MX2008009292A - Cyclohexyl sulfonamide derivatives having h3 receptor activity - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein R1to R3are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

Description

CYCLOHEXIL-SULFONAMIDE DERIVATIVES DESCRIPTION OF THE INVENTION The present invention relates to new cyclohexyl sulfonamide derivatives, to their preparation, to pharmaceutical compositions containing them and to their use as medicaments.

The active compounds of the present invention are useful for the treatment of obesity and other disorders. In particular, the present invention relates to compounds of the general formula wherein R1 is selected from the group consisting of lower alkyl, cycloalkyl, cycloalkylalkyl lower and tetrahydropyranyl; R 2 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl lower, halogeno lower alkyl, lower alkoxyalkyl and lower cyanoalkyl; R3 is selected from the group consisting of lower alkyl, _ (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the aryl ring is unsubstituted or Ref .: 194530 replaced by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, - (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl and -NRR5; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, lower halogenalkyl, lower alkoxyalkyl, lower cyanoalkyl, phenyl unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl and lower phenylalkyl, which phenyl ring may be unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoin, haloalkoxy lower and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur, a sulfinyl group or a sulfonyl group, the ring heterocyclic is unsubstituted or 'substituted by one, two or three groups independently chosen from lower alkyl, halogen, halogenoalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl or is fused with a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof. The compounds of the formula I are antagonists and / or inverse agonists of the histamine 3 receptor (H3 receptor). Histamine (2- (4-imidazolyl) ethylamine) is one of the aminergic neurotransmitters that is widely distributed, eg, through the gastrointestinal tract (Burks, in Johnson, L.R. (coord.), Physiology of the Gastrointestinal Tract, Raven Press, NY, pp. 211-242, 1994). Histamine regulates a wide variety of digestive pathophysiological events, for example, the secretion of gastric acid, intestinal motility (Leurs et al., Br. J. Pharmacol., 102, pp. 179-185, 1991), vasomotor responses, Intestinal inflammatory responses and allergic reactions (Raithel et al., Int. Arch. Allergy Immunol. 127-133, 1995). In the mammalian brain, histamine is synthesized in the histaminergic cell bodies that are centralized in the tuberomamilar nucleus of the posterior basal hypothalamus. From there they are projected to various brain regions (Panula et al., Proc. Nati. Acad. Sci.

USA 81, 2572-2576, 1984; Inagaki et al., J. Comp. Neurol. 273, 283-300, 1988). According to current knowledge, histamine intervenes in all the actions mentioned, both in the CNS and in the periphery by means of four different receptors of histamine, the histamine receptors H1, H2, H3 and H4. The H3 receptors are located predominantly in the central nervous system (CNS). In their autoreceptive condition, the H3 receptors constitutively inhibit the synthesis and secretion of histamine in histaminergic neurons (Arrang et al., Nature 302, 832-837, 1983; Arrang et al., Neuroscience 23, 149-157, 1987). In their condition of heterorreceptores they also modulate the release of other neurotransmitters, such as acetylcholine, dopamine, serotonin and norepinephrine, among others, both in the central nervous system and in peripheral organs, such as the lungs, the cardiovascular system and the gastrointestinal tract (Clapham &Kilpatrik, Br. J. Pharmacol., 107, 919-923, 1982; Blandina et al., in: The Histamine H3 Receptor (Leurs, RL and Timmermann, H., coord., pp. 27-40, 1998, Elsevier, Amsterdam, The Netherlands.) The H3 receptors are constitutively active, this means that even without exogenous histamine, the receptor is activated tonic.In the case of an inhibitory receptor, for example the H3 receptor, is Inherent activity causes the tonic inhibition of neurotransmitter release, so it may be important that the H3R antagonist has reverse agonist activity both to block the effects of exogenous histamine and to move the receptor from its constitutively active (inhibitory) form to a neutral state. The wide distribution of the H3 receptors in the CNS of mammals indicates the physiological role of this receptor.

Therefore, therapeutic potential has been proposed as an objective for the development of new drugs for various indications. The administration of H3R ligands - either as antagonists, inverse agonists, agonists or partial agonists - may influence the levels of histamine or the secretion of neurotransmitters from the brain and the periphery and thus may be useful for the treatment of various disorders. Such disorders include obesity, (Masaki et al., Endocrinol, 144, 2741-2748, 2003; Hancock et al., European J. of Pharmacol., 487, 183-197, 2004), cardiovascular disorders, for example infarction. of acute myocardium, dementia and cognitive disorders, such as attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease, neurological disorders, such as schizophrenia, depression, epilepsy, Parkinson's disease and seizures or attacks, sleep disorders, narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction, for example Meniere's disease, drug abuse and nausea (Timmermann, J. Med. Chem. 3_3, 4-11, 1990 ). It is therefore object of the present invention to develop antagonists or inverse agonists of selective and direct action H3 receptors. Such antagonists / inverse agonists are useful as therapeutically active substances, especially for the treatment and / or prevention of diseases associated with the modulation of H3 receptors. In the present description, the term "alkyl", alone or in combination with other groups, means a straight or branched chain monovalent saturated aliphatic hydrocarbon radical having one to twenty carbon atoms, preferably one to sixteen atoms of carbon, more preferably from one to ten carbon atoms. The term "lower alkyl" or "C? -C8 alkyl", alone or in combination, means a straight or branched chain alkyl moiety having from 1 to 8 carbon atoms, preferably a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms and with special preference a moiety straight or branched chain alkyl having from 1 to 4 carbon atoms. Examples of straight or branched chain C?-C8 alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl isomers, hexyl isomers, heptyl isomers and octyl isomers. , preferably methyl and ethyl, and especially methyl.

The term "cycloalkyl" or "C3-C7 cycloalkyl" means a cycloalkyl ring having from 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Especially preferred are cyclopropyl, cyclopentyl and cyclohexyl. The term "lower cycloalkylalkyl" or "(C3-C7 cycloalkyl) Ci-Cß alkyl" means lower alkyl moieties as defined above, wherein at least one of the hydrogen atoms of the lower alkyl moiety is substituted by a cycloalkyl group . A preferred example is cyclopropylmethyl. The term "alkoxy" means the this R'-O-, wherein R 'is lower alkyl and the term "lower alkyl" has the meaning defined above. Examples of lower alkoxy radicals are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy, and especially preferably methoxy. The term "lower alkoxyalkyl" or "(C 8 -alkoxy) -C 8 alkyl" means lower alkyl radicals as defined above in which at least one of the hydrogen atoms of the lower alkyl radical has been replaced by an alkoxy radical , preferably methoxy or ethoxy. Among the preferred lower alkoxyalkyl radicals are 2-methoxyethyl and 3-methoxypropyl.

The term "halogen" means fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred. The term "lower halogenalkyl" or "Ci-Cß halogenalkyl" means lower alkyl moieties as defined above in which at least one of the hydrogen atoms of the lower alkyl moiety is substituted by a halogen atom, preferably fluorine or chlorine, with special preference for fluorine. Among the preferred halogenated lower alkyl groups are trifluoromethyl, difluoromethyl, fluomethyl and chloromethyl, with trifluoromethyl being especially preferred. The term "lower halogenoalkoxy" or "Ci-Cβ halogenoalkoxy" means lower alkoxy moieties as defined above in which at least one of the hydrogen atoms of the lower alkoxy moiety has been replaced by a halogen atom, preferably fluorine or chlorine , with special preference fluorine. Among the halogenated lower alkyl radicals are trifluoromethoxy, difluoromethoxy, fluormetoxy and chloromethoxy, with trifluoromethoxy being particularly preferred. The term "lower hydroxyalkyl" or "hydroxy-Ci-C alquilo alkyl" means lower alkyl moieties as defined above, wherein at least one hydrogen atom of the lower alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl lower radicals are, inter alia, hydroxymethyl and hydroxyethyl. The term "lower cyanoalkyl" or "cyano-C C-C8 alkyl" means lower alkyl groups, as defined above, in which at least one of the hydrogen atoms of the lower alkyl group has been replaced by a cyano group. Examples of lower cyanoalkyl groups are cyanomethyl or cyanoethyl. The term "lower alkanoyl" means a moiety -CO-R ', wherein R' is lower alkyl and the term "lower alkyl" has the previously defined meaning. A -CO-R 'group is preferred, where R' is methyl, which means an acetyl group. The term "benzoyl" means the moiety -CO-phenyl, wherein the phenyl ring may be optionally substituted by one, two or three groups independently chosen from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, halogenoalkoxy inferior and cyano. The term "lower alkanoylamino" or "C alca-C8 alkanoylamino" means the moiety -NH-CO-R ', wherein R' is lower alkyl and the term "lower alkyl" has the previously defined meaning. Preferred is a group -NH-CO-R ', wherein R' is methyl, meaning acetylamino. The term "alkylsulfonyl" or "lower alkylsulfonyl" means a group R'-S (0) 2-, wherein R 'is lower alkyl and the term "lower alkyl" has the meaning defined above. Examples of alkylsulfonyl radicals include, among others, methylsulfonyl or ethylsulfonyl. The term "aryl" means a monovalent aromatic carbocyclic moiety consisting of an individual ring or one or more fused rings, in which at least one ring is of an aromatic nature. Preferred "aryl" moieties are phenyl and naphthyl, "aryl" is preferably a phenyl radical. The term "heteroaryl" means a 5- or 6-membered ring which may contain one, two or three atoms chosen from nitrogen, oxygen and / or sulfur. Examples of heteroaryl radicals are, for example, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl oxazolyl, imidazolyl or pyrrolyl. Especially preferred are pyridyl, thienyl, imidazolyl, isoxazolyl, thiazolyl and pyrazolyl. The term "heterocyclyl" means a 5- or 6-membered ring, saturated or partially unsaturated, which may have one, two or three atoms chosen from nitrogen, oxygen and / or sulfur. Examples of heterocyclic rings include piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl and thiamorpholinyl. A preferred heterocyclic moiety is piperidinyl or tetrahydropyranyl. The expression "form a 4, 5, 6 or 7 membered heterocyclic ring optionally containing another heteroatom selected from nitrogen, oxygen and sulfur" denotes a heterocyclic ring containing N, which may optionally contain other nitrogen, oxygen or sulfur atoms, for example azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or azepanyl. A "4-, 5-, 6- or 7-membered heterocyclic ring containing a sulfinyl group or a sulfonyl group" means a heterocyclic ring containing N and containing a group -S (0) - or a group -S02-, for example 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl. The heterocyclic ring may be unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, haloalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl. The heterocyclic ring can also be condensed on a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, lower alkoxy and halogen. Examples of such fused heterocyclic rings are 3-dihydro-1H-isoquinoline or 1,3-dihydroisoindole. The term "oxo" means that a C atom of the heterocyclic ring can be substituted by = 0, meaning in this way that the heterocyclic ring can contain one or more carbonyl groups (-C0-). The term "pharmaceutically acceptable salts" means those salts which retain the biological efficacy and properties of the free bases or free acids, which are not annoying either in a biological sense or in any other sense. The salts are formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid or with organic acids, for example acetic acid, propionic acid, glycolic acid, acid pyruvic, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N -acetylcysteine and the like. These salts can also be obtained by the addition of an inorganic base or an organic base on a free acid. Salts derived from an inorganic base include, but are not limited to: the sodium, potassium, lithium, ammonium, calcium and magnesium salts and the like. Salts derived from organic bases include, but are not limited to: salts of primary amines, secondary and tertiary, of substituted amines, including substituted amines of natural origin, cyclic amines and basic ion exchange resins, for example isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine , piperidine, polyimine resins and the like. The compound of the formula I can also be present in the form of zwitterion. The pharmaceutically acceptable salts of the compounds of the formula I are preferably hydrochloride salts. The compounds of the formula I can also be solvated, eg hydrated. The solvation can be carried out in the course of the manufacturing process or can take place, for example, as a consequence of the hygroscopic properties of an initially anhydrous compound of the formula I (hydration). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates. "Isomers" are compounds that have identical molecular formulas, but that differ in the nature and order of their atoms or in the arrangement of atoms in space. The isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are mirror images that exactly match when placed on each other are termed "enantiomers" or, sometimes, optical isomers. A carbon atom attached to four non-identical substituents is referred to as a "chiral center". In more detail, the present invention relates to compounds of the general formula wherein R1 is selected from the group consisting of lower alkyl, cycloalkyl, cycloalkylalkyl lower and tetrahydropyranyl; R 2 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl lower, halogeno lower alkyl, lower alkoxyalkyl and lower cyanoalkyl; R3 is selected from the group consisting of lower alkyl, - (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, _ (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl , lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl and -NRR5; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, lower halogenalkyl, lower alkoxyalkyl, lower cyanoalkyl, phenyl unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl and lower phenylalkyl, which phenyl ring may be unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower and lower hydroxyalkyl; or 5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 members optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur, a sulfinyl group or a sulfonyl group, the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, halogenoalkyl, cyano , hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl or is fused with a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof. Preferred compounds of formula I of the present invention are compounds of formula I, wherein R3 is lower alkyl. More preferred are the compounds of the formula I, wherein R3 is C3-C8 alkyl, with especially preferred compounds of the formula I, wherein R3 is propyl or isopropyl. Also preferred are compounds of the formula I, wherein R3 is selected from the group consisting of: ~ (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl and ~ ( CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one, two or three - - groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. Within this group, those compounds are preferred, wherein R3 is - (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the aryl ring is phenyl unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. Especially preferred are those compounds of formula I, in which R3 is phenyl substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. R3 is more preferably selected from the group consisting of 2-methylphenyl, 2,4,6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl , 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl , 3,4-dichlorophenyl, 2-cyanophenyl, 4-cyanophenyl, 3-cyano-4-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxyphenyl, 4-acetylphenyl, 4-acetylaminophenyl and 4-methanesulfonylphenyl. Another group of preferred compounds of the present invention is formed by the compounds of the formula I, wherein R3 is - (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl . R 3 is more preferably - (CH 2) n -heteroaryl, wherein n is the number 0, 1 or 2 and wherein heteroaryl is selected from the group consisting of pyridyl, thienyl, imidazolyl, isoxazolyl, thiazolyl and pyrazolyl, heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl . Still more preferably, n is 0. Especially preferred are compounds of the formula I, wherein R 3 is heteroaryl selected from the group consisting of pyridyl, thienyl, imidazolyl, isoxazolyl, thiazolyl and pyrazolyl, the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl and halogen. Examples of such heteroaryl groups include 6-chloropyridin-3-yl, thienyl, 3,5-dimethylisoxazol-4-yl, 2,4-dimethylthiazol-5-yl, 5-chloro-thien-2-yl, 1, 3-dimethyl-lH-pyrazol-4-yl, 5-bromo-β-chloro-pyridin-3-yl, 3-bromo-5-chloro-thien-2-yl, 4-bromo-5-chloro-thienyl, 2-yl, 5-bromo-pyridin-3-yl, 2,3-dimethyl-3H-imidazol-4-yl and 5-chloro-l, 3-dimethyl-lH-pyrazol-4-yl. Especially preferred are compounds of the formula I, wherein R 3 is pyridyl unsubstituted or substituted by halogen, preferably by chlorine. Also preferred compounds are compounds of the formula I of the present invention, wherein R3 is -NRR5 and wherein R4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenoalkyl, lower alkoxyalkyl and lower cyanoalkyl.; and R5 is selected from the group consisting of lower alkyl, lower halogenalkyl, lower alkoxyalkyl, lower cyanoalkyl, phenyl unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl and lower phenylalkyl, which phenyl ring may be unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl. Especially preferred are those compounds, wherein R3 is -NR4R5 and R4 and R5 are lower alkyl. With special preference, R4 and R5 are methyl. Also preferred are compounds of the formula I of the present invention, wherein R 1 is lower alkyl or cycloalkyl. The most preferred compounds of formula I of the invention are those, wherein R 1 is lower alkyl, with those compounds being particularly preferred, wherein R 1 is isopropyl or tert-butyl. Also preferred are compounds of the formula I, wherein R 1 is cycloalkyl, with the compounds being particularly preferred, wherein R 1 is cyclopentyl or cyclobutyl. Also preferred are compounds of the formula I, wherein R 1 is lower cycloalkylalkyl or tetrahydropyranyl. Lower cycloalkylalkyl is preferably cyclopropylmethyl. Also preferred are compounds of the formula I of the invention, wherein R 2 is selected from the group consisting of hydrogen, lower alkyl and cycloalkylalkyl lower. A group of preferred compounds of formula I is formed by those, wherein R 2 is hydrogen. Also preferred are compounds of the formula I, wherein R 2 is lower alkyl, with the compounds being particularly preferred, wherein R 2 is methyl or isopropyl. R2 is with special preference isopropyl. Another group of preferred compounds of formula I of the invention is formed by those, wherein R 2 is lower cycloalkylalkyl. Especially preferred are those compounds of the formula I, wherein R 2 is cyclopropylmethyl.

The preferred compounds of the formula I of the present invention are the following: N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} propane-1-sulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} propane-2-sulfonamide, N '-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -N, N-dimethylsulfamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 2-fluoro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexylbenzenesulfonamide, 4-fluoro-N-. { trans -4 - [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 4-cyano-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -4-methoxybenzenesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -3-methoxybenzenesulfonamide, 4-fluoro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 1- (3-fluorophenyl) -N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -methanesulfonamide, 2,4-difluor-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2,, 6-trimethylbenzenesulfonamide, 3-chloro-4-fluoro-N-. { trans -4- [(-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2,4-dimethoxybenzenesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2,5-dimethoxybenzenesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -3, -methoxybenzene sulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -4- (trifluoromethyl) benzenesulfonamide, 2, 4-dichloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 3,4-dichloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, N-. { cis-4- [(-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} propane-2-sulfonamide, N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2, 4, 6-trimethylbenzenesulfonamide, 3-chloro-4-fluoro-N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 2,4-dichloro-N-. { cis-4- [(4-isopropylpiperaz; ii? n-l-yl) carbonyl] cyclohexyl} benzene sulfonamide, 3,4-dichloro-N-. { cis-4- [(-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene-sulfonamide, 3, 4, 5-trifluor-N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 5-fluoro-N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 4-chloro-2-fluoro-N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 2-chloro-N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzenesulfonamide, 3,4-difluor-N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -l- [3- (trifluoromethyl) -phenyl] methanesulfonamide, N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -1- [4- (trifluoromethyl) -phenyl] methanesulfonamide, 1- (3,4-dichlorophenyl) -N-. { cis-4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -methanesulfonamide, 2-cyano-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, N-. { trans -4 - [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -4- (trifluoromethoxy) -benzenesulfonamide, - 3,4,5-trifluor-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 5-fluoro-N-. { trans -4- [(-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 4-chloro-2-fluoro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 4-chloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 2-chloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 4-acetyl-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} Benzene sulfonamide, 3,4-difluor-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexylbenzenesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -l- [3- (trifluoromethyl) -phenyl] methanesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -l- [4- (trifluoromethyl) -phenyl] methanesulfonamide, 1- (3,4-dichlorophenyl) -N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -methanesulfonamide, 3-cyano-4-fluoro-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-. { trans -4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylsulfamoyl] -phenyl} -acetamide, N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-methanesulfonyl-benzenesulfonamide, [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -amide of 6-chloro-pyridine-3-sulphonic acid, N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2, N-dimethyl-1-benzenesulfonamide, 2,4-difluoride N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N-methyl-benzenesulfonamide, N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] - 2,4,6, N-tetramethyl-benzenesulfonamide, 3-chloro-4-fluoro-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N-methyl-benzenesulfonamide, N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide, 3-dichloro-N- [trans-4- (4-isopropyl-piperazine-1 -carbonyl) -cyclohexyl] -N-methyl-benzenesulfonamide, 2-cyano-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) cyclohexyl] -N-methyl-benzenesulfonamide, N- [trans-4 - (4-isopropyl-piperazine-l-carbonyl) -ci clohexyl] -N-methyl-4-trifluoromethoxy-benzenesulfonamide, 4-cyano-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) cyclohexyl] -N-methyl-benzenesulfonamide, 3-cyano-4- Fluor-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N-methyl-benzenesulfonamide, N-isopropyl-N- [trans-4- (4-isopropyl-piperazine-1- carbonyl) -cyclohexyl] -2-methyl-benzenesulfonamide, N-isopropyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-methoxy-benzenesulfonamide, 2, -difluor-N -isopropyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-isopropyl-N- [trans-4- (-isopropyl-piperazine-1-carbonyl) -cyclohexyl ] -2, 4, 6-trimethyl-benzenesulfonamide, 3-chloro-4-fluoro-N-isopropyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N- isopropyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide, 2-cyano-N-isopropyl-N- [trans-4- (4-isopropyl- piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-isopropyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, 3-cyano-4-fluoro-N-isopropyl-N- [ trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N- (4-. { isopropyl- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -sulfamoyl} phenyl) -acetamide, isopropyl- [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 6-chloro-pyridine-3-sulfonic acid, N-cyclopropylmethyl-N- [trans] 4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2-methyl-benzenesulfonamide, N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4 -methoxy-benzenesulfonamide, N-cyclopropylmethyl-2,4-difluoro-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-cyclopropylmethyl-N- [trans-4-] (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2,4,6-trimethyl-benzenesulfonamide, 3-chloro-N-cyclopropylmethyl-4-fluoro-N- [trans-4- (4-isopropyl-piperazine -1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide, 3,4-dichloro-N -cyclopropylmethyl-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, 2-cyano-N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-cyclopropylmethyl-N- [trans-4- (4-isopropyl-piperazine -l-carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, 4-acetyl-N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, 4-cyano -N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide 3-cyano-N-cyclopropylmethyl-4-fluoro-N- [trans-4- (4- isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-methanesulfonyl-benzenesulfonamide, cyclopropylmethyl- [trans -4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 6-chloro-pyridine-3-sulfonic acid, trans-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) - cyclohexyl] -2-methyl-benzenesulfonamide, trans-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -2, -difluoro-benzene sulfonamide, trans-3-chloro-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -4-fluoro-benzenesulfonamide, trans-N- [4- (4-cyclopentyl-piperazine-1- carbonyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide, trans-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, trans-4-acetyl-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, trans-4-cyano-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, 3-cyano-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -4-fluoro-benzenesulfonamide, trans-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl ] -4-methanesulfonyl-benzenesulfonamide, [4- (4-cyclopentyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-6-chloro-pyridine-3-sulfonic acid, trans-N- [4- (4 -cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -2-methyl-benzenesulfonamide, trans-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -2, -difluor-benz enosulfonamide, trans-3-chloro-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) cyclohexyl] -4-fluoro-benzenesulfonamide, trans-N- [4- (4-cyclobutyl-piperazine-1-carbonyl ) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide, trans-2-cyano-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) cyclohexyl] -benzenesulfonamide, trans-N- [4- (4-cyclobutyl- piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, trans-4-acetyl-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, trans-4-cyano- N- [4- (4-cyclobutyl-piperazine-1-carbonyl) cyclohexyl] -benzenesulfonamide, trans-3-cyano-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) cyclohexyl] -4-fluor- benzenesulfonamide, trans-N-. { 4- [4- (4-cyclobuti1-piperazine-1-carbonyl) -cyclohexyl-sulfamoyl] -phenyl} -acetamide, trans-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -4-methanesulfonyl-benzenesulfonamide, [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -amide of trans-6-chloro-pyridine-3-sulfonic acid, trans-N- [4- (4-tert-butyl-piperazine-1-carbonyl) -cyclohexyl] -2-methyl-1-benzenesulfonamide, trans-N- [4- (4-tert-butyl-piperazine-1-carbonyl) -cyclohexyl] -3-chloro-4-fluoro-benzenesulfonamide, trans-N- [4- (4-tert-butyl-piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, trans-N- [4- (4-tert-butyl-piperazine-1-carbonyl) -cyclohexyl] -4-cyano-benzenesulfonamide, [4- (4-isopropyl-piperazine- l-carbonyl) -cyclohexyl] -amide of trans-thiophene-2-sulfonic acid, [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-3, 5-dimethyl-isoxazole- 4-sulfonic acid, trans-2, -dimethyl-thiazole-5-sulfonic acid [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide, [4- (4-isopropyl-piperazine-1-l- carbonyl) -cyclohexyl] -amide of trans-5-chloro-thiophene-2-sulfonic acid, [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-5-chloro-l, 3-dimethyl-lH-pyrazole -4-sulphonic, [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-5-bromo-6-chloro-pyridine-3-sulfonic acid, [4- (4-isopropyl-piperazine-1-carbonyl], [4- (-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -amide of trans-3-bromo-5-chloro-thiophene-2-sulfonic acid; trans-4-bromo-5-chloro-thiophene-2-sulphonic acid, [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-5-bromine -pyridine-3-sulfonic acid, [4- (4-cyclopentyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-thiophene-2-sulfonic acid, [4- (4-cyclopentyl-piperazine-1-carbonyl) trans-3, 5-dimethyl-isoxazole-4-sulfonic acid-cyclohexyl] -amide, trans-5-chloro-thiophene- [4- (4-cyclopenti-piperazine-1-carbonyl) -cyclohexyl] -amide of trans-5-chloro-thiophene- 2-sulphonic acid, trans-5-chloro-l, 3-dimethyl-lH-pyrazole-4-sulfonic acid [4- (4-cyclopentyl-piperazine-l-carbonyl) -cyclohexyl] -amide, [4- (4 trans-4-bromo-5-chloro-thiophene-2-sulfonic acid cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -amide, [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] - Trans-thiof acid amide eno-2-sulphonic, trans-2,3-dimethyl-3H-imidazole-4-sulfonic acid [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -amide, [4- (4-cyclobutyl Trans-3,5-dimethyl-isoxazole-4-sulphonic acid, [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -amide of trans-3-hydroxy-3-dimethyl-isoxazole-4-sulphonic acid, -piperazine-1-carbonyl) -cyclohexyl] -amide -2,4-dimethyl-thiazole-5-sulfonic acid, [4- (4-cyclobutyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-5-chloro-thiophene-2-sulfonic acid, [4- ( 4-Cyclobutyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-5-chloro-l, 3-dimethyl-lH-pyrazole-4-sulfonic acid, [4- (4-cyclobutyl-piperazine-l-carbonyl Trans-5-bromo-6-chloro-pyridine-3-sulfonic acid-cyclohexyl] -amide, trans-3-bromo [4- (4-cyclobutyl-piperazine-l-carbonyl) -cyclohexyl] -amide -5-chloro-thiophene-2-sulphonic, [4- (4-cyclobutyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-4-bromo-5-chloro-thiophene-2-sulfonic acid, [4- (4-tert-butyl-piperazine-1 -carbonyl) -cyclohexyl] -amide of trans-thiophene-2-sulfonic acid, [4- (4-tert-butyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-3,5-dimethyl-isoxazole -4-sulphonic, [4- (4-tert-butyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-5-chloro-thiophene-2-sulfonic acid, [4- (4-tert-butyl- Trans-3-bromo-5-chloro-thiophene-2-sulfonic acid piperazine-1-carbonyl) -cyclohexyl] -amide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2-methyl-N- (2,2, 2-trifluor-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-methoxy-N- ( 2,2,2-trifluoro-ethyl) -benzenesulfonamide, trans-2,4-difluoro-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2,2, 2- trifluor-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2,4,6-trimethyl-N- (2,2, 2-trifluor-ethyl) -benzenesulfonamide, trans-3-chloro-4-fluoro-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2, 2 , 2-trifluoro-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2,2,2-trifluor-ethyl) -4-trifluoromethyl- benzenesulfonamide, trans-3, -dichloro-N- [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -N- (2,2, 2-trifluor-ethyl) -benzenesulfonamide, trans-2-cyano -N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2,2, 2-trifluor-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl -piperazine-1-carbonyl) -cyclohexyl] -N- (2,2, 2-trifluor-ethyl) -4-trifluoromethoxy-benzenesulfonamide, trans-4-acetyl-N- [4- (4-isopropyl-piperazine-1 -carbonyl) -cyclohexyl] -N- (2,2,2-trifluoro-ethyl) -benzenesulfonamide, trans-4-cyano-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N - (2,2, 2-trifluoro-ethyl) -benzenesulfonamide, trans-3-cyano-4-fluoro-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2, 2, 2-tr ifluor-ethyl) -benzenesulfonamide, trans-N-. { 4 - [[4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] - (2,2,2-trifluor-ethyl) -sulfamoyl] -phenyl} -acetamide, [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] - (2, 2, 2-trifluoro-ethyl) -amide of trans-6-chloro-pyridine-3-sulfonic acid, trans) -N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -2-methyl-benzenesulfonamide, trans-2, -difluor-N- [4- ( 4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -2,4,6-trimethyl-benzenesulfonamide, trans-3-chloro-4-fluoro-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -4-trifluoromethyl-benzenesulfonamide, trans- 3, 4-dichloro-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl- piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -4-trifluoromethoxy-benzenesulfonamide, trans-4-acetyl-N- [4- (4-is opropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -benzenesulfonamide, trans-4-cyano-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] - N- (2-methoxy-ethyl) -benzenesulfonamide, trans-N-. { - [[4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] - (2-methoxy-ethyl) -sulfamoyl] -phenyl} -acetamide, trans-6-chloro-pyridine-3-suifonic, trans-4-cyano- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] - (2-methoxy-ethyl) -amide. N- [4- (4-cyclopropylmethyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, trans-4-cyano-N-. { 4- [4- (tetrahydro-pyran-4-yl) -piperazine-1-carbonyl] -cyclohexyl} -benzenesulfonamide, and the pharmaceutically acceptable salts thereof.

The following compounds are especially preferred: N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 4-cyano-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 4-fluor-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 1- (3-fluorophenyl) -N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -methanesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2, 4, 6-trimethylbenzenesulfonamide, 2,4-dichloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 2-chloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 3-chloro-4-fluoro-N-isopropyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, N-cyclopropylmethyl-N- [trans-4] - (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2-methyl-benzenesulfonamide, N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4- methoxy-benzenesulfonamide, N-cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2,4,6-trimethyl-benzenesulfonamide, N-cyclopropylmethyl-N- [trans-4 - (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, trans-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -2-methyl-1-benzenesulfonamide, trans-4-cyano-N- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, trans-4-cyano-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of trans-3-bromo-5-chloro-thiophene-2-sulfonic acid, [4- (4- trans-3-bromo-5-chloro-thiophene-2-sulfonic acid cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -amide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) - cyclohexyl] -2,4, 6-trimethyl-N- (2,2,2-trifluoro-ethyl) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N - (2-methoxy-ethyl) -2,4,6-trimethyl-benzenesulfonamide, and the pharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to compounds of the general formula wherein R1 is lower alkyl or cycloalkyl; R 2 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl lower, halogeno lower alkyl, lower alkoxyalkyl and lower cyanoalkyl; R3 is selected from the group consisting of lower alkyl, ~ (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, ~ (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl and -NR4R5; R is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, lower halogenalkyl, lower alkoxyalkyl, lower cyanoalkyl, phenyl unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl and lower phenylalkyl, which phenyl ring may be unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower and lower hydroxyalkyl; R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur, a sulfinyl group or a sulfonyl group, the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl or is fused with a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof. In addition, the pharmaceutically acceptable salts of the compounds of the formula I and the pharmaceutically acceptable esters of the compounds of the formula I individually constitute preferred embodiments of the present invention. The compounds of the formula I can form addition salts with acids, for example conventional pharmaceutically acceptable acids, for example hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulfate, pyruvate, citrate, lactate, mandelate, tartrate and methanesulfonate. . The hydrochloride salts are preferred. Solvates and hydrates of compounds of the formula I and their salts are also part of the present invention. The compounds of the formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, the racemates, the optically pure diastereomers, the mixtures of diastereomers, the diastereomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained, for example by resolution of the racemates, by asymmetric synthesis or by asymmetric chromatography (chromatography with a chiral adsorbent or eluant). The invention encompasses all these forms. It will be appreciated, that the compounds of the general formula I of this invention can be derivatized in the functional groups to provide derivatives that "in vivo" are capable of being converted back into the original compound. Physiologically acceptable and metabolically labile derivatives, which "in vivo" are capable of producing the original compounds of the general formula I are also contemplated within the scope of this invention. Another aspect of the present invention is the process for obtaining the compounds of the formula I already defined above, the process consists of: reacting a compound of the formula II wherein R 1 has the meaning defined above, with a sulfonyl chloride of the formula III O 3 HR-S-Cl III II or wherein R 3 has the meaning defined above, in the presence of a base to obtain compound of the formula IA wherein R is hydrogen and optionally alkylating the compound of the formula IA to obtain a compound of the formula IB wherein R is already defined before it is other than hydrogen, and, if desired, converting the compound obtained to a pharmaceutically acceptable acid addition salt. In this context, "alkylation" means, for example, the reaction of a compound of the formula IA with a suitable alcohol in the presence of an addition reagent, preferably a phosphorane, for example cyanomethylene-tri-n-butylphosphorane. The preparation of the compounds of the formula I of the present invention can be carried out by successive or convergent synthetic routes. The syntheses of the invention are illustrated in the following reaction schemes. Experts in organic chemistry already know the techniques required to carry out the reaction and purification of the resulting products. The substituents and Index used in the following description of the processes have the meanings defined above, unless otherwise indicated. In more detail, the compounds of the formula I can be obtained by the methods described below, by methods described in the examples or by similar methods. Those skilled in the art already know the appropriate conditions for carrying out the individual reaction steps. The starting materials are commercial products or compounds obtainable by methods similar to those described below, by methods described in the references cited in the description or examples or by methods known in the art. The compounds of the formula I of the present invention can be obtained according to the procedure described in reaction scheme 1. a) The 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid IV (cis or trans) is a commercial product and can be subsequently modified in the acid functional group according to the methods described in the technical literature, these methods are already known to those skilled in the art (as regards the reaction conditions described in the technical literature relating to these reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, editorial John Wiley &Sons, New York, NY, 1999). However, it is convenient to transform the acid functional group of IV by an amide formation reaction with the substituted piperazines V (which are commercial products or compounds accessible through the methods described in the references or from the methods already known in the art. if applicable) using an addition reagent. The reaction can be carried out in the presence or absence of a solvent and a base. There is no special limitation regarding the nature of the solvents to be used, provided that they are not adverse to the reaction or to the reagents involved in it and that it dissolves the reagents, at least to some extent. Suitable solvent examples include a: dimethylformamide (DMF), tetrahydrofuran (THF), dioxane and the like. There is no special limitation regarding the nature of the base used in this stage and any base can be used of those commonly used for this type of reaction. Examples of such bases include NEt3 or diisopropylethylamine (DIPEA) and the like. There is no special limitation regarding the nature of the addition agent employed in this stage and any addition reagent usually employed for this type of reaction can be used therein. Examples of such addition reagents include N, N-carbonyldiimidazole (CDI), 1- [bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium-3-oxide (HATU) hexafluorophosphate, 1-hydroxy-1,2,3-benzotriazole ( HOBT) O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the like. The reaction can take place over a wide range of temperatures and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction by heating between room temperature and reflux temperature. The 4! The time required for the reaction can also vary over a wide range, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of 0.5 h to several days may be sufficient to obtain compounds VI. Reaction scheme 1 IB The elimination of the LV protecting group can be carried out under various conditions, according to the methods described in the technical literature and to the procedures that the experts already know (as regards the reaction conditions described in the technical literature relating to these reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, editorial John Wiley &Sons, New York, NY, 1999). However, it is convenient to remove the Boc protecting group under acidic conditions, in the presence or absence of a solvent to obtain the intermediate amine II. There is no special limitation on the nature of the solvent to be employed, provided that it is not adverse to the reaction or for the reagents involved in it and that it can dissolve the reagents, at least to some extent. Suitable solvent examples include a: dioxane, THF, water and the like. There is no special limitation on the nature of the acid employed in this stage and any acid that is usually used for this type of reaction can be used. Examples of such acids include HCl, acetic acid and the like. The reaction can be carried out over a wide range of temperatures and the precise temperature is not critical to the invention. It is convenient to effect the reaction with heating between room temperature and reflux temperature. The time required for the reaction can also vary within wide ranges, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of 0.5 h to several days is usually sufficient to obtain the intermediate compound amine II. The reaction of the intermediate compounds amines II with the sulfonyl chlorides III has been described on numerous occasions in the technical literature and those skilled in the art are already familiar with these processes (as regards the reaction conditions described in the relative technical literature. to these reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, editorial John Wiley &Sons, New York, NY, 1999). The amines in question can conveniently be converted into the corresponding sulfonamides by addition with a sulfonyl chloride (commercial product or compound accessible by methods described in the references or by methods already known in the art, if applicable). It is convenient to carry out the reaction in a solvent of the dichloromethane (DCM) type and in the presence of a base. There is no special limitation on the nature of the solvent to be employed, provided that it is not adverse to the reaction or for the reagents involved in it and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include dichloromethane (DCM), dioxane, THF and the like. There is no special limitation on the nature of the base used in this stage and any type of base can also be used here, as is usually the case for this type of reaction. Examples of such bases include triethylamine, diisopropylethylamine (DIPEA) and the like. The reaction can take place over a wide range of temperatures and the precise temperature is not critical to the invention. We have considered it convenient to carry out the reaction with heating between room temperature and reflux temperature. The time required for the reaction may also vary within wide margins, depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 h to several days is usually sufficient to obtain the sulfonamide derivatives IA (R2 = H). The resulting compound of formula IA (R2 = H) is a compound of the present invention and may be the desirable product. Alternatively, it can be subjected to subsequent reactions, for example the alkylation of the sulfonamide under suitable conditions. There are several reaction conditions that are known from the technical literature to effect these transformations. However, it is convenient to convert the sulfonamides IA (R2 = H) to the sulfonamides IB (R2 = a group selected from lower alkyl, cycloalkyl, cycloalkylalkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl) by reaction of compound IA (R2 = H) with suitable alcohols in the presence of an addition agent, for example a phosphorane (adapted from: THL 4_3, 2187-2190). The reaction can be carried out in the presence or absence of a solvent. There is no special limitation on the nature of the solvent to be employed, provided that it is not adverse to the reaction or for the reagents involved in it and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include toluene and the like. There is no special limitation on the nature of the phosphorane used in this stage, provided that it affects the reaction. The reaction can take place over a wide range of temperatures and the precise temperature is not critical to the invention. We considered it appropriate to carry out the reaction with heating from room temperature to reflux temperature. The time required for the reaction can also vary within wide ranges, depending on many factors, especially the reaction temperature and the nature of the reactants. However, usually a period of 0.5 h to several days is sufficient to obtain the sulfonamides IB (R2 = a group chosen from lower alkyl, cycloalkyl, cycloalkylalkyl lower, halogeno lower alkyl, lower alkoxyalkyl and lower cyanoalkyl). As described above, the compounds of the formula I of the present invention can be used as medicaments for the treatment and / or prevention of diseases associated with the modulation of the receptors of H3 In this context, the expression "diseases associated with the modulation of H3 receptors" means diseases that can be treated and / or prevented by modulation of H3 receptors. Such diseases include, but are not limited to: obesity, the metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, memory dysfunction related to age, mild cognitive imbalance, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, vertigo, schizophrenia, depression, addiction, nausea and sleep disorders, including narcolepsy and other diseases, including asthma, allergy, respiratory responses induced by allergy, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders.

In a preferred aspect, the term "diseases associated with modulation of H3 receptors" refers to obesity, the metabolic syndrome (syndrome X) and other eating disorders, with obesity being especially preferred. The invention thus also relates to pharmaceutical compositions containing a compound as defined above and a pharmaceutically acceptable excipient and / or adjuvant. Furthermore, the invention relates to compounds already defined above, intended for the use of therapeutically active substances, in particular of therapeutically active substances for the treatment and / or prevention of diseases associated with the modulation of H3 receptors. In another embodiment, the invention relates to a method for the treatment and / or prevention of diseases associated with modulation of H3 receptors, the method comprising administering a therapeutically effective amount of a compound of formula I to a human or a human animal. A method for the treatment and / or prevention of obesity is preferred. The invention also relates to the use of the compounds of the formula I already defined above for the treatment and / or prevention of diseases associated with the modulation of H3 receptors. Furthermore, the invention relates to the use of the compounds of the formula I already defined above for the manufacture of medicaments for the treatment and / or prevention of diseases associated with the modulation of H3 receptors. The use of the compounds of the formula I already defined above for the manufacture of medicaments for the treatment and / or prevention of obesity is preferred. The invention further relates to the use of a compound of the formula I for the manufacture of a medicament for the treatment and prevention of obesity in a patient, who is already receiving treatment with a lipase inhibitor and, in particular, in the case that the lipase inhibitor is orlistat. Another preferred object is to provide a method for the treatment or prevention of obesity and disorders related to obesity, which consists of administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount. of other drugs for the treatment of obesity or eating disorders, so that together they produce the desired relief. Suitable additional drugs include, but are not limited to: lipase inhibitors, anorectic agents, selective serotonin reuptake inhibitors (SSRIs), and agents that stimulate the metabolism of body fat. The combinations or associations of the agents just mentioned may include separate, successive or simultaneous administration. The term "lipase inhibitor" denotes those compounds that are capable of inhibiting the action of lipases, for example gastric or pancreatic lipases. For example, the orlistat and the lipstatin described in the patent US-4,598,089 are potent inhibitors of lipases. Lipstatin is a natural product of microbial origin and orlistat is the result of the hydrogenation of lipstatin. Other lipase inhibitors are those belonging to the group of compounds commonly called panclicins. Panclicins are analogues of orlistat (Mutoh et al., 1994). The term "lipase inhibitor" also denotes a fixed lipase inhibitor on a polymer, for example that described in the international patent application WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they are substituted by one or several groups that inhibit lipases. The term "lipase inhibitor" also encompasses the pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably denotes tetrahydrolipstatin. Especially preferred is the administration of a therapeutically effective amount of a compound of formula I in combination or association with a therapeutically effective amount of tetrahydrolipstatin. Tetrahydrolipstatin (orlistat) is a known compound, useful for the control or prevention of obesity and hyperlipidemia, see US Pat. No. 4,598,089, published July 1, 1986, which also describes processes for the obtaining orlistat and US Pat. No. 6,004,996, which describes appropriate pharmaceutical compositions. Other suitable pharmaceutical compositions are described, for example, in international patent applications WO 00/09122 and WO 00/09123. European Patent Application Publication Nos. 0 185 359, 0 189 577, 0 443 449 and 0 524 495 describe additional processes for obtaining orlistat. Suitable anorectic agents for use in combination with a compound of the present invention include, but are not limited to: APD356, aminorex, amphechloram, amphetamine, axoquine, benzophetamine, bupropion, chlorphenrmine, clobenzorex, cloforex, clominorex, clortermin, CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin, norpseudoephedrine, pentorex, phendimetra.zina, phenmetrazine, phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine, SLV319, SNAP 7941, SR147778 (Surinabant), extract from stereogenic plants (eg P57) and TM30338 and pharmaceutically acceptable salts thereof. The most preferred anotonic agents are sibutramine, rimonabant and phentermine. Suitable inhibitors of selective serotonin reuptake that can be used in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline and pharmaceutically acceptable salts thereof. Suitable agents that stimulate the metabolism of body fat include, but are not limited to: a growth hormone agonist (eg, AOD-9604). It is also an object of the present invention to use a compound of the formula I in the manufacture of a medicament for the treatment or prevention of obesity in a patient further receiving treatment with a compound selected from the group consisting of an inhibitor. of lipase, an anorectic agent, a selective serotonin reuptake inhibitor and an agent that stimulates the metabolism of body fat. It is also an object of the present invention the use of a compound of the formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient further receiving treatment with a lipase inhibitor, preferably with tetrahydrolipstatin. Another preferred object is to provide a method of treatment or prevention of type II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in a human person, which comprises the administration of a therapeutically effective amount of a compound according to formula I in combination or combination with a therapeutically effective amount of a lipase inhibitor, in particular when the lipase inhibitor is tetrahydrolipstatin. The method described above is also subject of the invention for the separate, successive or simultaneous administration of a compound according to formula I and a lipase inhibitor, in particular tetrahydrolipstatin. Another preferred object is to provide a method of treatment or prevention of type II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in a human person, which consists in the administration of a therapeutically effective amount of a compound according to Formula I in combination or association with a therapeutically effective amount of an antidiabetic agent. The term "antidiabetic agent" indicates compounds selected from the group consisting of: 1) PPARγ agonists, for example pioglitazone (Actos) or rosiglitazone (Avandia) and the like; 2) biguanides, for example metformin (Glucophage) and the like; 3) sulfonylureas, for example glibenclamide, glimepiride (Amaril), glipizide (Glucotrol), glyburide (DiaBeta) and the like; 4) non-sulfonyl ureas, for example nateglinide (Starlix), repaglimide (Prandin) and the like; 5) PPARa /? Agonists, for example GW-2331 and the like 6) DPP-IV inhibitors, for example LAF-237 (vildagliptin), MK-0431, BMS-477118 (saxagliptin) or GSK23A and the like; 7) glucokinase activators, for example the compounds described, for example, in WO 00/58293 Al and the like; 8) β-glucosidase inhibitors, for example acarbose (Precosa) or miglitol (Glyset) and the like. The method described for the simultaneous, separate or successive administration of a compound according to formula I and a therapeutically effective amount of an antidiabetic agent is also an object of the invention. Another object of the present invention is the use of a compound of the formula I for the manufacture of a medicament for the treatment and prevention of type II diabetes in a patient also receiving treatment with an antidiabetic agent. Another preferred object is to provide a method of treating or preventing dyslipidemias in a human, which consists of administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of an agent that decreases the lipid level. The term "agent that decreases the level of lipids" indicates compounds chosen from the group consisting of: 1) bile acid sequestrants, for example cholestyramine (Questran), colestipol (Colestid) and the like; 2) HMG-CoA reductase inhibitors, for example, atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), pravastatin (Pravachol), simvastatin (Zocor) and the like; 3) cholesterol absorption inhibitors, for example ezetimibe and the like; 4) CETP inhibitors, for example torcetrapib, JTT 705 and the like; 5) PPARa agonists, for example beclofibrate, gemfibrozil (Lopid), fenofibrate (Lipidil), bezafibrate (Bezalip) and the like; 6) inhibitors of lipoprotein synthesis, for example niacin and the like; and 7) niacin receptor agonists, for example nicotinic acid and the like. It is also an object of the invention the method described above for the simultaneous, separate or successive administration of a compound according to formula I and a therapeutically effective amount of an agent that lowers the level of lipids.

It is also an object of the present invention the use of a compound of the formula I for the manufacture of a medicament for the treatment and prevention of dyslipidemias in a patient who also receives treatment with an agent that lowers the level of lipids. Another preferred object is a method of treating or preventing hypertension in a human, which consists of administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of antihypertensive agent. The term "antihypertensive agent" or "agent that lowers blood pressure" indicates compounds selected from the group consisting of: 1) angiotensin-converting enzyme (ACE) inhibitors, including benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Coversum), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik) and the like; 2) angiotensin II receptor antagonists, including candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micadisc), valsartan (Diovan) and the like; 3) adrenergic blockers (peripheral or central), for example beta-adrenergic blockers, including acebutolol (Sectrol), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol (Zebeta), carteolol (Cartrol), metoprolol (Lopressor); Toprol-XL), nadolol (Corgard), penbutolol (Levatol), pindolol (Visken), propranolol (Inderal), timolol (Blockadren) and the like; alpha / beta-adrenergic blockers, including carvedilol (Coreg), labetalol (Normodyne) and the like; alpha-1-adrenergic blockers, including prazosin (Minipress), doxazosin (Cardura), terazosin (Hytrin), phenoxybenzamine (Dibencillin) and the like; peripheral adrenergic-neuronal blockers, including guanadrel (Hilorel), guanethidine (Ismelin), reserpine (Serpasil) and the like; alpha-2-adrenergic blockers, including a-methyldopa (Aldomet), clonidine (Catapres), guanabenz (Wytensin), guanfacine (Tenex) and the like; 4) vasodilators, including hydralazine (Apresolina), minoxidil (Lonitren), clonidine (Catapres) and the like; 5) calcium channel blockers, including amlodipine (Norvasc), felodipine (Plendil), isradipine (Dynacirc), nicardipine (Cardina sr), nifedipine (Procardia, Adalat), nisoldipine (Sular), diltiazem (Cardizem), verapamil ( Isoptil) and the like; 6) diuretics, for example thiazides and thiazide-like agents, including hydrochlorothiazide (Hydrodiuril, Microzide), chlorothiazide (Diuril), chlorthalidone (Hygroton), indapamide (Lozol), metolazone (Mykrox) and the like; loop diuretics, for example bumetanide (Bumex) and furosemide (Lasix), ethacrynic acid (Edecrin), torsemide (Demadex) and the like; diuretics with potassium savings, including amiloride (Midamor), triamterene (Dyrenium), spironolactone (Aldactone) and thiamenidine (Symcor) and the like; 7) tyrosine hydroxylase inhibitors, including methirosine (Demser) and the like; 8) neutral endopeptidase inhibitors, including BMS-186716 (Omapatrilat), UK-79300 (Candoxatril), ecadotril (Sinorfan), BP-1137 (Fasidotril), UK-79300 (Sampatrilat) and the like; and 9) endothelin antagonists, including tezosentan (RO0610612), A308165 and the like. The method described above for the simultaneous, separate or successive administration of a compound according to formula I and a therapeutically effective amount of an antihypertensive agent is also an object of the invention. It is also an object of the present invention to use a compound of the formula I for the manufacture of a medicament for the treatment and prevention of hypertension in a patient who also receives treatment with an antihypertensive agent. The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been specifically found that the compounds of the present invention are good antagonists and / or inverse agonists of the histamine 3 receptors (H3R). The following test is carried out in order to determine the activity of the compounds of the formula (I). Fixation assay with (R) α-methylhistamine-H3 The saturation binding assays are carried out using HR3-CH0 membranes prepared in the manner described by Takahashi, K., Tokita, S., Kotani, H., J. Pharmacol. Exp. Therapeutics 307, 213-218, 2003. An appropriate amount of membrane (60 to 80 μg protein / well) is incubated with increasing concentrations of (R) a-methylhistamine-H3 dihydrochloride (from 0.10 to 10 nM). ). No specific fixation is determined when a larger excess of cold (R) a-methylhistamine dibromide (final concentration: 500 nM) is used. Incubation is carried out at room temperature (in deep-hole plates, stirring for three hours). The final volume of each hole is 250 μl. After incubation, rapid filtration is carried out on GF / B filters (preimpregnated with 100 μl of 0.5% PEI in 50 mM Tris buffer, shaking at a speed of 200 rpm for two hours). The filtration is carried out using a cell harvester and then the filter plates are washed five times with an ice-cold washing buffer, containing 0.5 M NaCl. After collection, the plates are dried at 55 ° C for 60 min. then scintillation liquid (Microscint 40, 40 microliters to each well) is added and the amount of radioactivity in the filter in a Packard top-counter apparatus is determined after the plates have been shaken for two hours at 200 rpm at room temperature. Fixation buffer: 50 mM Tris-HCl, pH 7.4 and 5 mM MgCl2x6H20, pH 7.4. Wash Buffer: 50 mM Tris-HCl, pH 7.4 and 5 mM MgCl2x6H20 and 0.5 M NaCl, pH 7.4. Indirect measurement of the affinity of the inverse agonists of the H3R: twelve increasing concentrations (located between 10 μM and 0.3 nM) of the selected compounds are always tested in competition binding assays using a membrane of the human cell line HR3-CHO. An appropriate amount of protein, eg approximately 500 cpm of RAMH binding in Kd, is incubated for 1 hour at room temperature in a final volume of 250 μl in 96-well plates in the presence of (R) a-methylhistamine- H3 (final concentration 1 nM = Kd). Non-specific binding is determined using a 200-fold excess of cold (R) a-methylhistamine dibrombide. All the compounds are tested in duplicate in a single concentration. Compounds exhibiting an inhibition of RAMH- [H3] greater than 50% are assayed again for IC50 in an assay with serial dilutions. The Ki values are calculated from the IC50 based on the Cheng-Prusoff equation (Cheng, Y., Prusoff, W.H., Biochem Pharmacol, 22, 3099-3108, 1973). The compounds of the present invention have Kx values within a range of 1 nM to 1000 nM, preferably between 1 nM and 100 nM and more preferably between 1 nM and 30 nM. In the following table the measured values for some selected compounds of the present invention are collected.

The demonstration of the additional biological activities of the compounds of the present invention can be carried out by "in vitro", "ex vivo" and "in vivo" assays, which are well known to those skilled in the art. For example, to demonstrate the efficacy of a pharmaceutical agent in the treatment of disorders related to obesity, for example diabetes, syndrome X or atherosclerotic disease and related disorders, for example hypertriglyceridemia and hypercholesterolemia, the following assays may be applied. Method for measuring blood glucose levels Db / db mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (either from the ocular vein or from the caudal vein) and are grouped according to equivalent glucose levels average in blood. The compound to be tested is administered orally (with a pharmaceutically acceptable carrier), once a day for a period of 7 to 14 days. At the end of the administration the animals are bled again by the ocular or caudal vein and the blood glucose levels are determined. Method for measuring triglyceride levels hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (either eye or caudal) and are grouped according to equivalent levels of average blood triglycerides. The compound to be tested is administered orally (with a pharmaceutically acceptable carrier), once a day for a period of 7 to 14 days. At the end of the administration, the animals are bled again by the ocular or caudal vein and the serum triglyceride levels are determined. Method for determining HDL cholesterol levels To determine HDL cholesterol levels in plasma, hApoAl mice are bled and grouped according to the equivalent levels of mean HDL cholesterol in plasma. The mice are orally administered once a day, the compound to be tested or a vehicle for a period of 7 to 14 days and the next day they are bled again. The plasma is analyzed to determine HDL cholesterol. The compounds of the formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, eg in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; rectally, eg in the form of suppositories, parenterally, eg in the form of injectable solutions or solutions for infusion, or topically, eg in the form of ointments, creams or oils. The production of the pharmaceutical preparations can be carried out in a manner that will be familiar to any person skilled in the art by incorporating the described compounds of the formula (I) and their pharmaceutically acceptable salts, into a galenic administration form together with suitable solid or liquid excipient materials, non-toxic, inert, therapeutically compatible and, if desired, the usual pharmaceutical adjuvants. The suitable excipient materials are inorganic excipient materials and also organic excipient materials. For example, as excipient materials for tablets, coated tablets, dragees and hard gelatin capsules may be used lactose, corn starch or derivatives thereof, talc, stearic acid or its salts. Suitable excipient materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, it is possible to dispense with the excipient in the case of soft gelatin capsules). Suitable excipient materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. The suitable excipient materials for the solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. The excipient materials suitable for suppositories are, for example, natural and hydrogenated oils, waxes, fats and semi-liquid and liquid polyols. Suitable excipient materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty acids, sterols, polyethylene glycols and cellulose derivatives. Suitable pharmaceutical adjuvants are usual stabilizers, preservatives, wetting agents and emulsifiers, consistency-imparting agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, dyes, masking agents and antioxidants. The dosage of the compounds of the formula (I) can vary within wide limits according to the disease to be controlled, the age and health status of the individual patient and the mode of administration and obviously must be adjusted to the peculiarities of the individual in each case. For adult patients, a daily dosage of 1 mg to 1000 mg, especially 1 mg to 100 mg, is taken into consideration. Depending on the daily dose, it is convenient to administer it divided into several sub-doses. The pharmaceutical preparations conveniently contain from 0.1 to 500 mg, preferably from 0.5 to 100 mg of a compound of the formula (I). The following examples serve to illustrate the present invention in greater detail. However, it is not intended to limit their scope in any way. Examples Example 1 N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} propane-1-sulfonamide a) Step 1: [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid tert -butyl ester A mixture of 3 g (12 g) is stirred at room temperature for 3 h mmoles) of 4-tert-butoxycarbonylamino-trans-cyclohexanecarboxylic acid (commercial product), 1.74 g (14 mmoles) of 1- (2-propyl) -piperazine (commercial product), 4.75 g (15 mmoles) of TBTU and 3.64 g (36 mmoles) of NEt3 in 10 ml of DMF. After concentrating, the residue is washed with an INN solution of NaHCO 3, extracted with DCM, the organic phases are combined, dried with MgSO 4 and concentrated to dryness, obtaining 4.56 g (94%) of the title compound. MS (m / e) = 354.3 (MH +). b) Step 2: trans- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride (intermediate 1) A mixture of 4.56 g (12 mmol) of [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid tert-butyl ester and 29 ml of 4N HCl is stirred at 50 ° C for 6 h. in dioxane, it is concentrated to dryness and used without further purification in the next step. MS (m / e) = 254.1 (MH +). c) Step 3 N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} propane-l-sulfonamide A mixture of 32.6 mg (0.1 mmol) of the trans- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride is stirred at 40 ° C for 16 h. , 28 mg (0.2 mmol) of propane-1-sulfonyl chloride and 101 mg (1 mmol) of NEt3 in 2 ml of DCM. After concentrating, methanol and DMF are added and the mixture is subjected to purification by preparative HPLC in reversed phase, eluting with a gradient of acetonitrile / water (0.1% of NEt3). The fractions containing product are combined and concentrated to dryness, obtaining 13.9 mg (39%) of the title compound. MS (m / e) = 360.4 (MH +). Intermediate compound 2 cis- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride a) Step 1: [cis-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -carbamic acid tert-butyl ester Using the procedure described for obtaining [trans-4- (4-isopropyl-piperazine- 1-carbonyl) -cyclohexyl] -carbamic acid tert-butyl compound is synthesized from 4-tert-butoxycarbonylamino-cis-cyclohexanecarboxylic acid (commercial product) and l- (2-propyl) -piperazine (commercial product). MS (m / e) = 354.3 (MH +). b) Step 2: cis- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride Using the procedure described for the preparation of trans- (4-amino-cyclohexyl) dihydrochloride ) - (4-isopropyl-piperazin-1-yl) -methanone, the title compound is synthesized from [cis-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid tert-butyl ester. EM (m / e) = 254. 4 (MH +). Intermediate compound 3 trans- (4-amino-cyclohexyl) - (4-cyclopentyl-piperazin-1-yl) -methanone dihydrochloride In a manner similar to the procedure described for the synthesis of the trans- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride (intermediate compound 1), the title compound is obtained from the acid 4-tert-butoxycarbonylamino-trans-cyclohexanecarboxylic (commercial product) and cyclopentyl-piperazine (commercial product) and subsequent removal in an acid medium of the tert-butylcarbonyloxy protecting group. MS (m / e) = 280.1 (MH +). Intermediate compound 4 trans- (4-amino-cyclohexyl) - (4-cyclobutyl-piperazin-1-yl) -methanone dihydrochloride In a manner similar to the procedure described for the synthesis of trans- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride (intermediate compound 1) the title compound is obtained from 4-tert-butoxycarbonylamino-trans-cyclohexanecarboxylic acid (commercial product) and 1-cyclobutyl-piperazine (commercial product) and subsequent removal in an acid medium of the tert-butylcarbonyloxy protecting group. MS (m / e) = 266.1 (MH +). Intermediate compound 5 trans- (4-amino-cyclohexyl) - (4-tert-butyl-piperazin-1-yl) -methanone dihydrochloride In a manner similar to the procedure described for the synthesis of the trans- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride (intermediate compound 1), the title compound is obtained from the acid 4-tert-butoxycarbonylamino-trans-cyclohexanecarboxylic (commercial product) and 1-tert-butyl-piperazine (commercial product) and subsequent removal in an acid medium of the tert-butylcarbonyloxy protecting group. MS (m / e) = 268.1 (MH +). In accordance with the procedure described for example 1, other piperazinylcarbonyl-cyclohexyl sulfonamide derivatives have been synthesized from the corresponding starting materials mentioned in table 1. Table 1 shows example 49 of example 49. . Table 1 1 - 2 - 13 -. 13 - - 16 -. 16 - ll - Example 50 N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2, N-dimethyl-benzenesulfonamide A mixture of 41 mg (0.1 mmol) is heated at 110 ° C for 16 h. the N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide (example 4), 72 mg (0.3 mmol) of cyanomethylene-tri-n-butylphosphorane and 32 mg (1 mmol) of methanol in 2 ml of toluene. After concentrating, methanol and DMF are added and the mixture is subjected to purification by preparative HPLC in reversed phase, eluting with a gradient of acetonitrile / water (0.1% of NEt3). The fractions containing product are combined and concentrated to dryness, obtaining 12.4 mg (29%) of the title compound. MS (m / e) = 422.2 (MH +). According to the procedure described for Example 50, other piperazinyl-carbonyl-cyclohexyl-sulfonamide derivatives are synthesized from the corresponding starting materials mentioned in Table 2. Table 2 shows examples from 51 to 84. Table 2 )4 - In a similar way to the procedure described for the synthesis of N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} propane-1-sulfonamide (example 1), other piperazinyl-carbonyl-cyclohexyl-sulfonamide derivatives are obtained from the corresponding starting materials mentioned in table 3. Table 3 covers examples from 85 to 137. Table 3 In a manner similar to the procedure described for the synthesis of N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2, N-dimethyl-benzenesulfonamide (example 50) other derivatives of piperazinyl-carbonyl-cyclohexyl-sulfonamide from the corresponding starting materials mentioned in table 4. Table 4 shows the examples from 138 to 162. Table 4 Example 163 trans-4-cyano-N- [4- (4-cyclopropylmethyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide a) Step trans-4- (4-cyano-benzenesulfonylamino) -cyclohexanecarboxylate benzyl It is stirred at room temperature during lh a mixture of 2 g (8.2 mmoles) of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (commercial product), 0.978 g (9.0 mmol) of phenyl-methanol (commercial product), 3.16 g (9.8 mmol) of 0-benzotriazole tetrafluoroborate- 1-N-N, N ', N' -tetramethyluronium (TBTU) and 1.24 g (12.3 mmol) of NEt3 in 10 ml of DMF. The mixture is concentrated to dryness and extracted with DCM and an aqueous solution of Na 2 CO 3. The organic phases are combined, dried over MgSO4 and concentrated. The residue is treated with 100 ml of 4N HCl in dioxane at room temperature for 4 h. The mixture is concentrated to dryness, obtaining the benzyl trans-4-amino-cyclohexanecarboxylate (MS (m / e) = 360.4 (MH +)), which is used without further purification. 150 ml of DCM, 2.95 g (14 mmol) of 4-cyano-benzenesulfonyl chloride (commercial product) and 6.17 g (61 mmol) of NEt3 are added and the mixture is stirred at room temperature for 16 h. The mixture is extracted with DCM and an aqueous IN-HCl solution, the organic phases are combined and concentrated. The residue was recrystallized from methanol to obtain 1.9 g (58%) of the title compound. MS (m / e) = 397.0 (MH ") b) Step 2 4-cyano-N- [4- (piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide A mixture of 1.9 is stirred at room temperature for 2 h. g (4.7 mmoles) of benzyl trans-4- (4-cyano-benzenesulfonylamino) -cyclohexanecarboxylate and 0.8 g (1.9 mmol) of LiOH in a mixture of methanol, THF and water. The mixture is concentrated to dryness and added to the mixture. 10 ml of DMF, 0.7 g (8.1 mmol) of piperazine, 2.87 g (8.9 mmol) of TBTU and 2.26 g (22 mmol) of NEt3, the mixture is stirred at room temperature for 1 h and concentrated to dryness. The residue was chromatographed on a silica gel column to obtain 0.3 g (16%) of the title compound MS (m / e) = 377.1 (MH +) c) Step 3: trans-4-cyano-N- [4 - (4-cyclopropylmethyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide A mixture of 0.1 g (0.26 mmol) of 4-cyano-N- [4- (piperazine-1-) is stirred at 80 ° C for 1 h. carbonyl) -cyclohexyl] -benzenesulfonamide, 0.022 g (0.31 mmol) of cyclopropanecarboxaldehyde (commercial product), 0.159 g (2.65 mmoles) of acetic acid and 0.073 g (0.34 mmoles) of sodium triacetoxyborohydride in 1 ml of THF. The mixture is subjected to purification by preparative HPLC, eluting with a gradient of acetonitrile and water. By concentration of the fractions containing product, 3 mg (2.6%) of the title compound is obtained. MS (m / e) = 431.4 (MH +). Example 164 trans-4-cyano-N-. { 4- [4- (tetrahydro-pyran-4-yl) -piperazine-1-carbonyl] -cyclohexyl} -benzenesulfonamide In a manner similar to the procedure described for the synthesis of trans-4-cyano-N- [4- (-cyclopropylmethyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide (example 163), the title compound is obtained from of 4-cyano-N- [4- (piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide and tetrahydro-pyran-4-one (commercial product). MS (m / e) = 461.3 (MH +). Example A Films coated with a film containing the following ingredients can be manufactured by a conventional method.

The active ingredient is screened and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and compressed, obtaining kernels of 120 and 350 mg, respectively. The cores are varnished with an aqueous solution / suspension of the film-like cover mentioned above. Example B Capsules containing the following ingredients can be manufactured by a conventional method.

The components are sieved, mixed and packed in size 2 capsules. Example C Injectable solutions can have the following composition: Example D Soft gelatin capsules containing the following ingredients can be manufactured by a conventional method: The active ingredient is dissolved in the hot melt of the other ingredients and the mixture is filled into soft gelatin capsules of the appropriate size. The filled soft gelatine capsules are treated according to the usual procedures.

Example E Sachets containing the following ingredients are manufactured by a conventional method: The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone and water. The granulate is mixed with magnesium stearate, the flavoring additives are added and it is packaged in sachets. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (30)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the general formula characterized in that R1 is selected from the group consisting of lower alkyl, cycloalkyl, cycloalkylalkyl lower and tetrahydropyranyl; R 2 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl lower, halogeno lower alkyl, lower alkoxyalkyl and lower cyanoalkyl; R3 is selected from the group consisting of lower alkyl, ~ (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, - (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl , lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl and -NR4R5; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, lower halogenalkyl, lower alkoxyalkyl, lower cyanoalkyl, phenyl unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl and lower phenylalkyl, whose phenyl ring may be unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 members optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur, a sulfinyl group or a sulfonyl group, the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, halogenoalkyl, cyano , hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl or is fused with a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof.
2. 2. Compounds of the formula I according to claim 1, characterized in that R3 is lower alkyl.
3. 3. Compounds of the formula I according to claim 1 or 2, characterized in that R3 is C3-C8-alkyl.
4. 4. Compounds of the formula I according to claim 1, characterized in that R3 is selected from the group consisting of - (CH2) m-aryl, wherein m is the number 0, 1 or 2 and wherein the ring aryl is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl and - (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl.
5. 5. Compounds of the formula I according to claim 1 or 4, characterized in that R3 is - (CH2) m-aryl, wherein m is the number 0, 1 or 2 and the aryl ring is unsubstituted or substituted phenyl by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl.
6. 6. Compounds of the formula I according to any of claims 1, 4 or 5, characterized in that R3 is phenyl substituted with one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino, and lower alkylsulfonyl.
7. 7. Compounds of the formula I according to any of claims 1, 2 or 4, characterized in that R3 is - (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and wherein the ring heteroaryl is unsubstituted or substituted by one or two groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl.
8. 8. Compounds of the formula I according to any of claims 1, 2 or 4, characterized in that R3 is - (CH2) n-heteroaryl, wherein n is the number 0, 1 or 2 and heteroaryl is selected from the group formed by pyridyl, thienyl, imidazolyl, isoxazolyl, thiazolyl and pyrazolyl, the heteroaryl ring is unsubstituted or substituted by one, two or three groups independently chosen from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl , benzoyl, lower halogenoalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl.
9. 9. Compounds of the formula I according to any of claims 1, 2 or 4, characterized in that R3 is pyridyl unsubstituted or substituted by halogen.
10. 10. Compounds of the formula I according to claim 1, characterized in that R3 is -NRR5 and R4 and R5 are lower alkyl.
11. 11. Compounds of the formula I according to claim 1, characterized in that R1 is lower alkyl or cycloalkyl.
12. 12. Compounds of the formula I according to any of claims 1 to 11, characterized in that R1 is lower alkyl.
13. 13. Compounds of the formula I according to any of claims 1 to 12, characterized in that R 1 is isopropyl or tert-butyl.
14. 14. Compounds of the formula I according to any of claims 1 to 11, characterized in that R1 is cycloalkyl.
15. 15. Compounds of the formula I according to any of claims 1 to 14, characterized in that R2 is selected from the group consisting of hydrogen, lower alkyl and cycloalkylalkyl lower.
16. 16. Compounds of the formula I according to any of claims 1 to 15, characterized in that R2 is hydrogen.
17. 17. Compounds of the formula I according to any of claims 1 to 15, characterized in that R2 is lower alkyl.
18. 18. Compounds of the formula I according to any of claims 1 to 15, characterized in that R2 is lower cycloalkylalkyl.
19. 19. Compounds of the formula I according to claim 1, characterized in that they are chosen from the group consisting of: N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 4-cyano-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 4-fluoro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2-methylbenzenesulfonamide, 1- (3-fluorophenyl) -N-. { trans -4 - [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -methanesulfonamide, N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} -2, 4, 6-trimethylbenzene-sulphonamide, 2,4-dichloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene sulfonamide, 2-chloro-N-. { trans -4- [(4-isopropylpiperazin-1-yl) carbonyl] cyclohexyl} benzene-sulfonamide, 3-chloro-4-fluoro-Ni-sopropi-1-N- [trans-4- (4-i-sopropi-1-piperazine-1 -carbonyl) -cyclohexyl] -benzenesulfonamide, N-cyclopropylmethyl-N- [trans-4- (4-i-sopropi-1-piperazin-1 -carbonyl) -cyclohexyl] -2-methyl-benzenesulfonamide, N-cyclopropylmethyl-N- [trans-4- (4-isopropylpiperazine-1 - carbonyl) -cyclohexyl] -methoxy-benzenesul fonamide, N-cyclopropylmethyl-N- [trans 4- (4-isopropyl-piperazine-1 -carbonyl) -cyclohexyl] -2,4,6-trimethyl-benzenesulfonamide, N -cyclopropylmethyl-N- [trans -4- (4-isopropyl-piperazinna-1 -carbonyl) -cyclohexyl] -4-trifluoromethoxy-benzenesulfonamide, trans-N- [4- (4-cyclopentyl-piperazine-1) -carbonyl) -cyclohexyl] -2-methyl-1-benzenesulfonamide, trans-4-cyano-N- [4- (4-cyclopentyl-1-piperazine-1-carbonyl-1-cyclohexyl] -benzenesulfonamide, trans- 4-cyano-N- [4- (4-cyclobutyl-piperazine-1-carbonyl) -cyclohexyl] -benzenesulfonamide, [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexy-1] -amide l trans-3-bromo-5-chloro-thiophene-2-sulphonic acid, t rans-3-bromo-5-chloro [4- (4-cyclobutyl-piperazine-l-carbonyl) -cyclohexyl] -amide. -thiophene-2-sulphonic, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -2,4,6-trimethyl-N- (2,2,2-trifluor-ethyl) ) -benzenesulfonamide, trans-N- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -N- (2-methoxy-ethyl) -2, 4,6-trimethyl-benzenesul-fonamide, and the salts pharmaceutically acceptable thereof.
20. 20. Process for obtaining compounds according to any of claims 1 to 19, characterized in that it consists in: reacting a compound of the formula II wherein R1 has the meaning defined in claim 1, with a sulfonyl chloride of the formula III wherein R3 has the meaning defined in claim 1, in the presence of a base to obtain compound of formula IA wherein R is hydrogen and optionally alkylating the compound of the formula IA to obtain a compound of the formula IB wherein R2 is already defined in claim 1 and which is other than hydrogen, and, if desired, converting the compound obtained to a pharmaceutically acceptable acid addition salt.
21. 21. Compounds according to any one of claims 1 to 19, characterized in that they are obtained according to a process according to claim 20.
22. 22. Pharmaceutical compositions characterized in that they contain a compound according to any one of claims 1 to 19 as well as as a pharmaceutically acceptable carrier and / or adjuvant.
23. 23. Pharmaceutical compositions according to claim 22, characterized in that they are for the treatment and / or prevention of diseases associated with the modulation of H3 receptors.
24. 24. Compounds according to any one of claims 1 to 19, characterized in that they are for use as therapeutically active substances.
25. 25. Compounds according to any one of claims 1 to 19, characterized in that they are for use as therapeutically active substances intended for the treatment and / or prevention of diseases associated with the modulation of H3 receptors.
26. 26. Use of compounds according to any of the rei indications from 1 to 19 for the manufacture of medicaments intended for the treatment and / or prevention of diseases associated with the modulation of H3 receptors.
27. 27. Use according to claim 27 for the treatment and / or prevention of obesity.
28. 28. Use of a compound of the formula I according to any of the rei indications from 1 to 19 for the manufacture of a medicament for the treatment or prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor.
29. 29. Use of a compound of the formula I according to any of claims 1 to 19 for the manufacture of a medicament for the treatment or prevention of type II diabetes in a patient who is also receiving -14! treatment with an antidiabetic agent.
30. 30. Use of a compound of formula I according to any of claims 1 to 19 for the manufacture of a medicament for the treatment or prevention of dyslipidemias in a patient who is also receiving treatment with a reducing agent. of 1 ipidos.