MX2008007545A

MX2008007545A - Pyrrolo[2,3-c]pyridine derivatives

Info

Publication number: MX2008007545A
Application number: MX/A/2008/007545A
Authority: MX
Inventors: Roche Olivier; Nettekoven Matthias
Original assignee: F Hoffmannla Roche Ag; Nettekoven Matthias; Roche Olivier
Priority date: 2005-12-15
Filing date: 2008-06-11
Publication date: 2008-09-02

Abstract

The present invention relates to compounds of formula (I) wherein R1to R4are 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

DERIVATIVES OF PIRRÓLO [2, 3-C] PYRIDINE Description of the Invention The present invention relates to new derivatives of 5-piperazinyl-lH-pyrrolo [2, 3-c] pyridine, to its manufacture, to pharmaceutical compositions that they already contain their use as medicines. The active compounds of the present invention are useful in 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, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl lower, Ref. 193689 phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, alkoxy lower and lower hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring may be substituted or unsubstituted with one or two lower alkyl groups, and heterocyclylalkyl lower wherein the heterocyclyl ring may be substituted or unsubstituted with one or two lower alkyl groups; R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, substituted or unsubstituted phenyl with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the ring of heterocyclyl can be substituted or unsubstituted with one or two of the lower alkyl groups, and heterocyclylalkyl lower wherein the heterocycloalkyl ring can be substituted or unsubstituted with one or two lower alkyl groups; or R1 and R2 together with the nitrogen atom to which they are attached form a saturated or partially saturated heterocyclic ring of 4, 5, 6 or 7 elements optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a group sulfonyl, the saturated or partially saturated heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is condensed with a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; R3 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower alkylsulfonyl, phenylsulfonyl wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, lower phenylalkyl, wherein the phenyl ring may be substituted or unsubstituted by one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, and substituted or unsubstituted heteroaryl with one or two groups independently selected from lower alkyl or halogen; R 4 is lower alkyl or cycloalkyl; and pharmaceutically acceptable salts thereof. The compounds of the formula I are antagonists and / or inverse agonists at the histamine 3 receptor (H3 receptor). Histamine (2- (4-imidazolyl) ethylamine) is one of the aminergic neurotransmitters that are widely distributed from beginning to end of the body, for example the gastrointestinal tract (Burks 1994 in Johnson LR ed., Physiology of the Gastrointestinal Tract, Raven Press, NY, pp. 211-242). Histamine regulates a variety of digestive pathophysiological events similar to gastric acid secretion, intestinal motility (Leurs et al., Br. J. Pharmacol., 1991, 102, pp. 179-185), vasomotor responses, inflammatory bowel responses, and allergic reactions (Raithel et al., Int. Arch. Allergy Immunol., 1995, 108, 127-133). In the mammalian brain, histamine is synthesized in the bodies of histaminergic cells that are found centrally in the tuberomamilar nuclei of the posterior basal hypothalamus. From there, the bodies of the histaminergic cells are projected to various regions of the brain (Panula et al., Proc. Nati, Acad. Sci. USA 1984, 81, 2572-2576, Inagaki et al., J. Comp.Neurol 1988 , 273, 283-300). According to common knowledge, histamine has a mediating role in all actions of both the CNS and the periphery through four different histamine receptors, the H1, H2, H3 and H4 receptors of histamine. The H3 receptors are located predominantly in the central nervous system (CNS). As an autoreceptor, H3 receptors constitutively inhibit the synthesis and secretion of histamine from histaminergic neurons (Arrang et al., Nature 1983, 302, 832-837, Arrang et al., Neuroscience 1987, 23, 149-157). . Like heteroreceptors, H3 receptors 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 body. gastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol, 1982, 107, 919-923; Blandina et al., In The Histamine H3 Receptor (Leurs RL and Timmermann H eds., 1998, pp. 27-40, Elsevier, Amsterdam, The Netherlands). The H3 receptors are constitutively active, meaning that even without the exogenous histamine, the receptor is activated tonic. In the case of an inhibition receptor such as the H3 receptor, this inherent activity causes the tonic inhibition of neurotransmitter release. Therefore, it may be important that an H3R antagonist could also reverse the antagonist activity both to block the effects of exogenous histamine and to displace the receptor from its constitutively active (inhibitory) form to a neutral state. The wide distribution of the H3 receptors in the mammalian SCN indicates the physiological role of this receptor. Therefore, therapeutic potential has been proposed as an objective of the development of a novel drug in several indications. The administration of H3R ligands - as agonists, inverse agonists, agonists or partial agonists - may have an influence on histamine levels or on the secretion of neurotransmitters in the brain and periphery and thus may be useful in the treatment of several disorders. Such disorders include obesity, (Masaki et al., Endocrinol, 2003, 144, 2741- 2748; Hancock et al., European J. of Pharmacol, 2004, 487, 183-197), cardiovascular disorders such as acute myocardial infarction, dementia and cognitive disorders such as attention deficit hyperactivity disorder (ADHD) and the disease of Alzheimer's, neurological disorders such as schizophrenia, depression, epilepsy, Parkinson's disease, and status epilepticus or seizures, sleep disorders, narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction such as Morbus Meniere, drug abuse and motion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-11). It is therefore an object of the present invention to provide antagonists or reverse agonists, of the H3 receptor that act directly, selectively. Such antagonists / inverse agonists are useful as therapeutically active substances, particularly in the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors. In the present description the term "alkyl", alone or in combination with other groups, refers to a straight or branched chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. The term "lower alkyl" or "C? -C8 alkyl", alone or in combination, means a straight chain or branched chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight chain alkyl group or branched with 1 to 4 carbon atoms. Examples of branched or straight-chain C?-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyl, the isomeric heptyls and the isomeric octyl, preferably methyl and ethyl and even more preferably methyl. The term "lower alkenyl" or "C2_8 alkenyl", alone or in combination, means a straight or branched chain hydrocarbon radical comprising an olefinic bond and up to 8, preferably up to 6, particularly preferably up to 4 carbon atoms. Examples of the alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. a preferred example is 2-propenyl. The term "lower alkynyl" or "alkynyl" C2_8", alone or in combination, means a branched or straight chain hydrocarbon residue comprising a triple bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms Examples of the alkynyl groups are ethynyl, 1-propynyl , or 2-propynyl, an example preferred is 2-propynyl. The term "cycloalkyl" or "C3-7 cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclopentyl is especially preferred. The term "lower cycloalkylalkyl" or "C 3-7 cycloalkyl-Ci-s alkyl" refers to lower alkyl groups as defined above, wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by cycloalkyl. A preferred example is cyclopropylmethyl. The term "alkoxy" refers to the group R'-O-, wherein R 'is lower alkyl and the term "lower alkyl" has a previously given meaning. Examples of the lower alkoxy groups are for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy and even more preferably methoxy. The term "lower alkoxyalkyl" or "lower alkoxy" C? -8-Ci-s alkyl "refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms and the lower alkyl groups is replaced by an alkoxy group, preferably methoxy or ethoxy. Among the lower alkoxyalkyl groups preferred are 2-methoxyethyl or 3-methoxypropyl. The term "alkylsulfañilo" or "alkylsulfañilo of Ci-β" refers to the group R'-S-, where R 'is lower alkyl and the term "lower alkyl" has the previously given meaning. Examples of the alkylsulfañyl groups are for example methylsulfañilo or etilsulfañilo. The term "lower alkylsulfanylalkyl" or "Ci-e alkyl alkylsulfanyl of Ci-s" refers to the lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl groups is replaced by a group of alkylsulfañilo, preferably metilsulfañilo. An example for a preferred lower alkylsulfanylalkyl group is 2-methylsulfanylethyl. The term "lower hydroxyalkyl" or "hydroxyalkyl of Ci-s" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxy group. Examples of the lower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl. The term "dialkylamino" refers to the group -R 'R ", wherein R' and R" are lower alkyl, and the term "lower alkyl" has the meaning given previously. A preferred alkylamino group is dimethylamino.

The term "lower dialkylaminoalkyl" or "C-8 dialkylamino of Ci-β alkyl" refers to the lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a dialkylamino group, preferably diethylamine. A preferred lower dialkylaminoalkyl group is 3-dimethylaminopropyl. The term "alkylsulfonyl" or "lower alkylsulfonyl" refers to the group R'-S (0) 2_, wherein R 'is lower alkyl and the term "lower alkyl" has the meaning given previously. Examples of the alkylsulfonyl groups are for example methylsulfonyl or ethylsulfonyl. The term "lower phenylsulfonyl" means the group "phenyl-S (O) 2-". The term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred. The term "lower halogenalkyl" or "halogen-Ci-s alkyl" refers to the lower alkyl groups as defined above, wherein at least one of the hydrogen atoms of the lower alkyl groups is replaced by an atom of halogen, preferably fluorine or chlorine, more preferably fluorine. Among the preferred halogenated lower alkyl groups are the trifluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially preferred. The term "lower halogenalkoxy" or "halogeno-C-8 alkoxy" refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a halogen atom, preferably fluorine or chlorine, even more preferably fluorine. Among the preferred halogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy, fluoromethoxy and chloromethoxy, with trifluoromethoxy being especially preferred. The term "lower alkanoyl" refers to the group -CO-R ', wherein R' is lower alkyl and the term "lower alkyl" has the meaning given above. A group of -CO-R 'is preferred, where R' is methyl, meaning an acetyl group. The term "carbamoyl" refers to the group -CO-NH2. The term "dialkylcarbamoyl" refers to the group -CO-NR'R ", wherein R 'and R" are lower alkyl and the term "lower alkyl" has the meaning given previously. A preferred dialkylcarbamoyl group is dimethylcarbamoyl. The term "dialkylcarbamoylalkyl" or "dialkylcarbamoyl of Ci-s-Ci-s alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a dialkylcarbamoyl group, preferably dimethylcarbamoyl. A preferred lower alkyl dialkylcarbamoylalkyl group is 3-di-ethylcarbamoylpropyl. The term "lower phenylalkyl" or "phenyl-Ci-s alkyl" with respect to the lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a phenyl group. Preferred phenyl-lower alkyl groups are benzyl or phenethyl. The term "heteroaryl" refers to a ring of 5 or 6 elements, aromatic, which may comprise one, two or three atoms selected from nitrogen, oxygen and / or sulfur. Examples of the heteroaryl groups are for example furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, or pyrrolyl. Pyridyl, thiazolyl and oxazolyl are especially preferred. The term "heteroarylalkyl lower" or "heteroarylC 8 alkyl" refers to the lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a heteroaryl group as HE defined previously. The term "heterocyclyl" refers to a ring of 5 or 6 elements, saturated or partially unsaturated which may comprise one, two or three atoms selected from nitrogen, oxygen and / or sulfur. Examples of the heterocyclyl rings include piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazalidinyl, morpholinyl, thiazolidinyl, isothiazolidilyl, thiadiazolidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyrinyl, and thiomorpholinyl. A preferred heterocyclyl group is piperidinyl or tetrahydropyranyl. The term "heterocyclylalkyl" or "heterocyclyl-Ci-s alkyl" refers to the lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a heterocyclyl group as defined previously. The term "forms a saturated, 5-, 6- or 7-membered heterocyclic ring optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur" refers to a saturated N-heterocyclic ring, which may optionally contain a nitrogen, oxygen atom or additional sulfur, such as azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl. A "partially unsaturated heterocyclic ring of 5, 6 or 7 elements" means a heterocyclic ring as defined above containing a double bond, for example, 2,5-dihydropyrrolyl or 3,6-dihydro-2H-pyridinyl. A "saturated or partially unsaturated heterocyclic ring of 5, 6 or 7 elements containing a sulfinyl group or a sulfonyl group" means an N-heterocyclic ring containing a group -S (O) - or a group '-S02-, for example 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl. The heterocyclic ring can be substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and oxo. The heterocyclic ring can also be fused with a phenyl ring, the phenyl ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. An example of such a fused heterocyclic ring is 1,4-dihydroisoindole. The term "oxo" means that a C atom of the heterocyclic ring can be substituted by = 0, meaning that the heterocyclic ring can contain one or more carbonyl groups (-C0-). The term "pharmaceutically acceptable salts" is refers to those salts that retain the biological efficacy and properties of free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic 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. Additionally, these salts can be prepared by the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from the organic bases include, but are not limited to the salts of the primary, secondary and tertiary amines, the substituted amines including the naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like. The compound of the formula I can also be present in the form of zwitterions. The pharmaceutically acceptable salts, particularly preferred, of the compounds of the formula I are the hydrochloride salts. The compounds of the formula I can also be solvated, for example hydrated. The solvation can be carried out in the course of the manufacturing process or can be carried out, 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 include physiologically acceptable solvates. The "isomers" are compounds that have identical molecular formulas but differ in the nature or sequence of their atoms or in the arrangement of their 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 each other are called "diastereomers" and stereoisomers that are not mirror images that can be superimposed, are called "enantiomers" or sometimes optical isomers. A carbon atom attached to four non-identical substituents is called a "chiral center". In detail, the present invention is refers to the compounds of the general formula wherein R1 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl lower, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, heteroarylalkyl lower wherein the heteroaryl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring may be substituted or unsubstituted with one or two lower alkyl groups, and heterocyclylalkyl lower wherein the heterocyclyl ring may be substituted. be substituted or unsubstituted with one or two lower alkyl groups; R2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl lower, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring it can be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and hydroxy lower alkyl, heteroarylalkyl lower wherein the heteroaryl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring may be substituted or unsubstituted with one or two of the lower alkyl groups, and heterocyclylalkyl lower wherein the heterocycloalkyl ring may be substituted or unsubstituted with one or two lower alkyl groups; or R1 and R2 together with the nitrogen atom to which they are attached form a saturated or partially saturated heterocyclic ring of 4, 5, 6 or 7 elements optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, the saturated or partially saturated heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is condensed with a phenyl ring, the phenyl ring is substituted or unsubstituted by one, two or three groups independently selected from alkyl lower, lower alkoxy and halogen; R3 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower alkylsulfonyl, phenylsulfonyl wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl, in wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, and substituted or unsubstituted heteroaryl with one or two selected groups s independently of lower alkyl or halogen; R 4 is lower alkyl or cycloalkyl; and pharmaceutically acceptable salts thereof. Preferred compounds of the formula I of the present invention are the compounds of the formula I, wherein R 1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl lower, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring can be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, heteroarylalkyl lower wherein the heteroaryl ring can be substituted or unsubstituted with one or two groups independently selected from alkyl lower, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring can be substituted or unsubstituted with one or two lower alkyl groups, and heterocyclylalkyl lower wherein the heterocyclyl ring can be substituted or unsubstituted with one or two lower alkyl groups; and R2 is hydrogen or lower alkyl. More preferred are those compounds of the formula I, wherein R1 is selected from the group consisting of lower alkyl, cycloalkyl and lower heterocyclyl wherein the heterocyclyl ring can be substituted or unsubstituted with one or two lower alkyl groups, with those compounds, wherein R1 is selected from a group consisting of lower alkyl, cycloalkyl and lower heterocyclyl wherein the heterocyclyl ring can be substituted or unsubstituted with one or two lower alkyl groups, and wherein R 2 is hydrogen or lower alkyl, which is especially preferred. Even more preferably, R1 is selected from the group consisting of ethyl, n-propyl, i-propyl, cyclopentyl, cyclohexyl and tetrahydropyran. In addition, the compounds of the formula I according to the present invention are preferred, wherein R1 and R2 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic ring of 5, 6 or 7 elements optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, the saturated or partially unsaturated heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is condensed with a phenyl ring, the phenyl ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. Within this group, those compounds are preferred, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, the heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is condensed with a phenyl ring, the phenyl ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. Especially preferred are those compounds of the formula I, wherein R 1 and R 2 together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group consisting of pyrrolidine, 2,5-dihydropyrrole, morpholine, piperidine, azepane and 1,3-dihydroisoindole, wherein the heterocyclic ring is substituted or unsubstituted by one, two or three independently selected groups of lower alkyl, halogen, halogenalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl. More preferably, R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of pyrrolidine, 3-hydroxypyrrolidine, 2-isopropyl-pyrrolidine, morpholine, piperidine, 3-methylpiperidine, -methylpiperidine, 4-methyl-piperidine, 3,5-dimethylpiperidine, 3,3-difluoropiperidine,, -difluoropiperidine, 4-methoxypiperidine, 3-hydroxypiperidine, 4-trifluoromethyl-piperidine, azepane and 1,3-dihydroisoindole. In addition, the compounds of the formula I agree with the present invention are preferred, wherein R3 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower cycloalkylalkyl, and lower cyanoalkyl. Especially preferred are compounds of formula I, wherein R3 is hydrogen. Additional preferred compounds of the formula I according to the invention are those wherein R 4 is lower alkyl, with those compounds, wherein R 4 is isopropyl, which are especially preferred. Also preferred are compounds of formula I according to the present invention, wherein R 4 is cycloalkyl. Especially preferred are those compounds of the formula I, wherein R 4 is cycloplentyl. Examples of the preferred compounds of the formula I are the following: [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] -pyrrolidin-1 -yl-methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -morpholin-1-yl-methanone, [5- (4 -cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (3-methyl-piperidin-1-yl) -methanone, cyclohexylamide of [5- (4- cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid [5- (-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin- 2- il] - (2-methyl-piperidin-1-yl) -methanone, cyclopentyl ida of [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] pyridin-2-acid] carboxylic acid, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - (4-methyl-piperidin-1-yl) -methanone, [ 5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] -pyridin-2-yl] - (3-hydroxy-pyrrolidin-1-yl) -methanone, [5- ( 4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - (3, 3-difluoro-piperidin-1-yl) -methanone, [5- (4 -cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] -pyridin-2-yl] - (4-methoxy-piperidin-1-yl) -methanone, [5- (4-cyclopentyl- piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - (3-hydroxy-piperidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazine-1) -yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - (4-trifluoromethyl-piperidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazine) propylamide -l-yl) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2 - il] - (2-isopropyl-pyrrolidin-1-yl) -methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -piperidine -1-yl-methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -pyrrolidin-1-yl-methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -morpholin-4-yl-methanone, (1,3-dihydro-isoindol-2-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5 - (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (3-methyl-piperidin-1-yl) -methanone, cyclohexylamide of the acid [5- (-isopropyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid, azepan-1-yl- [5- (4-isopropyl-piperazin-1-yl) -lH- pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - ( 2-methyl-piperidin-1-yl) -methanone, 5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid cyclopentylamide, [5- ( 4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (2-isopropyl-pyrrolidin-1-yl) -methanone, [5- (4-isopropyl- piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (4-methyl-piperidin-1-yl) -methanone, (3-hydroxy-pyrrolidin-1-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (4,4-difluoro-piperidin-1-yl) - [5 - (4-isopropyl- piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (3, 3-difluoro-piperidin-1-yl) - [5- (4-isopropyl-piperazine- 1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin -2-yl] - (-methoxy-piperidin-1-yl) -methanone, (2,5-dihydro-pyrrol-1-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH- pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (3-hydroxy-piperidin-1-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (3, 5-dimethyl-piperidin-1-yl) - [5- (-isopropyl-piperazin-1-yl) -lH-pyrrolo [2,3- c] pyridin-2-yl] -methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (4-trifluoromethyl) piperidin-1-yl) -methanone, 5- (4-isopropyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid, 5- (4-) 4- isopropyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid, 5- (4-isopropyl-piperazin-1-yl) (tetrahydro-pyran-4-yl) -amide ) -lH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid, and pharmaceutically acceptable salts thereof. Particularly preferred compounds of formula I of the present invention are the following: [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (3 -methyl-piperidin-1-yl) -metanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] pyridin-2-yl] - (4-methyl-piperidine) -l-yl) -metanone, 5- (4-cyclopentyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridin-2-yl-carboxylic acid propylamide, (3-hydroxy-pyrrolidin- 1-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, and 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 the preferred embodiments of the present invention. The compounds of formula I can form acid addition salts with acids, such as 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. Also the solvates and hydrates of the compounds of the formula I and their salts form part of the present invention. The compounds of formula I may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of the diastereoisomeric racemates. The optically active forms can be obtained, for example, by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with an eluent or chiral adsorbent). This invention encompasses all of these forms. It will be appreciated that the compounds of the general formula I in this invention can be derivatives in functional groups to provide derivatives that are capable of conversion back to the original compound in vivo. Metabolically and physiologically acceptable labile derivatives, which are capable of producing the original compounds of the general formula I in vivo are also within the scope of this invention. A further aspect of the present invention is the process for the manufacture of the compounds of the formula I as defined above, such a process comprising: coupling a compound of the formula II wherein R4 is as defined herein above, with an amine of formula III H-NRXR2 III wherein R1 and R2 are as defined hereinbefore, under basic conditions to obtain a compound of formula IA wherein R3 is hydrogen, and optionally the transfer to a compound of the formula IB wherein R is a group as defined above is different from hydrogen, and if desired, converting the compound obtained to a pharmaceutically acceptable acid addition salt. The transfer to a compound of the formula IB means the treatment of the compound of the formula IA with a suitable base in a suitable solvent under anhydrous conditions (for example sodium hydride in DMF) and reacting the intermediate anion with an alkylating agent or acylation R1-X, wherein X means a leaving group such as, for example, iodide, bromide, methanesulfonate or chloride, to obtain a compound of the formula IB wherein R1 means lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower hydroxyhalogenalkyl, lower cycloalkylalkyl, lower alkylcarbonyl, alkylsulfonyl or lower phenylsulfonyl. Typical examples of an alkylating or acylating agent R3-X are methyl iodide, benzyl bromide, 2,2,2-trifluoroethyl-methanesulfonate, acetyl chloride or benzenesufonyl chloride. In more detail, the compounds of the formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. The preparation of the compounds of the formula I of the present invention can be carried out in consecutive or convergent synthetic routes. The syntheses of the invention are shown in the following reaction schemes. The experiences required to carry out the reaction and purification of the resulting products are already known to those skilled in the art. The substituents and indices used in the following description of the process have the meaning given hereinbefore unless otherwise indicated. The raw materials are either commercially available or can be prepared by methods analogous to the methods given below, by the methods described in the references cited in the description or in the examples, or by the methods known in the art. the art. The intermediate compounds of the formula II can be prepared following the procedure as shown by the reaction scheme 1. Reaction scheme 1 IV VII II VTII The compounds of the formula II can be prepared according to the reaction scheme 1 by a process starting from the ethyl ester of (Z) -3- (2-chloro-5-nitro-pyridin-4-yl) -2- hydroxy-acrylic (V). V is formed by the condensation of aldol from 2-chloro-4-methyl-5-nitropyridine (IV) and diethyl oxalate in the presence of a strong base such as potassium ethoxide, potassium tert-butylate or preferably 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).

The coupling of the chloro substituted pyridine derivatives with the piperazines is widely described in the literature and the procedures are already known to those skilled in the art (for the reaction conditions described in the literature affecting such reactions, see for example Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, John Wiley &Sons, New York, NY, 1999). The ethyl ester of (Z) -3- (2-chloro-5-nitro-pyridin-4-yl) -2-hydroxy-acrylic acid (V) can be conveniently converted to the piperazinyl derivatives VII by means of the reaction with a piperazine derivative VI (either commercially available or accessible by the methods described in the references or by methods known in the art, as appropriate). The reaction can be carried out in the presence or in the absence of a solvent and in the presence or absence of a base. It has been found convenient to carry out the reaction in a solvent similar to water and / or in dimethylformamide (DMF) and, if necessary, in the presence of a base similar to triethylamine or diisopropyl-ethylamine (DIPEA). There is no particular restriction on the nature of the solvent that is going to be used, provided that it does not have any adverse effect on the reaction or on the reagents involved and provided that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include DMF, dichloromethane (DCM), dioxane, tetrahydrofuran (THF), and the like. The reaction can be carried out under a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from room temperature to reflux temperature. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the reactants. A period from 0.5 h to several days will usually be sufficient to provide the piperazinyl pyridine derivatives VII. The compounds of the formula II are then obtained from the piperazinyl pyridine VII derivatives by: a) the reaction with iron powder in acetic acid to give the esters VIII in a temperature range of 70 to 90 ° C, and b) the hydrolyzation of the esters VIII under basic conditions (for example with lithium hydroxide in polar solvents such as for example tetrahydrofuran, methanol or water or mixtures thereof). A period from 12 h to 24 h at room temperature will be sufficient to give the carboxylic acids of formula II.

Reaction scheme 2 IB The compounds of the general formula IA and IB can be prepared according to the reaction scheme 2. The coupling of the carboxylic acids II with the amines III (either commercially available or accessible by the methods described in the references or by the methods known in the art) is widely described in the literature (eg Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 / a. edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999) and can be effected employing the use of coupling agents such as, for example, N, N-carbonyldiimidazole (CDI), 1-hydroxy-1,2,3-benzotriazole (HOBT) or O-benzotriazol-1-yl-N, N, N, N-tetrafluoroborate tetramethyluronium (TBTU) in a similar suitable solvent, for example dimethylformamide (DMF) or dioxane in the presence of a base (for example triethylamine or diisopropylethylamine). Intermediates of the formula IB can be obtained, for example, by treating the intermediates of the formula IA with a suitable base in a suitable solvent under anhydrous conditions (for example sodium hydride in DMF) and reacting the intermediate anion with an alkylating or acylating agent R3-X such as, for example, methyl iodide, 2-bromopropane, 2,2,2-trifluoroethyl-methanesulfonate, methanesulfonyl or phenylsulfonylchloride. In these cases R3 means a methyl, trifluoromethyl, isopropyl or an alkyl or arylsulfonyl group and X means a leaving group such as, for example, iodide, bromide, methanesulfonate or chloride. Compounds of the formula IB wherein R3 means a phenyl or a substituted phenyl group can be synthesized by the processes known to those skilled in the art and are described in the literature (for example WWKR Mederski et al., Tetrahedron, 1999, 55 , 12757). For example, the intermediates of the formula IA are reacted with an optionally substituted phenylboronic acid using a suitable catalyst (for example copper (II) acetate) and a base (eg, pyridine) in a solvent suitable similar, for example, to dichloromethane. 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 that are associated with the modulation of the H3 receptors. In this context, the expression "diseases associated with modulation of H3 receptors" means diseases that can be treated and / or prevented by the modulation of H3 receptors. Such diseases include, but are not limited to, obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, deficit hyperactivity disorder of attention, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, attacks, fading, schizophrenia, depression, addiction, motion sickness and sleep disorders including narcolepsy, and other diseases including asthma, allergy, pathway responses Respiratory induced by allergy, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. In a preferable aspect, the expression "diseases associated with the modulation of H3 receptors" refers to to obesity, metabolic syndrome (syndrome X), and other eating disorders, with obesity being especially preferred. Therefore, the invention also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant. In addition, the invention relates to compounds as defined above for their use as therapeutically active substances, particularly as therapeutically active substances for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors. In another embodiment, the invention relates to a method for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors, such method comprising administering an active therapeutic amount of a compound of formula I to a human or animal A method for the treatment and / or prevention of obesity is preferred. The invention further relates to the use of the compounds of the formula I as defined above for the treatment and / or prevention of diseases that are associated with the modulation of the H3 receptors. In addition, the invention relates to the compounds of the formula I as defined above for the preparation of the medicaments for the treatment and / or prevention of diseases that are associated with the modulation of the H3 receptors. The use of the compounds of the formula I as defined above for the preparation of the medicaments for the treatment and / or prevention of obesity is preferred. In addition, the present invention 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 also receiving treatment with a lipase inhibitor and particularly, wherein the Lipase inhibitor is Orlistat. It is a further preferred object of the present invention to provide a method for the treatment or prevention of obesity and disorders related to obesity, comprising the administration of 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 they can provide effective relief. Other suitable drugs include, but are not limited to, anorectic agents, lipase inhibitors, selective serotonin reuptake inhibitors (SSRIs). in English) and agents that stimulate the metabolism of body fat. The combinations or associations of the above agents may encompass separate, consecutive or simultaneous administration. The term "lipase inhibitor" refers to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. For example, orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent inhibitors of lipases. Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin. Other inhibitors of lipase include a class of compounds commonly referred to as panclicins. Panclicines are analogous to orlistat (Mutoh et al., 1994). The term "lipase inhibitor" also refers to the lipase inhibitors attached to the polymer described for example in the international patent application WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they have been substituted with one or more groups that inhibit lipases. The term "lipase inhibitor" also comprises the pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably refers to tetrahydrolipstatin. The administration of a therapeutically effective amount of a compound according to Formula I in combination or association with a therapeutically effective amount of tetrahydrolipstatin is especially preferred. Tetrahydrolipstatin (orlistat) is a known compound that is useful for the control or prevention of obesity and hyperlipidemia. See U.S. Pat. No. 4,598,089, issued July 1, 1986, which also describes processes for making orlistat and U.S. Pat. No. 6,004,996, which describes appropriate pharmaceutical compositions. Additional suitable pharmaceutical compositions are described, for example, in international patent applications WO 00/09122 and WO 00/09123. Additional processes for the preparation of orlistat are described in the publications of European patent applications Nos. 0 185 359, 0 189 577, 0 443 449, and 0 524 945. The anorectic agents suitable for use in combination with a compound of the present invention include, but are not limited to, APD356, aminorex, amphelolamine, amphetamine, axoquine, benzefetamine, bupropion, chlorphentermine, clobenzorex, cloforex, clominorex, clortermma, CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine, dextroamphetamine, diethylpropion, diffetoxidin, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfuplmethylamphetamine, levamfetamine, levofacetoperane, mazindol, nefenorex, methamphepramone, methamphetamine, metreleptin, norseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine, SLV319, SNAP 7941, SR147778 (Surinabant), a spheroidal vegetable extract (for example P57) and TM30338 and the pharmaceutically acceptable salts thereof. The most preferred anorexic agents are sibutramine, rimonabant and phentermine. Suitable selective serotonin reuptake inhibitors for use in combination with a compound of the 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, the growth hormone agonist (eg, AOD-9604). The use of a compound of formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a compound selected from the group consisting of a lipase inhibitor, an anorectic agent, a serotonin reuptake inhibitor, selective, and an agent that stimulates the metabolism of body fats, 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 who is also receiving treatment with a lipase inhibitor, preferably with tetrahydrolipstatin, is also an object of the present invention. invention. It is a further object to provide a method of treatment or prevention of type II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in a human being, which comprises administering a therapeutically effective amount of a compound according to the invention. Formula I in combination or in association with a therapeutically effective amount of a lipase inhibitor, particularly, wherein the lipase inhibitor is tetrahydrolipstatin. Also an object of the invention is the method as described above for the simultaneous, separate or consecutive administration of a compound according to formula I and a lipase inhibitor, particularly tetrahydrolipstatin. It is a further preferred object of the invention to provide a method of treatment or prevention of type II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in a human being, which comprises administering a therapeutically effective amount of a compound according to formula I in combination or in association with a therapeutically effective amount of an antidiabetic agent. The term "antidiabetic agent" refers to compounds selected from the group consisting of: 1) PPAR agonists? such as pioglitazone (acts) or rosiglitazone (avandia), and the like; 2) biguanides such as metformin (glucophage) and the like; 3) sulfonylureas such as glibenclamide, glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta) and the like; 4) substances other than sulfonylureas such as nateglinide (starlix), repaglimide (prandin) and the like; 5) PPARa agonists /? such as GW-2331, and the like; 6) DPP-IV inhibitors such as LAF-237 (vildagliptin), MK-0431, BMS-477118 (saxagliptin) or GSK23A and the like; 7) glucokinase activators such as the compounds described for example in WO 00/58293 Al, and the like; 8) α-glucosidase inhibitors such as acarbose (precose) or miglitol (glyset), and the like. Also an object of the invention is the method as described above for the simultaneous, separate or consecutive administration of a compound according to formula I and a therapeutically effective amount of an antidiabetic agent.

It is also an object of the present invention to use a compound of formula I in the manufacture of a medicament for the treatment and prevention of type II diabetes in a patient who is also receiving treatment with an antidiabetic agent. In a further preferred object of the invention provide a method of treatment or prevention of dyslipidemias in a human, which comprises administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of a lipid reducing agent. The term "lipid reducing agent" refers to compounds selected from the group consisting of: 1) bile acid capture agents such as cholesteramine (questran), colestipol (colestid), and the like; 2) HMG-CoA reductase inhibitors such as atorvastatin (lipitor), cerivastatin (baycol), fluvastatin (lescol), pravastatin (pravachol), sinvastatin (zocor) and the like; 3) cholesterol absorption inhibitors such as ezetimibe and the like; 4) CETP inhibitors such as torcetrapib, JTT 705, and the like; 5) PPARa agonists such as beclofibrate, gemfibrozil (lopid) fenofibrate (lipidil), bezafibrate (bezalip) and the like; 6) inhibitors of lipoprotein synthesis such as niacin, and the like; and 7) niacin receptor agonists such as nicotinic acid, and the like. Also an object of the invention is the method as described above for the simultaneous, separate or consecutive administration of a compound according to formula I and a therapeutically effective amount of a lipid reducing agent. The use of a compound of formula I in the manufacture of a medicament for the treatment and prevention of dyslipidemias in a patient who is also receiving a treatment with a lipid-lowering agent is also an object of the present invention. It is a further preferred object to provide a method of treating or preventing hypertension in a human being, comprising administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of an agent. antihypertensive The term "antihypertensive agent" or "blood pressure reducing agent" refers to compounds selected from the group consisting of: 1) angiotensin-converting enzyme (ACE) inhibitors including benazepplo (lotensin), captopril ( capoten), enalapril (vasotec), fosinopril (monopril), lisinopril (prinivil, zestril), moexipril (univasc), perindopril (coversum), quinapril (accupril), ramipril (altace), trandolaprilo (mavik) and the like; 2); angiotensin II receptor antagonists that include candesartan (atacand), eprosartan (teveten), irbesartan (avapro), losartan (cozaar), telmisartan (micadisc), valsartan (diovan), and the like; 3) adrenergic blockers (peripheral or central) such as beta-adrenergic blockers including acebutolol (sectrol), atenolol (tenormin), betaxolol (kerlone), bisoprolol (zebeta), carteolol (cartrol), metropolol (lopressor, toprol-XL), nadolol (corgard), penbutolol (levatol), pindolol (visken), propranolol (inderal), timolol (blockandrem), and the like; alpha / beta adrenergic blockers including carvedilol (coreg), labetol (normodyne), and the like; alpha-1 adrenergic blockers including prazosin (minipress), doxazosin (cardura), terazosin (hitrin), phenoxybenzamine (dibenzyline), and the like; peripheral neuronal-adrenergic blockers including guanadrel (hylorel), guanethidine (ismelin), reserpine (serpasil) and the like; alpha-2 adrenergic blockers including a-methyldopa (aldomet), clonidine (catapres), guanabenz (witensina), guanfacine (tenex), and the like; 4) blood vessel dilators (vasodilators) including hydralazine (apresoline), minoxidil (lonitren), clonidine (catapres), and the like; 5) calcium channel blockers including amlodipine (norvasc), felodipine (plendil), isradipine (dynacirc), nicardipine (cardine sr), nifedipine (procardia, adalat), nisoldipine (sular), diltiazem (cardizem), verapamil (isoptil) and the like; 6) diuretics such as thiazides and thiazide-like agents, including hydrochlorothiazide (hydrodiuril, microzide), chlorothiazide (diuril), chlorthalidone (hygroton), indapamide (lozol), metolazone (mykrox), and the like; closed-system diuretics, such as bumetanide (bumex) and furosemide (lasix), ethacrynic acid (edecrine), torsemide (demadex), and the like; potassium-free diuretics 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 (sinorphan), BP-1137 (fasidotril), UK-79300 (sampatrilat) and the like; and 9) endothelin antagonists including tezosentan (RO0610612), A308165, and the like. Also an object of the invention is the method as described above for the simultaneous, separate or consecutive administration of a compound according to formula I and a therapeutically effective amount of a antihypertensive agent. The use of a compound of a formula I in the manufacture of a medicament for the treatment and prevention of hypertension in a patient who is also receiving treatment with an antihypertensive agent is also an object of the present invention. As described above, the compounds of the formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good antagonists and / or inverse agonists of the histamine receptor 3 (H3R). The following test was carried out to determine the activity of the compounds of the formula (I). Agglutination assay with 3H- (R) -a-methylhistamine Saturation agglutination experiments were performed using HR3-CH0 membranes prepared as described in Takahashi, K. Tokita, S., Kotani, H. (2003) J Pharmacol. Exp. Terapeuthics, 307, 213-218. An appropriate amount of the membrane (60 to 80 μm protein / well) was incubated with increasing concentrations of 3H (R) a-methylhistamine dihydrochloride (0.10 to 10 nM). Non-specific agglutination was determined using a 200-fold excess of cold (R) a-methylhistamine dibrombromide (final concentration 500 nM). The incubation was carried out at room temperature (in plates with deep cavities that are shaken for three hours). The final volume in each cavity was 250 μl. Incubation was followed by rapid filtration on GF / B filters (pre-oar with 100 μl of 0.5% PEI in 50 mM Tris with shaking at 200 rpm for two hours). Filtration was done using a cell collector and the filter plates were then washed five times with an ice-cooled wash buffer containing 0.5 M NaCl. After collection, the plates were dried at 55 ° C for 60 minutes, then the scintillation fluid (Microscint 40, 40 micromol in each cavity) and the amount of radioactivity on the filter were determined in a Packard top-counter device) after stirring the plates for two hours at 200 rpm at room temperature ambient. Agglutination buffer: 50 mM Tris-HCl, pH 7.4 and 5 mM MgCl2x6H20 pH 7.4. Washing 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 H3R inverse agonists: twelve increasing concentrations (ranging from 10 μM to 0.3 nM) of the selected compounds were always tested in competition agglutination experiments using a membrane of the human HR3-CH0 cell line . An appropriate amount of the protein, for example approximately an agglutination of 500 cpm from RAMH to Kd, was incubated for 1 hour at room temperature in a final volume of 250 μl in 96-well plates in the presence of 3 H (R) α-methylhistamine (final concentration 1 mM Kd). The non-specific agglutination was determined using a 200-fold excess of cold (R) a-methylhistamine dibromide. All the components were tested at a single concentration in duplicate. Compounds that showed an inhibition of [3 H] -RAMH by more than 50% were tested again for IC 50 in a serial dilution experiment. The Kis were calculated from IC50 based on the Cheng-Prusoff equation (Cheng, Y, Prusoff, WH (1973) Biochem Pharmacol 22, 3099-3108). The compounds of the present invention exhibit Kx values in the range of about 1 nM to about 1000 nM, preferably from about 1 nM to about 100 nM, and more preferably from about 1 nM to about 30 nM. The following tables show the measured values for some selected compounds of the present invention.

The demonstration of the additional biological properties of the compounds of the present invention can be effected by means of in vitro tests, ex vivo, and in vivo that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of obesity-related disorders such as diabetes, syndrome X or atherosclerotic disease and related disorders such as hypertriglyceridemia and hypercholesterolemia, the following assays may be used. Method for measuring blood glucose levels Db / db mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (either by the vein of the eye or the tail) and grouped according to blood glucose levels averages. They are dosed orally (by priming in a pharmaceutically acceptable vehicle) with the test compound once daily for 7 to 14 days. At this point, the animals are bled again by means of the vein of the eye or tail and blood glucose levels were determined. Method for measuring triglyceride levels The hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (either through the vein of the eye or the tail) and grouped together. according to serum triglyceride levels, averages, equivalents. They are dosed orally (by priming in a pharmaceutically acceptable vehicle) with the test compound once daily for 7 to 14 days. The animals are re-bled again by means of the vein of the eye or tail and the triglyceride levels in the serum were determined. Method to measure cholesterol / HDL levels To determine plasma HDL-cholesterol levels, hApoAl mice were devoid of blood and grouped with plasma HDL-cholesterol levels, averages, equivalents, mice are then dosed orally once a day with the vehicle or test compound for 7 to 14 days, and then the blood is drawn the next day. The plasma is analyzed to check HDL-cholesterol levels. The compounds of the formula (I) and their pharmaceutically acceptable salts and ethers 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, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories, parenterally, by example in the form of injection solutions or infusion solutions, or topically, for example in the form of ointments, creams or oils. The production of the pharmaceutical preparations can be effected in a manner that will be familiar to anyone skilled in the art using the compounds of the formula (I) and their pharmaceutically acceptable salts, in a galenic administration form together with liquid carrier materials or suitable solids, non-toxic, inert, therapeutically compatible, and if desired, usual pharmaceutical adjuvants. Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch and derivatives thereof, talc, stearic acid or its salts, can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for hard gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols. (depending on the nature of the active ingredient, no carrier is required, however, in the case of soft gelatin capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, and similar. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hydrogenated oils, waxes, fats and liquid or semi-liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycends, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives. The usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffering substances, solubilizers, dyes and masking agents and antioxidants, arrive to be considered as pharmaceutical adjuvants. The dosage of the compounds of the formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will be adapted, of course, to the patients. individual requirements in each particular case. For adult patients a daily dose from about 1 mg to about 1000 mg, especially from about 1 mg to about 100 mg, come into consideration. Depending on the dosage it is convenient to administer the target dose in several dosage units. The pharmaceutical preparations conveniently contain approximately 0.1-500 mg, preferably 0.5-100 mg of a compound of the formula (I) - The following examples serve to illustrate the present invention in greater detail. However, they are not proposed to limit the scope in any way. Examples Example 1 [5- (4-c? Clopent? Lp? Peraz? Nl-? L) -lH-pyrrolo [2, 3-b] p? Pd? N-2-yl] -p? Rrol? D? n-1? -metanone: a) Stage 1: (Z) -3- (2-chloro-5-n? tro-p? r? d? n-4-? l) -2 ethyl ester -h? drox? -acrylic? A mixture of 1.5 g (8.7 mmol) of 2-chloro-4-met? l-5-n? trop? r? d? na (commercially available) in 5.88 ml (43.5 mmol) of diethyl oxalate is treated with 2.34 ml (15.6 mmol) of 1,8-d? azab? c? clo [5.4.0] undec-7-ene and stirred for 4 h at room temperature. After the evaporation of all volatile substances the residue is acidified with aqueous 1N KHSO4 and extracted with DCM. The combined organic layers were dried with MgSO?. and concentrated under reduced pressure to give 3.16 g of the title compounds that were used without further purification in the next step. MS: (m / e): 273.0 (MH +, 100%). b) Stage 2: (Z) -3- [2- (4-Cyclopentyl-piperazin-1-yl) -5-nitro-pyridin-4-yl] -2-hydroxy-acrylic acid ethyl ester A mixture of 3.16 g of (Z) -3- (2-chloro-5-nitro-pyridin-4-yl) -2-hydroxy-acrylic acid ethyl ester in 40 ml of DMF is treated with 2.96 g (192 mmol) of the 1-cyclopentyl-piperazine and heated at 110 ° C for 1.5 h. The mixture is diluted with 1 N aqueous NaHCO 3 and extracted with DCM. The combined organic extracts are dried with MgSO 4 and evaporated to dryness to give the title compound which was used without further purification. MS: (m / e): 391.1 (MH +, 100%). c) Stage 3: 5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-carboxylic acid ethyl ester The ethyl ester of (Z) -3- [2- (4-cyclopentyl-piperazin-1-yl) -5-nitro-pyridin-4-yl] -2-hydroxy-acrylic is reacted with 0.47 g of iron powder in 40 ml of acetic acid for 6 hours. It has 80 ° C. After evaporation of all volatile substances the residue is taken up in water and extracted with DCM. The combined organic layers are Dry with MgSO4 and evaporate to dryness. Purification on silica eluting with a gradient mixture of n-heptane / ethyl acetate / 0.1% NEt3 produced after evaporation of the product, fractions of 0.65 g (23% of the 2-chloro-4-methyl-5- nitropyridine) of the title compound as a light brown solid. MS: (m / e): 343.1 (MH +, 100%). d) Step 4: 5- (4-Cyclopentyl-piperazin-1-yl) -1H-pyrrolo [2, 3-c] pyridine-2-carboxylic acid (Intermediate Compound 1) A mixture of 0.65 g (1.9 mmol) of the 5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid ethyl ester and LiOH x H20 in THF / methanol / water was stirred at room temperature for 16 h. After evaporation of all volatile substances, the residue was taken up in water and concentrated HCl was added. After evaporation the residue is treated with filtered diethyl ether, washed again with diethyl ether and dried to give 0.46 g (69%) of the title compound as an orange solid. MS: (m / e): 315.4 (MH +, 100%). e) Step 5: [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -pyrrolidin-1-yl-methanone A mixture of 0.46 g ( 1.31 mmol) of 5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo oxychloride [2, 3 c) pyridine-2-carboxylic acid 0.56 ml (6.6 mmol), and 0.03 ml of DMF in 30 ml of DCM is stirred at room temperature for 1 h and evaporated to dryness. An aliquot containing 0.054 mmol of intermediate acid chloride was treated with 27 mg (0.27 mmol) of triethylamine and 11.6 mg (0.16 mmol) of pyrrolidine in 2 ml of DCM for 16 h at room temperature. After the evaporation of all volatile substances, the residue is received in a mixture of DMF / methanol / water / NEt3 and subjected to purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile / water (NEt3 0.05%). After evaporation of the product, product fractions of 4.1 mg (14%) of the title compound were obtained. MS: (m / e): 386.3 (MH +; 100%). Intermediate 2 Acid 5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pi ridin-2 -carboxylic acid a) Stage 1: Ethyl ether of the acid (Z) - 2-Hydroxy-3- [2 - (4-i-sopropyl-piperazin-1-yl) -5-nitro-pyridin-4-yl] -acrylic acid According to the procedure described for the synthesis of Example 1, Step 2 ( (Z) -3- [2- (4-cyclopentyl-piperazin-1-yl) -5-nitro-pyridin-4-yl] -2-hydroxy-acrylic acid ethyl ester) the title compound was synthesized from of 2-chloro-4-methyl-5-nitropyridine and isopropyl-piperazine and was used after isolation without further purification.

MS (m / e): 365.0 (MH +, 100%). b) Step 2: 5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid ethyl ester According to the procedure described for the synthesis of Example 1 , Step 3 (5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid ethyl ester), the title compound was synthesized from the ethyl ester of (Z) -2-hydroxy-3- [2- (4-isopropyl-piperazin-1-yl) -5-nitro-pyridin-4-yl] -acrylic acid and was used after isolation without further purification. MS (m / e): 317.3 (MH +, 100%). c) Step 3: 5- (4-isopropyl-piperazin-1-yl) -1H-pyrrolo [2, 3-c] pyridine-2-carboxylic acid (Intermediate 2) In accordance with the procedure described for the synthesis of Example 1; Step 4 (5- (4-cyclopentyl-piperazin-1-yl) -1H-pyrrolo [2, 3-c] pyridine-2-carboxylic acid (intermediate 1)) was synthesized from the ethyl ester of 5- (-iso? ropil-piperazin-1-yl) -1H-pyrrolo [2, 3-c] pyridine-2-carboxylic acid and was used after isolation without further purification. MS (m / e): 289.0 (MH +, 100%). In accordance with the procedure described for the synthesis of example 1, additional 5- (piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridine derivatives have been synthesized from the respective intermediate mentioned in Table 1 and the respective amine mentioned in Table 1. The examples are grouped in table 1 and comprise from example 2 to example 36. Table 1 Example A The film coated tablets containing the following ingredients can be manufactured in a conventional manner. Ingredients Per tablet Core: Compound of the formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Hydrated lactose 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium and sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Core weight) 120.0 mg 350.0 mg Film coating: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg The active ingredient is sifted 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 to give cores of 120 or 350 mg respectively. The cores are treated with lacquer, with a aqueous solution / suspension of the film coating mentioned above. Example B Capsules containing the following ingredients can be manufactured in the conventional manner: Ingredients Per capsule Compound of the formula (I) 25.0 mg Lactose 150.0 mg Corn starch 20.0 mg Talc 5.0 mg The components are sieved and mixed and filled into capsules of size # 2. Example C The injection solutions can have the following composition: Compound of the formula (I) 3.0 mg Gelatin 150.0 mg Phenol 4.7 mg Sodium carbonate to obtain a final pH of 7 Water for injection solutions add up to 1.0 ml Example D Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner.

Contents of the capsule Compound of the formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated soybean oil 8.0 mg Partially hydrogenated vegetable oils 34.0 mg Soybean oil 110.0 mg Weight of the contents of the capsule 165.0 mg Gelatin capsule Gelatin 75.0 mg 85% glycerol 32.0 mg Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Yellow iron oxide 1.1 mg The active ingredient is dissolved in a hot melt material of the other ingredients and the mixture is filled into soft gelatin capsules of the appropriate size. The filled soft gelatin capsules are treated according to the usual procedures. Example E The sachets containing the following ingredients can be manufactured in a conventional manner: Compound of the formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose 1 .0 mg Polyvinylpyrrolidone K 30 10.0 mg Magnesium stearate 10.0 mg Flavoring additives 1.0 mg The active ingredient is mixed with lactose, crystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into the sachets. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. The compounds of the general formula: characterized in that: R1 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl lower, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring can be replaced or not replaced with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, heteroarylalkyl lower wherein the heteroaryl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl in wherein the heterocyclyl ring may be substituted or unsubstituted with one or two lower alkyl groups, and heterocyclylalkyl lower wherein the heterocyclyl ring may be substituted or unsubstituted with one or two lower alkyl groups; R2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl, substituted or unsubstituted phenyl with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, heteroarylalkyl lower wherein the heteroaryl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring can be substituted or unsubstituted with one or two of the lower alkyl groups, and heterocyclylalkyl wherein the heterocycloalkyl ring may be substituted or unsubstituted with one or two lower alkyl groups; or R1 and R2 together with the nitrogen atom to which they are attached form a saturated or partially saturated heterocyclic ring of 4-, 5-, 6- or 7- elements optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur , a sulfinyl group or a sulfonyl group, the saturated or partially saturated heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from alkyl lower, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is condensed with a phenyl ring, the phenyl annulus is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; R3 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower alkylsulfonyl, phenylsulfonyl wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, lower phenylalkyl, in wherein the phenyl ring may be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower hydroxyalkyl, and heteroaryl substituted or unsubstituted with one or two groups independently selected from lower alkyl or halogen, R 4 is lower alkyl or cycloalkyl; and pharmaceutically acceptable salts thereof.
2. The compounds of formula I according to claim 1, characterized in that R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl; cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, dialkylcarbamoylalkyl lower, phenyl substituted or unsubstituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, phenylalkyl lower wherein the phenyl ring it can be substituted or unsubstituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, heteroarylalkyl lower wherein the heteroaryl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring may be substituted or unsubstituted with one or two lower alkyl groups, and heterocyclylalkyl lower wherein the heterocyclyl ring can be substituted or unsubstituted with one or two lower alkyl groups; and R2 is hydrogen or lower alkyl.
3. The compounds of the formula I according to claim 1 or 2, characterized in that R1 is selected from the group consisting of lower alkyl, cycloalkyl and lower heterocyclyl, wherein the heterocyclyl ring can be substituted or unsubstituted with one or two lower alkyl groups.
4. The compounds of the formula I according to claim 1, characterized in that R1 and R2 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic ring of 4, 5, 6 or 7 elements that optionally contains an additional heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, the saturated or partially unsaturated heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is condensed with a phenyl ring, the phenyl ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.
5. The compounds of the formula I according to claim 1 or 4, characterized in that R1 and R2 together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group consisting of morpholine, piperidine, , 5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, the heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or which is fused with a phenyl ring, the phenyl ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen 6.
The compounds of formula I in accordance with any of claims 1, 4 or 5, characterized in that R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of pyrrolidine, 2,5-dihydropyrrole, morpholine, piperidine, azepam and 1,3-dihydroisoindole, wherein the heterocyclic ring is substituted or unsubstituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl.
The compounds of the formula I according to any of claims 1 or 4 to 6, characterized in that R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of pyrrolidine , 3-hydroxypyrrolidine, 2-isopropyl-pyrrolidine, morpholine, piperidine, 3-methylpiperidine, 2-methylpiperidine, 4-methyl-piperidine, 3,5-dimethylpiperidine, 3, 3-difluoropiperidine, 4, -dif luoropiperidine, 4-methoxy ? eridine, 3-hydroxypiperidine, 4-trifluoromethylpiperidine, azepane and 1,3-dihydroisoindole.
8. The compounds of the formula I according to any of claims 1 to 7, characterized in that R3 is hydrogen.
9. The compounds of the formula I according to any of claims 1 to 8, characterized in that R4 is lower alkyl.
10. The compounds of the formula I according to any of claims 1 to 9, characterized in that R 4 is isopropyl.
11. The compounds of the formula I according to any of claims 1 to 10, characterized in that R4 is cycloalkyl.
12. The compounds of the formula I according to any of claims 1 to 9, characterized in that R4 is cyclopentyl.
13. The compounds of formula I according to claim 1, characterized in that they are selected from the group consisting of: [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] -pyrrolidin-1-yl-methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -morpholin- 1-yl-methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (3-methyl-piperidin-1-yl) - methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] pyridine-2-carboxylic acid [5- (4-cyclopentyl-piperazin-1-yl)] - cyclohexylamide lH-pyrrolo [2,3-c] pyridin-2-yl] - (2-methyl-piperidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-cyclopentylamide] -pyrrolo [2, 3-c] pyridine-2-carboxylic acid, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin- 2-yl] - (4-methyl-piperidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - ( 3, 3-difluoro-piperidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - (4 -methoxy-piperidin-1-yl) -methanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] -pyridin-2-yl] - (3-hydroxy) piperidin-1-yl) -metanone, [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] -pyridin-2-yl] - (4-trifluoro-methyl-piperidin -1-yl) -metanone, [5- (4-cyclopentyl-piperazin-1-yl) -1H-pyrrolo [2, 3-c] pi idin-2-carboxylic acid propylamide, [5- (4-cyclopentyl -piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (2-isopropyl-pyrrolidin-1-yl) -methanone, [5- (4-isopropyl-piperazine-1) -yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -piperidin-1-yl-methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -pi rrolidin-1-yl-methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -morpholin-4-yl-methanone, (1 , 3-dihydro-isoindol-2-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5- ( 4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (3-methyl-piperidin-1-yl) -methanone, [5- (4-isopropyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid cyclohexylamide, azepan-1-yl- [5- (4-isopropyl-piperazine- 1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin -2-yl] - (2-methyl-piperidin-1-yl) -methanone, cyclopentylamide of 5- (4-isopropyl-piperazin-1-yl) -1H-pyrrolo [2, 3-c] pyridin-2 -carboxylic acid, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (2-isopropyl-pyrrolidin-1-yl) -methanone, [ 5- (-isopropy1-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (4-methyl-piperidin-1-yl) -methanone, (3-hydroxy-pyrrolidine) -l-il) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (4,4-difluoro-piperidin-1) -yl) - [5- (-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (3, 3-difluoro-piperidin-1-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5- (4-isopropyl-piperazin-1-yl) - lH-pirrolo [ 2,3-c] pyridin-2-yl] - (4-methoxy-piperidin-1-yl) -methanone, (2,5-dihydro-pyrrol-1-yl) - [5- (4-isopropyl-piperazine -l-il) -1H-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, (3-hydroxy-piperidin-1-yl) - [5- (4-isopropyl-piperazin-1-yl) ) -lH-pyrrolo [2,3-c] pyridin-2-yl] -methanone, (3, 5-dimethyl-piperidin-1-yl) - [5- (4-isopropyl-piperazin-1-yl) - lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] - (4-trifluoro-methyl-piperidin-1-yl) -methanone, 5- (4-isopropyl-piperazin-1-yl) -1H-pyrroloic acid propylamide [2 , 3-c] pyridine-2-carboxylic acid, 5- (4-isopropyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid diethylamide, (tetrahydro-pyran-4) -yl)-5- (-isopropyl-piperazin-1-yl) -lH-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, and pharmaceutically acceptable salts thereof.
14. The compounds of formula I, according to claim 1, characterized in that they are selected from the group consisting of: [5- (4-cyclopentyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] ] pyridin-2-yl] - (3-methyl-piperidin-1-yl) -methanone, [5- (-cyclopenti-1-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2- il] - (4-methyl-piperidin-1-yl) -methanone, 5- (4-cyclopentyl-piperazin-1-yl) -1H-pyrrolo [2,3-c] pyridin-2-i1- carboxylic acid, (3-hydroxy-pyrrolidin-1-yl) - [5- (4-isopropyl-piperazin-1-yl) -lH-pyrrolo [2, 3-c] pyridin-2-yl] -methanone, and salts thereof pharmaceutically acceptable.
15. A process for the manufacture of the compounds according to any of claims 1 to 14, characterized in that it comprises: coupling a compound of formula II wherein R is as defined in claim 1, with an amine of formula III H-NRXR2 III wherein R1 and R2 are as defined in claim 1, under basic conditions to obtain a compound of formula IA wherein R is hydrogen, and optionally the transfer to a compound of the formula IB where R is a group in accordance with the claim 1 different from hydrogen, and if desired, convert the obtained compound to a pharmaceutically acceptable acid addition salt.
16. The compounds according to any of claims 1 to 14, characterized in that they are manufactured by a process according to claim 15.
17. Pharmaceutical compositions, characterized in that they comprise a compound according to any of claims 1 to 14 as well as as a pharmaceutically acceptable carrier and / or adjuvant.
18. The pharmaceutical compositions according to claim 17, characterized in that they are used for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors.
19. The compounds according to any of claims 1 to 14, characterized in that they are used as therapeutically active substances.
The compounds according to any of claims 1 to 14, characterized in that they are used as therapeutically active substances for the treatment and / or prevention of diseases that are associated with the modulation of the H3 receptors.
21. The use of the compounds in accordance with any of claims 1 to 14, for the preparation of the medicaments for the treatment and / or prevention of diseases that are associated with the modulation of the H3 receptors.
22. The use according to claim 21, for the treatment and / or prevention of obesity.
The use of a compound of the formula I according to any of claims 1 to 14, in the manufacture of a medicament for the treatment or prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor .
The use of a compound of the formula I according to any of claims 1 to 14, in the manufacture of a medicament for the treatment or prevention of type II diabetes in a patient who is also receiving treatment with an agent antidiabetic
25. The use of a compound of the formula I according to any of claims 1 to 14, in the manufacture of a medicament for the treatment or prevention of dyslipidemia in a patient, which is also receiving treatment with a reducing agent of the lipids.