood, disturbances in the ability to observe and combine, changes in personality, in particular emotional lability, hallucinations, ego-disturbances, distractedness, ambivalence, autism, depersonalization and false perceptions, delusional ideas, chanting speech, lack of synkinesia, short-step gait, flexed posture of trunk and limbs, tremor, poverty of facial expression, monotonous speech, depressions, apathy, impeded spontaneity and decisiveness, impoverished association ability, anxiety, nervous agitation, stammering, social phobia, panic disturbances, withdrawal symptoms in association with dependency, maniform syndromes, states of excitation and confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g. Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigo syndromes, e.g. peripheral positional, rotational and oscillatory vertigo, melancholia, hysteria, hypochondria and the like.

Within the meaning of the invention, a treatment also includes a preventive treatment (prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term treatment, for example within the context of a maintenance therapy.

The compounds according to the invention are preferentially suitable for treating diseases of the central nervous system, more preferably for treating cognitive dysfunctions and in particular, for treating cognitive dysfunctions associated with schizophrenia or with Alzheimer's disease.

According to another aspect of the invention the compounds of the present invention are particularly suitable for treating addiction diseases caused for instance by the abuse of psychotropic substances, such as pharmaceuticals, narcotics, nicotine or alcohol, including psychic disorders and behavioral disturbances related thereto. The compounds of the present invention are likewise particularly suitable for treating addiction diseases which are not caused by the abuse of psychotropic substances, such as gaming (gambling), including problem gambling (compulsive gambling, ludomania), computer or video game addiction and internet addiction. With regard to addiction diseases, the compound of the present invention can be used for the therapy during addiction and also for preventing relapse into addiction.

According to another aspect of the invention the compounds of formulae (I) and (I)', their salts and their N-oxides are particularly suitable for treating nutritional disorders, such as obesity, as well as diseases related thereto, such as cardiovascular diseases, digestive diseases, respiratory diseases, cancer or type 2 diabetes.

Within the context of the treatment, the use according to the invention of the described compounds involves a method. In this method, an effective quantity of one or more compounds, as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other active compounds or active compound-containing preparations such that a daily dose of preferably from about 0.1 to 1000 mg/kg of bodyweight, in the case of oral administration, or of from about 0.1 to 100 mg/kg of bodyweight, in the case of parenteral administration, is supplied to an individual to be treated.

The invention also relates to the production of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being, productive animal or domestic animal. Thus, the compounds of formulae I or I', their salts and/or their N-oxides are customarily administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient together with at least one compound according to the invention and, where appropriate, other active compounds. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to the invention are optionally mixed or diluted with one or more excipients. Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.

Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to explain the present invention without limiting its scope.

The compounds were either characterized via proton-NMR in d₆-dimethylsulfoxid or d-chloroform on a 400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode), or melting point.

The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (δ) expressed in parts per million (ppm). The relative area of the shifts in the ¹H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).

I. Preparation of the intermediate compounds V and IX I.1 Preparation of the intermediate compounds V PREPARATION EXAMPLE 1: N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonamide

1.1 2,2,2-Trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone

29.9 g of 2,2,2-trifluoroacetic anhydride (104 mmol) were dissolved in 150 mL of dichloromethane, cooled to -20°C, and 20 g of 1-o-tolylpiperazine-1,4-diium chloride (80 mmol) - dissolved in 150 mL of dichloromethane - added dropwise. After stirring for 16 h at room temperature, 400 ml of ice water were added, the organic phase separated, washed twice with water, and the pH adjusted to neutral with 1 % aqueous sodium bicarbonate solution. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulphate, filtered and the solvent evaporated to yield 21.5 g of product which crystallized upon cooling.

1.2 4-Methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride

To a solution of 2 g of 2,2,2-trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone (7.35 mmol) in 5 mL of dichloromethane at -5°C were slowly added 19.7 g of chlorosulfonic acid (169 mmol). After stirring for 2h at -5°C, the reaction mixture continued stirring for 16 h, thereby slowly allowed to warm to room temperature. After cooling to 0°C, the reaction mixture was slowly added to a water/ice mixture. The aqueous phase was extracted five times with dichloromethane, the combined organic phases washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over magnesium sulphate, filtered, and the solvent evaporated to yield 2.2 g of product as a white solid.

1.3 N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonamide

0.429 g of 3-(difluoromethoxy)-aniline (2.7 mmol) were dissolved in 5 mL of pyridine. 1 g of 4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonylchloride (2.7 mmol) were added slowly at room temperature. After stirring for 16 h at room temperature, the reaction mixture was evaporated several times after addition of toluene. The residue was dissolved in dichloromethane and washed several times with 5% aqueous ammonium chloride. The organic phase was then washed with saturated aqueous sodium chloride, dried over sodium sulphate, filtered, and the solvent evaporated. The crude product was purified via silica gel chromatography using dichloromethane/methanol (0-5%) to yield 0.63 g of product.

For the preparation of the intermediate compounds V' or V'a, respectively, i.e. compounds of the formula V or V', respectively, wherein the sulphonamide hydrogen (R⁴ = H) is replaced by C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂-(compounds V or V', respectively, with R⁴ = C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂-), where R⁴ is e.g. a methyl group, the corresponding trifluoroacetyl group has to be removed by reaction under basic conditions, followed by reprotection with tert.butyl-dicarbonate, reaction of this Boc-protected intermediate V with sodium hydride and an alkylating agent, e.g. in case that R⁴ is methyl, methyl iodide. The N-methylated derivative can then be deprotected at the piperazine or homopiperazine moiety under standard acidic conditions to yield final products.

PREPARATION EXAMPLE 2: N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-[1,4]diazepan-1-yl]-benzenesulfonamide

The compound can be prepared as described for PREPARATION EXAMPLE 1 starting from commercially available 1-o-tolyl-[1,4]diazepane.

1.2 Preparation of intermediate compounds IX PREPARATION EXAMPLE 3: 1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methylphenyl]-4-(toluene-4-sulfonyl)-piperazine

3.1 1-(5-Iodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine

9.97 g of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (30.3 mmol) and 5.03 g of potassium iodide (30.3 mmol) in 75 mL of cyclohexanol were stirred for 1 h at 80°C. After addition of 7.7 g of sodium carbonate (72.7 mmol) and 5.65 g of 5-iodo-2-methylaniline (24.2 mmol), stirring continued for 8h at 160°C. At room temperature, the mixture was filtered, washed with dichloromethane, and the filtrate evaporated to dryness. The residue was dissolved in dichloromethane, filtered, and the solvent evaporated. The remaining residue was trituated with n-heptane and the crystalline product filtered off, washed several times with n-heptane and dried in vacuo to yield 10.7 g of product.

3.2 1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-sulfonyl)-piperazine

0.521 g of 1-(5-lodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine (1.14 mmol), 0.315 g of sodium 3-(difluoromethoxy)benzenesulfinate (1.37 mmol), 0.558 g of cesium carbonate (1.713 mmol), 0.026 g of Pd(dba)₃ (0.029 mmol), 0.033 g of Xantphos (0.059 mmol) and 0.381 g of tetrabutylammonium chloride (1.37 mmol) were stirred for 8 h in 10 mL of toluene. The reaction mixture was filtered and the solvent evaporated. The crude product was purified via silica gel chromatography with toluene/methanol 20:1 (2.5% triethylamine), fractions containing the product combined and the solvents evaporated to yield 0.386 g of product.

II. Preparation of the compounds I Example 1: N-(3-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

0.63 g of N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonamide (1.28 mmol) were dissolved in 90 ml of methanol, 2.77 ml of 6N aqueous sodium hydroxide (16.6 mmol) added and the reaction stirred at 67°C for 10 min. 150 mL of water were added, the aqueous layer extracted with ethyl acetate, and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent evaporated. The residue was converted to the hydrochloride salt by addition of HCl in diethyl ether. Evaporation to dryness followed by dissolution of the remaining white solid in water and lyophilisation of the aqueous phase yielded 0.535 g of product. ESI-MS: 398.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.45 (s, 1H), 9.0 (broad, 2H), 7.3-7.45 (m, 3H), 7.25 (m, 1 H), 7.15 (t, 1 H), 6.95 (d, 1 H), 6.9 (s, 1 H), 6.85 (d, 1 H), 3.25 (broad, 4H), 3.0 (broad, 4H), 2.25 (s, 3H).

Example 2: 3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide hydrochloride

The product was obtained as described for Example 1 by reaction of N-(3-difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-[1,4]diazepan-1-yl]-benzenesulfonamide with aqueous sodium hydroxide. ESI-MS: 412.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s, 1 H), 9.55 (s, broad, 2H), 7.45 (s, 1 H), 7.0-7.4 (several m, 4H), 7.0 (d, 1 H), 6.95 (s, 1 H), 6.8 (d, 1 H), 4.0 (s, broad, 2H), 3.2 (broad, 6H), 3.0 (m, 2H), 2.25 (s, 3H).

Example 3 1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazine hydrochloride

0.75 g of 4-hydroxy-benzoic acid (7.06 mmol) and 2.485 mL of 32% HBr in acetic acid (72.4 mmol) were mixed under stirring and the suspension cooled to 0°C. 0.379 g of 1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-sulfonyl)-piperazine (0.706 mmol) dissolved in 5 mL of acetic acid were added and the reaction mixture stirred for 16 h. Additional 30 equivalents of HBr in acetic acid were added, stirred for 18 h, and the reaction added slowly to ice water. The pH was adjusted to neutral conditions with addition of aqueous ammonia, the aqueous layer extracted three times with dichloromethane, the combined organic layers dried over magnesium sulphate, filtered and the solvent evaporated. The crude product was purified via silica gel chromatography using toluene/methanol 5:1 (2.5% triethylamine), the solvents evaporated and the residue redissolved in a small amount of ethyl acetate. The hydrochloride was precipitated by addition of 2 N hydrochlorid acid in diethyl ether yielding 0.059 g of product. ESI-MS: 383.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.8 (d, 1 H), 7.7 (s, 1 H), 7.65 (m, 1 H), 7.6 (d, 1 H), 7.5 (m, 2H), 7.45 (d, 1 H), 7.4 (t, 1 H), 3.2 (broad, 4H), 3.1 (broad, 4H), 2.3 (s, 3H).

The compounds of Examples 4 to 49 can be prepared in a manner analogous to the preparations described above.

Example 4 N-(2-Difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 6.9-7.5 (several m, 9H), 3.5 (broad, 8H), 3.1 (s, 3H), 2.75 (s, 3H).

Example 5 N-(2-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.4 (broad, 1 H), 9.9 (s, 1 H), 7.4 (s, 1 H), 7.05-7.35 (several m, 6H), 6.95 (t, 1 H), 3.45 (broad, 2H), 3.2 (broad, 2H), 3.1 (broad, 4H), 2.8 (s, 3H), 2.3 (s, 3H).

Example 6 N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzene-sulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 3H), 7.45 (s, 1 H), 7.38 (d, 1 H), 7.32 (d, 1 H), 7.15 (d, 1 H), 7.05 (t, 1 H), 6.95 (s, 1 H), 6.9 (d, 1 H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.25 (s, 3H), 2.05 (s, 3H).

Example 7 N-(4-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 398.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.35 (broad, 1H), 9.55 (broad, 2H), 7.25-7.45 (several m, 3H), 7.15 (t, 1 H), 7.15 (d, 2H), 7.05 (d, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.25 (s, 3H).

Example 8 N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 1 H), 7.25-7.45 (several m, 3H), 7.2 (d, 1 H), 7.1 (m, 1 H), 6.9 (d, 1 H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (broad, 3H).

Example 9 N-Cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 452.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (broad, 2H), 7.05-7.5 (several m, 7H), 7.1 (t, 1 H), 3.35 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (broad, 3H), 0.75 (m, 1 H), 0.3 (m, 2H), -0.05 (m, 2H).

Example 10 N-Cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 452.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 2H), 6.8-7.55 (several m, 8H), 3.4 (m broad, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.35 (broad, 3H), 0.75 (m broad, 1 H), 0.35 (m broad, 2H), 0.0 (m broad, 2H).

Example 11 N-(2-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-sulfonamide hydrochloride

ESI-MS: 440.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (broad, 2H), 7.4 (m, 2H), 7.3 (d, 1 H), 7.25 (d, 2H), 7.1 (t, 1 H), 7.1 (m, 2H), 3.4 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H), 1.3 (m, 2H), 0.8 (t, 3H).

Example 12 N-(3-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamide hydrochloride

ESI-MS: 440.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.4 (broad, 2H), 7.4 (m, 2H), 7.3 (t, 1 H), 7.25 (d, 1 H), 7.15 (d, 1 H), 6.95 (s, 1 H), 6.95 (d, 1 H), 6.85 (s, 1 H), 3.45 (t, 2H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.35 (s, 3H), 1.3 (m, 2H), 0.8 (t, 3H).

Example 13 N-(3-Difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide hydrochloride

ESI-MS: 426.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.35 (broad, 2H), 7.4 (m, 2H), 7.25 (t, 1H), 7.25 (d, 1 H), 7.2 (d, 1 H), 7.0 (s, 1 H), 6.95 (d, 1 H), 6.85 (s, 1 H), 3.55 (m, 2H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.35 (s, 3H), 0.95 (t, 3H).

Example 14 N-(3-Difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (broad, 2H), 7.4 (m, 2H), 7.3 (t, 1H), 7.2 (d, 1 H), 7.1 (d, 1 H), 7.0 (d, 1 H), 6.95 (s, 1 H), 6.9 (s, 1 H), 3.55 (m, 2H), 3.2 (broad, 4H), 3.1 (s, 3H), 2.95 (broad, 4H), 2.35 (s, 3H).

Example 15 N-(2-Difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide hydrochloride

ESI-MS: 426.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (broad, 2H), 7.4 (m, 2H), 7.35 (d, 1H), 7.25 (m, 2H), 7.15 (t, 1 H), 7.15 (d, 1 H), 7.1 (d, 1 H), 3.5 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.35 (s, 3H), 0.95 (t, 3H).

Example 16 N-(2-Difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 2H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (m, 2H), 7.1 (t, 1 H), 7.1 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 3.05 (s, 3H), 2.3 (s, 3H).

Example 17 N-(2-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 398.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.85 (s, 1 H), 9.1 (broad, 2H), 7.3-7.4 (m, 3H), 7.25 (d, 1 H), 7.1-7.2 (m, 3H), 6.9 (t, 1 H), 3.25 (broad, 4H), 3.0 (broad, 4H), 2.3 (s, 3H).

Example 18 N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-sulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8-7.2 (t, 1 H), 6.9 (s, 1 H), 6.8 (d, 1 H), 3.8 (s, 3H), 2.8 (s, 8H, 2.1 (s, 3H).

Example 19 N-(4-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 414.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.25 (s, 1H), 9.5 (broad, 2H), 7.35 (d, 1H), 7.25 (d, 1 H), 7.15 (d, 2H), 7.15 (t, 1 H), 7.05 (m, 3H), 3.8 (s, 3H), 3.2 (broad, 8H).

Example 20 3-[1,4]Diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.8 (s, 1 H), 9.4 (s broad, 2H), 7.4 (s, 1 H), 7.2-7.3 (m, 3H), 7.1-7.2 (m, 3H), 6.9 (t, 1 H), 3.25 (m, 6H), 3.0 (m, 2H), 2.3 (s, 3H), 2.0 (m, 2H).

Example 21 3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methylbenzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s, 1 H), 9.4 (s broad, 2H), 7.4 (s, 1 H), 7.3 (m, 2H), 7.15 (d, 1 H), 7.05 (t, 1 H), 6.95 (m, 1 H), 6.85 (m, 1 H), 3.2-3.3 (m, 6H), 3.0 (m, 2H), 2.3 (s, 3H), 2.1 (s, 3H), 2.05 (m, 2H).

Example 22 N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 3H), 7.4 (s, 1H), 7.3 (m, 2H), 7.1 (d, 1 H), 6.9-7.0 (m, 2H), 6.9 (t, 1 H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H), 2.25 (s, 3H).

Example 23 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.4-9.9 (broad, 3H), 7.4 (s, 1H), 7.3 (m, 2H), 7.1 (s, 1 H), 6.9-7.0 (m, 2H), 6.85 (t, 1 H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H), 2.2 (s, 3H).

Example 24 N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 414.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s, 1H), 9.6 (s broad, 2H), 7.4 (d, 1H), 7.3 (s, 1 H), 7.25 (m, 1 H), 7.15 (t, 1 H), 7.1 (d, 1 H), 7.0 (m, 1 H), 6.95 (s, 1 H), 6.8 (d, 1 H), 3.8 (s, 3H), 3.1-3.2 (broad, 8H).

Example 25 N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 444.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.05 (s, 1 H), 9.3 (s broad, 2H), 7.35 (d, 1 H), 7.25 (s, 1 H), 6.8-7.1 (several m, 5H), 3.8 (s, 1 H), 3.7 (s, 3H), 3.2 (s broad, 4H), 3.15 (s broad, 4H).

Example 26 N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 414.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.8 (s, 1 H), 9.7 (s broad, 2H), 7.35 (d, 1 H), 7.3 (s, 1 H), 7.25 (d, 1 H), 7.1-7.2 (several m, 3H), 7.05 (d, 1 H), 7.0 (t, 1 H), 3.8 (s, 3H), 3.2 (broad, 8H).

Example 27 N-(2-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

27.1 tert-butyl 4-(5-(N-(2-(difluoromethoxy)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate

1 g of N-(2-(difluoromethoxy)phenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonamide (2.419 mmol) were dissolved in 15 mL of tetrahydrofuran. 0.674 mL of triethylamine (4.84 mmol) were added, followed by addition of 0.528 g of di-tert-butyl dicarbonate (2.419 mmol) in 2 mL of tetrahydrofurane. The reaction mixture was stirred at room temperature for 16 h. After evaporation of the solvent, the residue was dissolved in dichloromethane, washed with 5% aqueous citric acid. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulphate, filtered, and the solvent evaporated. The crude product containing ca. 25% of the bis-boc derivative was used without further purification in the next step (1.2 g).

27.2 tert-butyl 4-(5-(N-(2-(difluoromethoxy)phenyl)methyl-sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate

0.15 g of tert-butyl 4-(5-(N-(2-(difluoromethoxy)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate (0.219 mmol) were dissolved in 5 mL of dimethylformamide. 11.4 mg of sodium hydride (0.285 mmol, 60%) were added and the reaction stirred at 50°C for 20 min. At room temperature, 0.018 mL of methyl iodide (0.285 mmol) were added. Stirring was continued for 16 h at room temperature followed by addition of additional 0.018 mL of methyl iodide and stirring for 16 h. The solvent was evaporated, the residue dissolved in dichloromethane and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and the solvent evaporated. Purification via silica gel chromatography (Redisep NP-cartridge) with cyclohexane/ethyl acetate (0-50%) yielded 0.104 g of the title compound. ESI-MS: 528.2 [M+H]+

27.3 N-(2-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

0.104 g tert-butyl 4-(5-(N-(2-(difluoromethoxy)phenyl)methyl-sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate (0.197 mmol) were dissolved in 5 mL of dichloromethane. At room temperature, 0.296 mL of 2 N aqueous hydrochloric acid (0.591 mmol) were added and the reaction stirred for 16 h and 2 h at 35°C. After addition of methanol, stirring continued for 1 h before the solvents were evaporated and the residue co-destilled several times with diethyl ether to remove residual hydrochloric acid. The remaining solid was dissolved in water (pH 4), extracted several times with dichloromethane, and aqueous layer lyophilized to yield 0.08 g of the title compound. ESI-MS: 428.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.3 (s broad 2H), 7.45 (m, 1H), 7.4 (m, 1H), 7.25 (m, 2H), 7.2 (d, 1 H), 7.1 (d, 1 H), 7.1 (t, 1 H), 7.0 (s, 1 H), 3.9 (s, 3H), 3.2 (s broad, 4H), 3.15 (s broad, 4H), 3.05 (s, 3H).

Examples 9, 10, 11, 12, 13, 14, 15, 16, 28, 29, 30, 31, 32, 33, 34, 36, 39, and 43 were prepared as described for Example 27, using either methyl iodide, ethyl iodide, propyl bromide, isopropyl bromide or cyclopropyl-methylen-bromide as alkylating reagents.

Example 28 N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 458.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (s broad, 2H), 9.05 (s broad, 1H), 7.2 (m, 1 H), 7.25 (m, 2H), 7.05 (t, 1 H), 6.95 (m, 1 H), 6.9 (s, 1 H), 6.8 (s, 1 H), 3.9 (s, 3H), 3.85 (s, 3H), 3.2 (broad, 8H), 3.05 (s, 3H).

Example 29 N-(3-Difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 442.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.4 (m, 1H), 7.25 (t, 1H), 7.25 (m, 1 H), 7.1-7.2 (several m, 2H), 6.9 (d, 1 H), 6.8 (s, 2H), 3.85 (s, 3H), 3.5 (m, 2H), 3.2 (s broad, 4H), 3.15 (s broad, 4H), 0.9 (t, 3H).

Example 30 N-(3-Difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 472.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.3 (s broad, 2H), 7.25 (d, 1H), 7.1-7.2 (m, 2H), 7.0 (t, 1 H), 6.95 (m, 1 H), 6.9 (s, 1 H), 6.8 (s, 1 H), 3.9 (s, 3H), 3.85 (s, 3H), 3.5 (m, 2H), 3.2 (s broad, 4H), 3.15 (s broad, 4H), 0.95 (t, 3H).

Example 31 N-(2-Difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 442.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s, broad, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.2-7.3 (m, 2H), 7.2 (m, 1 H), 7.15 (t, 1 H), 7.1 (d, 1 H), 7.0 (s, 1 H), 3.9 (s, 3H), 3.5 (m, 2H), 3.1-3.25 (s broad, 8H), 0.95 (t, 3H).

Example 32 N-(3-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s broad, 2H), 9.0 (s, broad, 1H), 7.4 (m, 1 H), 7.3 (t, 1 H), 7.25 (m, 1 H), 7.1-7.2 (m, 2H), 7.0 (d, 1 H), 6.95 (s, 1 H), 6.7 (s, 1 H), 3.9 (s, 3H), 3.2 (s broad, 4H), 3.1 (s broad, 4H), 2.5 (m, 3H).

Example 33 N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide hydrochloride

ESI-MS: 486.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.3 (s broad, 2H), 7.25 (d, 1H), 7.15 (m, 2H), 7.0 (t, 1 H), 6.95 (d, 1 H), 6.85 (d, 1 H), 6.75 (s, 1 H), 3.9 (s, 3H), 3.8 (s, 3H), 3.4 (t, 2H), 3.2 (broad, 4H), 3.1 (broad, 4H), 1.8 (m, 2H), 0.8 (t, 3H).

Example 34 N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide hydrochloride

ESI-MS: 456.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (s broad, 2H), 7.4 (m, 1 H), 7.25 (d, 2H), 7.15 (m, 2H), 6.95 (d, 1 H), 6.85 (s, 1 H), 6.8 (s, 1 H), 3.85 (s, 3H), 3.45 (t, 2H), 3.2 (broad, 4H), 3.1 (broad, 4H), 1.8 (m, 2H), 0.8 (t, 3H).

Example 35 N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.45 (d, 1H), 7.2 (m, 2H), 6.8-7.0 (several m, 4H), 6.45 (t, 1 H), 3.9 (s, 3H), 3.0 (s, 4H), 2.6 (s, 4H), 2.35 (s, 3H).

Example 36 N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide hydrochloride

ESI-MS: 456.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.0 (broad, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 6.9-7.3 (several m, 6H), 3.9 (s, 3H), 3.4 (t, 2H), 3.2 (broad, 4H), 3.15 (broad, 4H), 1.3 (m, 2H), 0.8 (t, 3H).

Example 37 N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s broad, 1H), 9.7 (s, 1H), 7.4 (d, 1H), 7.3 (m, 2H), 7.05-7.2 (several m, 4H), 6.95 (t, 1 H), 3.85 (s, 3H), 3.45 (m, 4H), 3.2 (m, 2H), 2.95 (m, 2H), 2.8 (d, 3H).

Example 38 N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 458.1 [M+H]⁺ ¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.35 (m, 2H), 7.0 (m, 1H), 6.9 (s, 1H), 6.8 (m, 2H), 6.5 (t, 1 H), 3.9 (s, 3H), 3.8 (s, 3H), 3.2 (broad, 4H), 2.8 (broad, 4H), 2.5 (s, broad, 3H).

Example 39 N-(2-Difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 440.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s broad, 2H), 6.95-7.55 (several m, 8H), 4.3 (m, 1 H), 3.2 (broad, 4H), 3.1 (broad, 4H), 2.3 (s, 3H), 1.0 (d, 3H), 0.9 (d, 3H).

Example 40 N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.4 (s, 1 H), 9.6 (s broad, 2H), 7.35 (d, 1 H), 7.25 (s, 1 H), 7.2 (d, 1 H), 7.1 (m, 2H), 6.9 (d, 1 H), 3.85 (s, 3H), 3.2 (broad, 8H).

Example 41 N-(2-Difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 384.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.9 (s, 1H), 9.75 (s broad, 2H), 7.4 (m, 2H), 7.25 (m, 2H), 7.1-7.2 (m, 4H), 6.95 (t, 1 H), 3.4 (broad, 4H), 3.15 (broad, 4H),

Example 42 N-(2-Difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 398.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.45 (s broad, 1 H), 9.9 (s broad, 1 H), 7.35-7.45 (m, 2H), 7.25 (m, 2H), 7.1-7.2 (m, 4H), 7.0 (t, 1 H), 3.0-3.9 (broad, 8H), 2.75 (s, 3H).

Example 43 N-(2-Difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 398.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.5 (m, 1H), 7.45 (m, 1H), 7.3 (m, 1 H), 7.2 (m, 2H), 7.1 (m, 3H), 7.05 (t, 1 H), 3.4 (broad, 4H), 3.2 (broad, 4H), 3.1 (s, 3H).

Example 44 N-(2-Difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.5 (broad, 1H), 7.55 (m, 1H), 7.5 (m, 1H), 7.45 (d, 1 H), 7.25 (m, 2H), 7.05-7.2 (several m, 4H), 3.4 (broad, 8H), 3.1 (s, 3H), 2.8 (s, 3H).

Example 45 1-[3-(3-Difluoromethoxy-benzenesulfonyl)-phenyl]-piperazine hydrochloride

ESI-MS: 369.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s broad, 2H), 7.85 (d, 1 H), 7.75 (s, 1 H), 7.7 (m, 1 H), 7.45-7.55 (several m, 3H), 7.4 (t, 1 H), 7.4 (d, 1 H), 7.3 (m, 1 H), 3.5 (s broad, 4H), 3.15 (s broad, 4H).

Example 46 1-[3-(3-Difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazine hydrochloride

ESI-MS: 383.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.85 (d, 1H), 7.8 (s, 1H), 7.7 (m, 1H), 7.45-7.55 (several m, 3H), 7.4 (d, 1 H), 7.4 (t, 1 H), 7.3 (d, 1 H), 3.95 (d, 2H), 3.65 (d, 2H), 3.25 (m, 2H), 3.15 (m, 2H), 2.8 (d, 3H).

Example 47 1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine hydrochloride

ESI-MS: 399.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.65 (m, 2H), 7.45 (d, 1 H), 7.4 (t, 1 H), 7.4 (m, 1 H), 7.2 (d, 1 H), 3.85 (s, 3H), 3.25 (s broad, 4H), 3.2 (s broad, 4H).

Example 48 1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-piperazine hydrochloride

ESI-MS: 413.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.8 (d, 1H), 7.75 (s, 1H), 7.65 (m, 2H), 7.5 (d, 1 H), 7.4 (t, 1 H), 7.4 (s, 1 H), 7.2 (d, 1 H), 3.85 (s, 3H), 3.55 (m, 2H), 3.45 (m, 2H), 3.05-3.2 (m, 4H), 2.8 (s, 3H).

Example 49 1-[5-(3-Difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine hydrochloride

ESI-MS: 429.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (s broad, 2H), 7.85 (d, 1H), 7.7 (s, 1H), 7.6 (d, 1 H), 7.3 (m, 2H), 7.2 (t, 1 H), 7.17 (d, 1 H), 3.9 (s, 3H), 3.85 (s, 3H), 3.25 (s broad, 4H), 3.2 (s broad, 4H).

Example 50 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 442,1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 1 H), 9.0 (broad, 2H), 7.35 (d, 1 H), 7.27 (s, 1 H), 7.1 (s, 1 H), 7.05 (d, 1 H), 6.95 (m, 2H), 6.85 (t, 1 H), 4.1 (q, 2H), 3.2 (broad, 4H), 3.15 (broad, 4H), 2.2 (s, 3H), 1.35 (t, 3H).

Example 51 N-(3,4-Bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 494 [M+H]⁺

Example 52 N-(3,4-Bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 464.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.6 (broad, 1 H), 9,6 (broad, 2H), 7.3-7.45 (m, 3H), 6.9-7.3 (several m, 5H), 3.2 (broad, 4H), 3.05 (broad, 2H), 2.3.

Example 53 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 462 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (broad, 1 H), 10.05 (broad, 1 H), 7.4 (d, 1 H), 7.35 (s, 1 H), 7.32 (s, 1 H), 7.23 (d, 1 H), 7.18 (d, 1 H), 7.1 (d, 1 H), 7.0 (t, 1 H), 3.85 (s, 3H), 3.5 (broad, 4H), 3.2 (broad, 2H), 3.0 (broad, 2H), 2.8 (s, 3H).

Example 54 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide

ESI-MS: 440.1 [M+H]⁺

Example 55 N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 442.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.6 (broad, 1 H), 9.6 (broad, 1 H), 7.35 (d, 1 H), 7.05-7.25 (several m, 4H), 6.9 (d, 1 H), 6.8 (s, 1 H), 3.85 (s, 3H), 3.1-3.7 (broad, 8H), 3.4 (s, 3H), 2.0 (s, 3H).

Example 56 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 446.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.4 (very broad, 2H), 7.48 (s, 1 H), 7.4 (m, 2H), 7.33 (s, 1H), 7.23 (d, 1H), 7.18 (d, 1H), 6.98 (t, 1H), 2.95-3.7 (broad, 8H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 57 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 448.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.05 (s, 1 H), 9.1 (broad, 2H), 7.4 (d, 1 H), 7.32 (m, 2H), 7.22 (d, 1 H), 7.17 (d, 1 H), 7.10 (d, 1 H), 7.0 (t, 1 H), 3.85 (s, 3H), 3.2 (broad, 4H), 3.15 (broad, 4H).

Example 58 N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.2-7.4 (several m, 3H), 7.15 (d, 1 H), 7.1 (t, 1 H), 6.88(d, 1 H), 6.82 (s, 1 H), 3.1 (broad, 4H), 2.9 (broad, 4H), 2.3 (s, 3H), 1.95 (s, 3H).

Example 59 N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.65-9.8 (broad, 3H), 7.3 (d, 1 H), 7.2 (s, 1 H), 7.18 (d, 1H), 7.12 (t, 1H), 7.1 (d, 1H), 6.9 (d, 1H), 6.75 (s, 1H), 3.8 (s, 3H),3.15 (broad, 8H), 1.95 (s, 3H).

Example 60 N-(3,4-Bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 480.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.55 (s, 1 H), 9.5 (s, 2H), 7.43 (d, 1 H), 7.25 (m, 2H), 6.9-7.15 (m, 5H), 3.9 (s, 3H), 3.2 (broad, 8H).

Example 61 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 446 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.25 (broad, 1 H), 9.55 (broad, 2H), 7.5 (s, 1 H), 7.4 (m, 2H), 7.3 (s, 1 H), 7.25 (d, 1 H), 7.2 (d, 1 H), 7.0 (t, 1 H), 3.25 (broad, 4H), 3.05 (broad, 4H), 2.7 (q, 2H), 1.2 (t, 3H).

Example 62 N-(2-Difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (broad, 2H), 7.3-7.4 (m, 3H), 7.1 (d, 1 H), 6.97 (d, 1 H),6.93 (s, 1 H), 6.9 (t, 1 H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.68 (q, 2H), 2.25 (s, 3H), 1.18 (t, 3H).

Example 63 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 426.2 [M+H]⁺ ¹H-NMR (methanol-d₄, 400 Hz): δ [ppm] 7.3-7.45 (m, 4H), 6.9-7.05 (m, 2H), 6.4 (t, 1H), 2.7-3.7 (several m, 7H), 2.4 (s, 3H), 2.3 (s, 3H), 1.4 (d, 3H).

Example 64 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 426.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.85 (s, 1 H), 9.65 (broad, 1 H), 9.4 (broad, 1 H), 7.4 (s, 1 H), 7.35 (s, 2H), 7.1 (s, 1 H), 6.95-7.0 (m, 2H), 7.0 (t, 1 H), 3.4 (broad, 3H), 3.1 (m, 2H), 2.95 (m, 1 H), 2.8 (m, 1 H), 2.3 (s, 3H), 2.22 (s, 3H), 1.3 (d, 3H).

Example 65 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.85 (broad, 1 H), 9.6 (broad, 2H), 7.45 (s, 1 H), 7.4 (m, 2H), 7.1 (s, 1 H), 6.95-7.0 (m, 2H), 6.85 (t, 1 H), 3.22 (broad, 4H), 3.02 (broad, 4H), 2.68 (q, 2H), 2.2 (s, 3H), 1.15 (t, 3H).

Example 66 N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 442.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.1 (broad, 1 H), 7.33 (d, 1 H), 7.28 (d, 1 H), 7.08-7.15 (m, 2H), 7.05 (d, 1 H), 6.8 (d, 1 H), 3.8 (s, 3H), 2.9 (broad, 4H), 2.45 (broad, 4H), 2.2 (s, 3H).

Example 67 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

0.429 g N-(2-(difluoromethoxy)-5-methylphenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonamide (1.004 mmol) were dissolved in 5 mL of dichloromethane. 0.086 mL of acetic acid (1.505 mmol) and 0.319 g of sodium triacetoxyborohydride (3.01 mmol) were added. After stirring for 10 min, 0.083 mL of aqueous formaldehyde solution (3.01 mmol) were added and the reaction stirred for 72 h at room temperature. The solvents were evaporated and the residue purified via preparative silica gel chromatography (Super Flash cartridge (Interchim)) using a dichloromethane (+0.1% triethylamine) and methanol gradient as eluent. Fractions containing the product were combined, the solvents evaporated, and the product converted to the hydrochloride salt by addition of hydrochloric acid in diethyl ether and subsequent evaporation to dryness (yield 0.169 g of product). ESI-MS: 442.1 [M+H]+ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 1 H), 7.3 (d, 1 H), 7.2 (s, 1 H), 7.1 (s, 1 H), 6.9-7.05 (several m, 3H), 6.8 (t, 1 H), 3.8 (s, 3H), 2.9 (broad, 4H), 2.45 (broad, 4H), 2.2 (two s, 6H).

Example 68 N-(3-Difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 384.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.6 (s, 1 H), 9.85 (broad, 1 H), 9.45 (broad, 2H), 7.4 (m, 2H), 7.2-7.35 (m, 3H), 7.2 (t, 1 H), 7.0 (m, 1 H), 6.95 (s, 1 H), 6.85 (d, 1 H), 3.15-3.65 (broad, 8H).

Example 69 N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 446.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.85 (broad, 1 H), 9.75 (s, 1 H), 7.2-7.35 (m, 3H), 7.0-7.1 (m, 3H), 7.07 (t, 1 H), 3.85 (s, 3H), 3.5 (m, 4H), 3.18 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H).

Example 70 N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 442.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.2 (broad, 1 H), 9.6 (s, 1 H), 7.3 (m, 2H), 7.12 (d, 1 H), 7.05 (d, 1 H), 6.9-7.0 (several m, 2H), 6.92 (t, 1 H), 3.8 (s, 3H), 3.45 (m, 4H), 3.17 (m, 2H), 3.05 (m, 2H), 2.8 (s, 3H), 2.25 (s, 3H).

Example 71 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 432.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s, 1H), 9.75 (broad, 2H), 7.15-7.5 (several m, 6H), 7.05 (t, 1 H), 3.2 (broad, 4H), 3.07 (broad, 4H), 2.3 (s, 3H).

Example 72 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 463,9306 1 H-NMR (DMSO-d6, 400 Hz): d [ppm] 9.7 (broad, 1 H), 9.6 (broad, 2H), 7.35 (d, 1 H), 7.3 (s, 1 H), 7.1 (s, 1 H), 7.05 (d, 1 H), 6.9-7.0 (m, 2H), 6.85 (t, 1 H), 3.8 (s, 3H), 3.1-3.25 (broad, 8H) 2.2 (s, 3H).

Example 73 N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.3 (d, 1 H), 7.2 (s, 1 H), 7.15 (d, 1 H), 6.95 (d, 1 H), 6.9 (d, 1 H), 6.85 (t, 1 H), 3.8 (s, 3H), 2.8-2.95 (broad, 8H) 2.2 (s, 3H).

Example 74 N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 416.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.15-7.35 (several m, 4H), 7.1 (t, 1 H), 6.8-6.95 (m, 2H), 3.0 (broad, 4H), 2.85 (broad, 4H), 2.2 (s, 3H).

Example 75 N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.35 (broad, 1 H), 10.4 (s, 1 H), 7.4 (s, 1 H), 7.35 (m, 2H), 7.15 (d, 1 H), 7.1 (t, 1 H), 7.0 (s, 1 H), 6.9 (m, 1 H), 3.5 (broad, 2H), 3.2 (broad, 2H), 3.1 (broad, 4H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (s, 3H).

Example 76 N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.4 (broad, 1 H), 7.4 (m, 1 H), 7.37 (m, 2H), 7.03 (d, 1 H), 6.9 (t, 1 H), 6.87 (s, 1 H), 6.65 (d, 1 H), 3.7 (s, 3H), 3.25 (broad, 4H), 3.0 (broad, 4H), 2.25 (s, 3H).

Example 77 N-(5-Difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide trifluoroacetate

ESI-MS: 442.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s, 1 H), 7.3-7.45 (m, 3H), 7.07 (d, 1 H), 7.05 (t, 1 H), 6.95 (m, 2H), 3.55 (s, 3H), 3.55 (broad, 2H), 3.2 (broad, 4H), 2.9 (broad, 2H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 78 N-(2-Difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide trifluoroacetate

ESI-MS: 442.1 [M+H]⁺ ¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.5 (d, 1 H), 7.37 (s, 1 H), 7.2 (d, 1 H), 6.93 (m, 2H), 6.6 (d, 1 H), 6.2 (t, 1 H), 3.8 (s, 3H), 3.67 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 79 N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide trifluoroacetate

ESI-MS: 430.1 [M+H]⁺ ¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.63 (m, 1H), 7.38 (m, 2H), 6.95 (m, 1H), 6.85 (s, 1 H), 6.78 (d, 1 H), 6.27 (t, 1 H), 3.7 (m, 2H), 3.25 (m, 2H), 2.95-3.2 (broad, 4H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 80 N-(5-Difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide trifluoroacetate

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 9.8 (broad, 2H), 7.52 (d, 1 H), 7.38 (s, 2H), 7.1 (s, 1 H), 6.8 (m, 1 H), 6.7 (m, 1 H), 6.45 (t, 1 H), 3.7 (s, 3H), 3.35 (broad, 4H), 3.1 (broad, 4H), 2.3 (s, 3H).

Example 81 N-(2-Difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 2H), 7.45 (s, 1 H), 7.35 (m, 2H), 7.05 (d, 1 H), 6.8 (d, 1 H), 6.8 (t, 1 H), 6.7 (d, 1 H), 3.65 (s, 3H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H).

Example 82 N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 432.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.15-7.35 (several m, 3H), 6.9-7.05 (several m, 3H), 6.85-7.15 (t, 1 H), 3.8 (s, 3H), 3.05 (m, 4H), 3.0 (m, 4H).

Example 83 N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.35 (d, 1 H), 7.15-7.2 (m, 2H), 7.05 (s, 1 H), 7.0 (d, 1 H), 6.85 (d, 1 H), 3.8 (s, 3H), 2.85-3.0 (broad, 8H).

Example 84 N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412,1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.4 (s, 1 H), 9.25 (broad, 2H), 7.4 (s, 1 H), 7.35 (m, 2H), 7.28 (d, 1 H), 7.15 (m, 1 H), 6.88 (d, 1 H), 3.25 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H).

Example 85 N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 428.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 8.8-10.4 (very broad, 3H), 7.3-7.4 (m, 3H), 7.03 (d, 1 H), 6.95 (t, 1 H), 6.85-7.0 (m, 2H), 3.75 (s, 3H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.25 (s, 3H).

Example 86 N-(3-Difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 443.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (very broad, 1 H), 10.15 (s, 1 H), 7.4 (s, 1 H), 7.3 (m, 2H), 7.05 (d, 1 H), 6.95 (m, 2H), 6.95 (t, 1 H), 3.7 (s, 3H), 3.05-3.5 (broad, 8H), 2.8 (s, 3H), 2.25 (s, 3H).

Example 87 N-(4-Difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 427.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s broad, 1 H), 7.3-7.4 (m, 3H), 7.15 (d, 1 H), 7.0 (t, 1 H), 6.95 (s, 1 H), 6.88 (m, 1 H), 3.4 (broad, 4H), 3.1 (broad, 4H), 2.8 (s, 3H), 2.25 (s, 3H), 2.1 (s, 3H).

Example 88 N-(4-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 413.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.25 (s broad, 1 H), 7.3-7.4 (m, 3H), 7.1 (dd, 2H), 7.05 (dd, 2H), 7.05 (t, 1 H), 3.4 (broad, 4H), 3.1 (broad, 4H), 2.75 (s, 3H), 2.3 (s, 3H).

Example 89 N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 442.2 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.2 (s broad, 1 H), 7.4 (d, 1 H), 7.3 (s, 2H), 7.15 (d, 1 H), 7.08 (m, 1 H), 7.03 (t, 1 H), 6.95 (s, 1 H), 6.9 (d, 1 H), 3.8 (s, 3H), 3.0-3.6 (broad, 8H), 2.8 (s, 3H), 2.1 (s, 3H).

Example 90 N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide

ESI-MS: 458.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.42 (d, 1 H), 7.27 (s, 1 H), 7.05 (m, 2H), 6.9 (d, 1 H), 6.9 (t, 1 H), 6.7 (d, 1 H), 3.8 (s, 3H), 3.7 (s, 3H), 3.1 (broad, 4H), 2.9 (broad, 4H), 2.5 (s, 3H).

Example 91 N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 427.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (broad, 1 H), 9.7 (s broad, 1 H), 7.4 (s, 1 H), 7.25-7.35 (m, 2H), 7.1 (d, 1 H), 6.97 (d, 1 H), 6.95 (s, 1 H), 6.9 (t, 1 H), 3.0-3.5 (broad, 8H), 2.8 (s, 3H), 2.3 (s, 3H), 2.25 (s, 3H).

Example 92 N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 427.5 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (broad, 1 H), 9.8 (s broad, 1 H), 7.4 (s, 1 H), 7.32 (s, 2H), 7.1 (s, 1 H), 7.0 (m, 2H), 6.85 (t, 1 H), 6.9 (t, 1 H), 3.0-3.5 (broad, 8H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H).

Example 93 N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 444.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 8.4 (broad, 1 H), 7.42 (m, 1 H), 7.24 (s, 1 H), 7.0-7.15 (m, 2H), 6.85-7.0 (m, 2H), 6.7 (m, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 3.0 (broad, 8H).

Example 94 N-(3-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s broad, 1 H), 7.2-7.4 (several m, 3H), 7.15 (t, 1 H), 7.0 (d, 1 H), 6.92 (s, 1 H), 6.82 (d, 1 H), 3.0-3.5 (broad, 8H), 2.8 (s, 3H), 2.25 (s, 3H).

Example 95 N-(4-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 428.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (broad, 1 H), 10.2 (s, 1 H), 7.38 (d, 1 H), 7.3 (s, 1 H), 7.15 (dd, 2H), 7.07 (m, 3H), 7.1 (t, 1 H), 3.8 (s, 3H), 3.4 (broad, 4H), 3.1 (broad, 4H), 2.8 (s, 3H).

Example 96 3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.53 (s, 1 H), 9.55 (s, 2H), 7.45 (s, 1 H), 7.2-7.4 (m, 3H), 7.15 (t, 1 H), 7.0 (d, 1 H), 6.95 (s, 1 H), 6.8 (d, 1 H), 3.25 (broad, 6H), 3.05 (m, 2H), 2.25 (s, 3H), 2.05 (broad, 2H).

Example 97 3-[1,4]Diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.8 (s, 1H), 9.4 (s, 2H), 7.4 (s, 1H), 7.2-7.35 (m, 3H), 7.1-7.2 (m, 3H), 6.9 (t, 1 H), 3.25 (broad, 6H), 3.05 (m, 2H), 2.3 (s, 3H), 2.05 (broad, 2H).

Example 98 3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s, 1 H), 9.45 (s, 2H), 7.4 (s, 1 H), 7.3 (s, 2H), 7.15 (d, 1 H), 7.05 (t, 1 H), 6.95 (s, 1 H), 6.87 (d, 1 H), 3.25 (broad, 6H), 3.05 (m, 2H), 2.3 (s, 3H), 2.1 (s, 3H), 2.05 (broad, 2H).

Example 99 N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 440.2 [M+H]⁺

Example 100 N-(2-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺ ¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5-11.0 (very broad, 2H), 7.4 (s, 1 H), 7.2-7.35 (m, 3H), 7.1-7.2 (m, 3H), 6.93 (t, 1 H), 3.4 (broad, 6H), 3.05 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.15 (broad, 2H).

Example 101 N-(3-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide hydrochloride

ESI-MS: 426.2 [M+H]⁺

Example 102 N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl benzenesulfonamide

Example 103 N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperazin-1-yl benzenesulfonamide

Example 104 N-(5-Difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-yl benzenesulfonamide

Example 105 N-(5-Difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-yl benzenesulfonamide

III. Biological investigations

Displacement of radioligands binding to the following cloned human receptors

1. Preparation of membranes by ultrasonic treatment and differential centrifugation

Cells from stable clonal cell lines expressing the corresponding receptor (5-HT₆, α₁-adrenergic, dopamine D₂ or histamine H₁ receptors) were washed with PBS (w/o Ca⁺⁺, Mg⁺⁺) and harvested in PBS with 0.02% EDTA. The cells were collected by centrifugation at 500 g for 10 min. at 4°C, washed with PBS and centrifuged (500 g, 10 min. 4°C). The pellets were stored at -80°C until use. For membrane preparation, the thawed cell pellet was resuspended in ice-cold sucrose buffer (0.25 M sucrose, 10 mM Hepes (pH 7.4), 1 mM Phenylmethylsulfonyl fluoride (PMSF) in DMSO, 5 µg/ml Pepstatin-A, 3 mM EDTA, 0.025 % Bacitracin) and homogenized with a Branson Sonifier W-250 (Settings: Timer 4; Output Control 3; Duty Cycle constant; 2 to 3 cycles). Cell disruption was checked with the aid of a microscope. Remaining unbroken cells were pelleted at 1.000 g for 10 min. at 4°C. The sucrose buffer supernatant was then centrifuged at 60.000 g for 1 h at 4°C (Beckman Ultrazentrifuge XL 80). The pellet was resuspended in 30 ml ice-cold Tris buffer (20 mM TRIS (pH 7.4), 5 µg/ml Pepstatin A, 0.1 mM PMSF, 3 mM EDTA) by pipetting through a 10 ml serological pipet and centrifuged for 1 h at 4°C at 60.000 g. A final resuspension was performed in a small volume of ice-cold Tris buffer (see above) by pressing through a serological pipet followed by ultrasonic treatment with a Branson Sonifier W-250 (Settings: Timer 1; Output Control 3; Duty Cycle constant; 1 cycle). Protein concentration was determined (BCA-Kit; Pierce) and aliquots stored at -80°C or in liquid nitrogen for long-term storage.

2. Receptor binding experiments

All receptor binding experiments were carried out in the corresponding assay buffer in a total volume of 200 µl in the presence of various concentrations of test compound (10^-5 M to 10^-9 M, tenfold serial dilution, duplicate determinations). The assays were terminated by filtration on polyethylenimine (PEI 0.1% or 0.3%) presoaked Packard Unifilter Plates (GF/C or GF/B) with a Tomtec Machlll U 96well-plate harvester. After the plates had been dried for 2 h at 55°C in a drying chamber scintillation cocktail (BetaPlate Scint; PerkinElmer) was added. Radioactivity was measured in a Microbeta Trilux two hours after the addition of the scintillation mixture. Data derived from liquid scintillation counting were analysed by iterative non-linear regression analysis with the use of the Statistical Analysis System (SAS): a program similar to "LIGAND" as described by Munson and Rodbard (Analytical Biochemistry 107, 220-239 (1980).

a) 5-HT₆ receptor binding assay

HEK293 cells stably expressing the h-5-HT₆ receptor (NCBI Reference Sequence XM 001435) were cultured in RPMI1640 medium supplemented with 25 mM HEPES, 10 % fetal calf serum and 1-2 mM glutamine. The membrane preparation was performed as described in section 1. For these membranes a K_D of 1.95 nM for [³H]-LSD (Lysergic Acid Diethylamide; Amersham, TRK1038) was determined by means of saturation binding experiments. On the day of the assay, the membranes were thawed, diluted in assay buffer (50 mM Tris-HCl, 5 mM CaCl₂, 0.1% ascorbic acid, 10 µM pargyline, pH 7.4) to a concentration of 8 µg protein/assay and homogenized by gentle vortexing For inhibition studies, 1 nM [³H]-Lysergic Acid Diethylamide was incubated in the presence of various concentrations of test compound in assay buffer. Non-specific binding was defined with 1 µM methiothepin. The binding reaction was carried out for 3.5 h at room temperature. During the incubation, the plates were shaken on a plate shaker at 100 rpm and terminated by filtration on Packard Unifilter GF/C (0.1 % PEI) plates, followed by 2 wash cycles with ice-cold 50 mM Tris-HCl, 5 mM CaCl₂.

a) Dopamine D₂ receptor binding assay

HEK293 cells stably expressing the dopamine D₂ receptor (NCBI Reference Sequence NM_000795) were cultured in RPMI1640 medium supplemented with 25 mM HEPES, 10 % fetal calf serum and 1-2 mM glutamine. The membrane preparation was performed as described in section 1. For these membranes a K_D of 0.22 nM for [¹²⁵I]-iodospiperone (PerkinElmer Life Sciences, NEX284) was determined by means of saturation binding experiments. On the day of the assay, the membranes were thawed, diluted in assay buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl₂, 5 mM KCI, 1.5 mM CaCl₂, pH 7.4) to a concentration of 15 µg protein/assay and homogenized by gentle vortexing. For inhibition studies, 0.01 nM [¹²⁵I]-iodospiperone (PerkinElmer Life Sciences, NEX284) was incubated in the presence of various concentrations of test compound in assay buffer. Non-specific binding was defined with 1 µM haloperidol. The binding reaction was carried out for 1 h at room temperature and terminated by filtration on Packard Unifilter GF/B (0.1 % PEI) plates, followed by 6 wash cycles with an ice-cold 7 % polyethylenglycol solution.

b) α₁-Adrenergic receptor binding assay

CHO-K₁ cells stably expressing the α₁-adrenergic receptor (NCBI Reference Sequence NM_033303) were cultured in RPMI1640 medium supplemented with 25 mM HEPES, 10 % fetal calf serum and 1-2 mM glutamine. The membrane preparation was performed as described in section 1. For these membranes a K_D of 0.12 nM for [³H]-prazosine (PerkinElmer Life Sciences, NET823) was determined by means of saturation binding experiments. On the day of the assay, the membranes were thawed, diluted in assay buffer (50 mM Tris-HCl, pH 7.4) to a concentration of 4 µg protein/assay and homogenized by gentle vortexing. For inhibition studies, 0.1 nM [³H]-prazosine (PerkinElmer Life Sciences, NET823) was incubated in the presence of various concentrations of test compound in assay buffer. Non-specific binding was defined with 1 µM phentolamine. The binding reaction was carried out for 1 h at room temperature and terminated by filtration on Packard Unifilter GF/C (0.1 % PEI) plates, followed by 3 wash cycles with ice-cold assay buffer.

c) H₁ receptor binding assay

CHO-K₁ cells stably expressing the histamine H₁ receptor (Euroscreen-ES-390-C, NCBI Reference Sequence NM_000861) were cultured in RPMI1640 medium supplemented with 25 mM HEPES, 10 % fetal calf serum and 1-2 mM glutamine. The membrane preparation was performed as described in section 1. For these membranes a K_D of 0.83 nM for [³H]-pyrilamine (PerkinElmer Life Sciences, NET594) was determined by means of saturation binding experiments. On the day of the assay, the membranes were thawed, diluted in assay buffer (50 mM Na₂HPO₄, 50 mM KH₂PO₄, pH 7.4) to a concentration of 6 µg protein/assay and homogenized by gentle vortexing. For inhibition studies, 1 nM [³H]-pyrilamine (PerkinElmer Life Sciences, NET594) was incubated in the presence of various concentrations of test compound in assay buffer. Non-specific binding was defined with 1 µM pyrilamine. The binding reaction was carried out for 50 minutes at room temperature and terminated by filtration on Packard Unifilter GF/C (0.3% PEI) plates, followed by 2 wash cycles with ice-cold assay buffer.

3. Data Analysis

Data derived from liquid scintillation counting were analyzed by iterative non-linear regression analysis with the use of the Statistical Analysis System (SAS): a program similar to "LIGAND" as described by Munson and Rodbard (Anal. Biochem. 1980, 107, 220-239). Fitting was performed according to formulae described by Feldman (Anal. Biochem. 1972, 48, 317-338). IC₅₀, nH and K_i values were expressed as geometrical mean. For receptors with a low affinity for the test compound, where the highest tested compound concentration inhibited less than 30% of specific radioligand binding, K_i-values were determined according to the equation of Cheng and Prusoff (Biochem. Pharmacol. 1973, 22, 2099-2108) and expressed as greater than (>).

The results of the receptor binding studies are expressed as receptor binding constants K_i(5-HT₆), K_i(D₂), K_i(α₁-adrenergic) and K_i(H₁), respectively, as described herein before, and given in table I.

In these tests, the compounds according to the invention exhibit very good affinities for the 5-HT₆ receptor (K_i < 500 nM or < 100 nM or < 50 nM or < 20 nM and frequently < 10 nM). Furthermore those compounds bind selectively to the 5-HT₆ receptor, as compared to the affinity for the D₂, the α₁-adrenergic or the H₁ receptors. These compounds exhibit little affinities for the D₂, α₁-adrenergic or H₁ receptors (K_i > 500 nM or > 1000 nM and frequently > 10000 nM).

<10 nM

<50 nM

<500 nM

<50 nM

<500 nM

<50 nM

<100 nM

<500 nM

<10 nM

<50 nM

<10 nM

<50 nM

<10 nM

<500 nM

<50 nM

<10 nM

<500 nM

<10 nM

<50 nM

<10 nM

<50 nM

<10 nM

<50 nM

<10 nM

<50 nM

<500 nM

<50 nM

<500 nM

<10 nM

<50 nM

<10 nM

<50 nM

<10 nM

<50 nM

<500 nM

<10 nM

3. Determination of the metabolic stability

The metabolic stability of the compounds of the invention was determined in the following assay by analyzing the microsomal half-life. The test substances are incubated in a concentration of 0.5 µM as follows:

0.5 µM test substance is preincubated together with liver microsomes of various species (0.25 mg of protein/ml) in 0.05M potassium phosphate buffer pH 7.4 in microtiter plates at 37°C for 5 min. The reaction is started by adding NADPH (1 mg/mL). Aliquots are taken after 0, 5, 10, 15, 20 and 30 min, and the reaction is stopped with the same volume of acetonitrile and cooled down. The remaining test compound concentrations are being determined by liquid chromatography - mass spectrometry analysis. Intrinsic clearance values are calculated using the elimination rate constant of test compound depletion.

Claims

N-Phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) of formula (I) or (I') wherein
X is a bond or a group N-R⁴;

R¹ is hydrogen or methyl;

R² is hydrogen or methyl;

R³ is hydrogen, C₁-C₃ alkyl, fluorine, C₁-C₂ alkoxy or fluorinated C₁-C₂ alkoxy;

R⁴ is hydrogen, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂-;

R⁵ is hydrogen, fluorine, chlorine, C₁-C₂ alkyl, fluorinated C₁-C₂ alkyl, C₁-C₂ alkoxy or fluorinated C₁-C₂ alkoxy;

R⁶ is hydrogen, fluorine or chlorine; and

n is 1 or 2,
or a physiologically tolerated acid addition salt or an N-oxide thereof.
The compound as claimed in claim 1, where R¹ is hydrogen.
The compound as claimed in any one of claims 1 or 2, wherein X is a group N-R⁴.
The compound as claimed in any one of claims 1 to 3, wherein n is 1.
The compound as claimed in any one of claims 1 to 4, wherein R³ is methyl or methoxy.
The compound as claimed in any of claims 1 to 4, wherein R³ is hydrogen or fluorine.
The compound as claimed in any of claims 1 to 6, wherein R⁴ is hydrogen.
The compound as claimed in any one of claims 1 to 7, wherein R⁵ is hydrogen, methyl, methoxy, difluoromethoxy, chlorine or fluorine.
The compound as claimed in any one of claims 1 to 8, wherein R⁶ is hydrogen.
The compound as claimed in any of claims 1 to 4, wherein R⁵ and R⁶ are hydrogen, R³ is selected from the group consisting of C₁-C₂ alkyl and C₁-C₂ alkoxy, and R⁴ is selected from the group consisting of hydrogen, C₁-C₄ alkyl and cyclopropylmethyl.
The compound as claimed in claim 1, wherein
X is a bond or a group N-R⁴;

R¹ is hydrogen or methyl;

R² is hydrogen;

R³ is hydrogen, C₁-C₂ alkyl or C₁-C₂ alkoxy ;

R⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropylmethyl;

R⁵ is hydrogen, methyl or methoxy;

R⁶ is hydrogen; and

n is 1 or 2.
The compound as claimed in any one of claims 1 to 11, wherein the OCHF₂-radical in formula I is located on the benzene ring in the ortho-position with respect to X.
The compound as claimed in any of claims 1 to 11, wherein the OCHF₂-radical in formula I is located on the benzene ring in the meta-position with respect to X.
The compound as claimed in any of claims 1 to 11, wherein the OCHF₂-radical in formula I is located on the benzene ring in the para-position with respect to X.
The compound as claimed in claim 1, which are selected from the group consisting of
N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide,

1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazine, N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide,

N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(4-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-sulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide,

N-(3-difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide,

N-(2-difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-sulfonamide,

N-(4-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide,

3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide,

N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-piperazine,

1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazine,

1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine,

1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methylpiperazine,

1-[5-(3-difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(3,4-bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(5-difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(5-chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(4-difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(4-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

N-(4-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide,

3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide,

3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide,

3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide,

N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide,

N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide,

N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide,

N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperazin-1-yl benzenesulfonamide,

N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-yl-benzenesulfonamide,

N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-yl benzenesulfonamide,
the physiologically tolerated acid addition salts thereof and the N-oxides thereof.
The compound as claimed in any one of claims 1 to 15 for use in therapy.
A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1 to 15, optionally together with at least one physiologically acceptable carrier or auxiliary substance.
The compound as claimed in any one of claims 1 to 15 for use in treating a disorder selected from diseases of the central nervous system, addiction diseases and obesity.